Breast cancer, HER2-positive

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	TBA

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: these are regimens tested in biomarker-specific populations, please see the main breast cancer page for other regimens.

• Regimens for ER/HER2 co-expressing ("double positive") breast cancer are here.
• Regimens for CNS metastases are here.

123 regimens on this page 201 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

• 2022: Ramakrishna et al. Management of Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases PubMed
  • 2018: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update PubMed
  • 2014: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline PubMed
• 2022: Giordano et al. Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer PubMed
  • 2018: Giordano et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO Clinical Practice Guideline update PubMed
  • 2014: Giordano et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline PubMed
• 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline PubMed
• 2020: Denduluri et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update PubMed
  • 2018: Denduluri et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update PubMed
  • 2016: Harris et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline PubMed
• 2015: Van Poznak et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline PubMed

ASCO/CAP

• 2023: Wolff et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update PubMed
  • 2014: Wolff et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update PubMed
  • 2013: Wolff et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update PubMed
  • 2007: Wolff et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer PubMed

ESMO

• 2023: Tarantino et al. ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer PubMed
• 2017: Cardoso et al. 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). PubMed
• 2015: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Breast Cancer.

St Gallen Breast Guidelines

• 2019: Burstein et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019 PubMed

• 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017 link to PMC article PubMed
• 2015: Coates et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015 link to PMC article PubMed

Neoadjuvant therapy, sequential regimens

AC-TH (Paclitaxel)

AC-TH: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Phase 3 (C)	1. AC-THL	Might have inferior pCR rate
			2. AC-TL	Did not meet primary endpoint of pCR rate

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion (cycles 5 to 8)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 6 to 8: 2 mg/kg IV once per day on days 1, 8, 15, 22

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (AC x 4; TH x 4)

Subsequent treatment

• Surgery, then adjuvant trastuzumab for a total of 52 weeks of therapy.

References

1. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains dosing details in abstract PubMed NCT00486668

AC-THL (Paclitaxel)

AC-THL: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Lapatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Phase 3 (E-esc)	1. AC-TH	Might have superior pCR rate (primary endpoint)
			2. AC-TL	Might have superior pCR rate (primary endpoint)

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, THL portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THL portion (cycles 5 to 8)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 6 to 8: 2 mg/kg IV once per day on days 1, 8, 15, 22
• Lapatinib (Tykerb) as follows:
  • Cycles 5 to 8: 750 mg PO once per day

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (AC x 4; THL x 4)

Subsequent treatment

• Surgery, then adjuvant trastuzumab for a total of 52 weeks of therapy

References

1. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains dosing details in abstract PubMed NCT00486668

AC-THP (Docetaxel)

AC-THP: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tan et al. 2021 (FeDeriCa)	2018-06-14 to 2018-12-24	Phase 3 (C)	1a. ddAC-THP (Paclitaxel, Phesgo) 1b. AC-THP (Docetaxel, Phesgo)	Non-inferior serum trough

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 8)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 8: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 8: 420 mg IV once on day 1

21-day cycle for 8 cycles (AC x 4; THP x 4)

Subsequent treatment

• Surgery, then adjuvant HP

References

1. FeDeriCa: Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga JY, Jung KH, Schem C, Hogea A, Badovinac Crnjevic T, Heeson S, Shivhare M, Kirschbrown WP, Restuccia E, Jackisch C; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021 Jan;22(1):85-97. Epub 2020 Dec 21. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. link to original article PubMed NCT03493854

AC-THP (Docetaxel, Phesgo)

AC-THP (Phesgo): Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxotere (Docetaxel) and Phesgo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tan et al. 2021 (FeDeriCa)	2018-06-14 to 2018-12-24	Phase 3 (E-RT-switch-ic)	1a. ddAC-THP 1b. AC-THP	Non-inferior serum trough (primary endpoint)

Note: Docetaxel dose was esclated in cycles 6 to 8 if tolerated.

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, THP (Phesgo) portion (cycles 5 to 8)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 to 8: 100 mg/m² IV once on day 1

Targeted therapy, THP (Phesgo) portion (cycles 5 to 8)

• Pertuzumab and Trastuzumab hyaluronidase (Phesgo) as follows:
  • Cycle 5: 1200/600 SC once on day 1
  • Cycles 6 to 8: 600/600 SC once on day 1

21-day cycle for 8 cycles (AC x 4; THP (Phesgo) x 4)

Subsequent treatment

• Surgery, then adjuvant Phesgo

References

1. FeDeriCa: Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga JY, Jung KH, Schem C, Hogea A, Badovinac Crnjevic T, Heeson S, Shivhare M, Kirschbrown WP, Restuccia E, Jackisch C; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021 Jan;22(1):85-97. Epub 2020 Dec 21. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. link to original article PubMed NCT03493854

ddAC-THP (Paclitaxel)

ddAC-THP: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab
ddAC-PacPH: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Paclitaxel, Pertuzumab, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Swain et al. 2018 (BERENICE)	2014-2015	Phase 2 (RT)
Tan et al. 2021 (FeDeriCa)	2018-06-14 to 2018-12-24	Phase 3 (C)	1a. ddAC-THP (Paclitaxel, Phesgo) 1b. AC-THP (Docetaxel, Phesgo)	Non-inferior serum trough
Huober et al. 2022 (IMpassion050)	2019-01 to 2020-08	Phase 3 (C)	ddAC-THP & Atezolizumab	Did not meet primary endpoint of pCR rate

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion (cycles 5 to 8)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 8: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 8: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 4 cycles (ddAC x 4; THP x 4)

Subsequent treatment

• Surgery, then adjuvant HP

References

1. BERENICE: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Kiermaier A, Eng-Wong J, Dang C; BERENICE Study Group. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018 Mar 1;29(3):646-653. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02132949
   1. Update: Dang C, Ewer MS, Delaloge S, Ferrero JM, Colomer R, de la Cruz-Merino L, Werner TL, Dadswell K, Verrill M, Eiger D, Sarkar S, de Haas SL, Restuccia E, Swain SM. BERENICE Final Analysis: Cardiac Safety Study of Neoadjuvant Pertuzumab, Trastuzumab, and Chemotherapy Followed by Adjuvant Pertuzumab and Trastuzumab in HER2-Positive Early Breast Cancer. Cancers (Basel). 2022 May 24;14(11):2596. link to original article link to PMC article PubMed
2. FeDeriCa: Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga JY, Jung KH, Schem C, Hogea A, Badovinac Crnjevic T, Heeson S, Shivhare M, Kirschbrown WP, Restuccia E, Jackisch C; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021 Jan;22(1):85-97. Epub 2020 Dec 21. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. link to original article PubMed NCT03493854
3. IMpassion050: Huober J, Barrios CH, Niikura N, Jarząb M, Chang YC, Huggins-Puhalla SL, Pedrini J, Zhukova L, Graupner V, Eiger D, Henschel V, Gochitashvili N, Lambertini C, Restuccia E, Zhang H; IMpassion050 Trial Investigators. Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. J Clin Oncol. 2022 Sep 1;40(25):2946-2956. Epub 2022 Jun 28. link to original article link to PMC article PubMed NCT03726879

ddAC-THP (Paclitaxel, Phesgo)

ddAC-THP (Phesgo): dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel) and Phesgo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tan et al. 2021 (FeDeriCa)	2018-06-14 to 2018-12-24	Phase 3 (E-RT-switch-ic)	1a. ddAC-THP 1b. AC-THP	Non-inferior serum trough (primary endpoint)

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP (Phesgo) portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP (Phesgo) portion (cycles 5 to 8)

• Pertuzumab and Trastuzumab hyaluronidase (Phesgo) as follows:
  • Cycle 5: 1200/600 SC once on day 1
  • Cycles 6 to 8: 600/600 SC once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 4 cycles (ddAC x 4; THP (Phesgo) x 4)

Subsequent treatment

• Surgery, then adjuvant Phesgo

References

1. FeDeriCa: Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga JY, Jung KH, Schem C, Hogea A, Badovinac Crnjevic T, Heeson S, Shivhare M, Kirschbrown WP, Restuccia E, Jackisch C; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021 Jan;22(1):85-97. Epub 2020 Dec 21. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. link to original article PubMed NCT03493854

AC-TL (Paclitaxel)

AC-TL: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel) & Lapatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Phase 3 (E-switch-ic)	1. AC-TH	Did not meet primary endpoint of pCR rate
			2. AC-THL	Might have inferior pCR rate (primary endpoint)

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, TL portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TL portion (cycles 5 to 8)

• Lapatinib (Tykerb) 1250 mg PO once per day on days 1 to 28

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (AC x 4; TL x 4)

Subsequent treatment

• Surgery, then adjuvant trastuzumab for a total of 52 weeks of therapy

References

1. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains dosing details in abstract PubMed NCT00486668

EC-TH (Docetaxel)

EC-TH: Epirubicin & Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)
EC-DT: Epirubicin & Cyclophosphamide, followed by Docetaxel & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Alba et al. 2014 (GEICAM 2006-14)	2009-02 to 2010-10	Phase 3 (C)	EC-TL	Superior pCR rate (primary endpoint)

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 5 to 8)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 8: 6 mg/kg IV once on day 1

21-day cycle for 8 cycles (EC x 4; TH x 4)

Subsequent treatment

• Surgery

References

1. GEICAM 2006-14: Alba E, Albanell J, de la Haba J, Barnadas A, Calvo L, Sánchez-Rovira P, Ramos M, Rojo F, Burgués O, Carrasco E, Caballero R, Porras I, Tibau A, Cámara MC, Lluch A. Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial. Br J Cancer. 2014 Mar 4;110(5):1139-47. Epub 2014 Jan 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00841828

ECH-TH (Docetaxel)

ECH-TH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab), followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Untch et al. 2012 (GeparQuintoHER2)	2007-2010	Phase 3 (C)	ECL-TL	Seems to have superior pCR rate (primary endpoint)

Chemotherapy, ECH portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Targeted therapy, ECH portion (cycles 1 to 4)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 5 to 8)

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycle for 8 cycles (ECH x 4; TH x 4)

Subsequent treatment

• Surgery, then adjuvant trastuzumab for 1 year total

References

1. GeparQuinto_HER2: Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. link to original article contains dosing details in manuscript PubMed NCT00567554
   1. Update: Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG; AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. link to original article PubMed

FEC-TH (Paclitaxel)

FEC-TH: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2013 (ACOSOG Z1041)	2007-2011	Phase 3 (C)	TH-FEC & H	Did not meet primary endpoint of pCR

Chemotherapy, FEC portion (cycles 1 to 4)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 6 to 8: 2 mg/kg IV once per day on days 1, 8, 15

'21-day cycle for 8 cycles (FEC x 4; TH x 4)

Subsequent treatment

• surgery

References

1. ACOSOG Z1041: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00513292
   1. Update: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. link to original article link to PMC article PubMed

FEC-THP (Docetaxel)

FEC-THP: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1, 3 x 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase 2 (E-RT-switch-ic)	1. FEC & HP-THP 2. TCHP	Not reported	Similar rates of LVSD (co-primary endpoint)

Chemotherapy, FEC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 4 to 6)

• Docetaxel (Taxotere) as follows:
  • Cycle 4: 75 mg/m² IV once on day 1
  • Cycles 5 & 6; if no toxic effects occurred: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 4 to 6)

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 & 6: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 4: 840 mg IV once on day 1
  • Cycles 5 & 6: 420 mg IV once on day 1

21-day cycle for 6 cycles (FEC x 3; THP x 3)

Subsequent treatment

• Surgery, then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)

Regimen variant #2, 4 x 4

Study	Dates of enrollment	Evidence
Swain et al. 2018 (BERENICE)	2014-2015	Phase 2 (RT)

Chemotherapy, FEC portion (cycles 1 to 4)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 8)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 to 8; if no toxic effects occurred: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 8)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 8: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 8: 420 mg IV once on day 1

21-day cycle for 8 cycles (FEC x 4; THP x 4)

Subsequent treatment

• Surgery, then adjuvant HP

References

1. TRYPHAENA: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. link to original article contains dosing details in manuscript PubMed NCT00976989
   1. Update: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J, Kirk S, Cortés J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018 Jan;89:27-35. Epub 2017 Dec 8. link to original article PubMed
2. BERENICE: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Kiermaier A, Eng-Wong J, Dang C; BERENICE Study Group. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018 Mar 1;29(3):646-653. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02132949
   1. Update: Dang C, Ewer MS, Delaloge S, Ferrero JM, Colomer R, de la Cruz-Merino L, Werner TL, Dadswell K, Verrill M, Eiger D, Sarkar S, de Haas SL, Restuccia E, Swain SM. BERENICE Final Analysis: Cardiac Safety Study of Neoadjuvant Pertuzumab, Trastuzumab, and Chemotherapy Followed by Adjuvant Pertuzumab and Trastuzumab in HER2-Positive Early Breast Cancer. Cancers (Basel). 2022 May 24;14(11):2596. link to original article link to PMC article PubMed

Neratinib & Paclitaxel, then AC

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2016 (I-SPY 2 neratinib)	2010-2013	Adaptively Randomized Phase 2 (E-switch-ic)	1a. TH-AC 1b. TH-ddAC	Seems to have superior pCR rate (primary endpoint)

Targeted therapy, neratinib & paclitaxel portion (cycles 1 to 4)

• Neratinib (Nerlynx) 240 mg PO once per day

Chemotherapy, neratinib & paclitaxel portion (cycles 1 to 4)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Supportive therapy, neratinib & paclitaxel portion (cycles 1 to 4)

• Loperamide (Imodium) 4 mg PO once on day 1, then 2 mg PO once 8 hours later, then 2 mg PO twice per day for two weeks, then decreased per patient choice, started on day 1 of neratinib

Chemotherapy, AC portion (cycles 5 to 8)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 8 cycles (neratinib & paclitaxel x 4; AC x 4)

Subsequent treatment

• surgery

References

1. I-SPY 2 neratinib: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01042379

Neratinib & Paclitaxel, then ddAC

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2016 (I-SPY 2 neratinib)	2010-2013	Adaptively Randomized Phase 2 (E-switch-ic)	1a. TH-AC 1b. TH-ddAC	Seems to have superior pCR rate (primary endpoint)

Targeted therapy, neratinib & paclitaxel portion (cycles 1 to 4)

• Neratinib (Nerlynx) 240 mg PO once per day

Chemotherapy, neratinib & paclitaxel portion (cycles 1 to 4)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Supportive therapy, neratinib & paclitaxel portion (cycles 1 to 4)

• Loperamide (Imodium) 4 mg PO once on day 1, then 2 mg PO once 8 hours later, then 2 mg PO twice per day for two weeks, then decreased per patient choice, started on day 1 of neratinib

Chemotherapy, ddAC portion (cycles 5 to 8)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 5 to 8)

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy

21-day cycle for 4 cycles, then 14-day cycle for 4 cycles (neratinib & paclitaxel x 4; ddAC x 4)

Subsequent treatment

• surgery

References

1. I-SPY 2 neratinib: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01042379

TH-AC (Paclitaxel)

TH-AC: Taxol (Paclitaxel) & Herceptin (Trastuzumab), followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2016 (I-SPY 2 neratinib)	2010-2013	Adaptively Randomized Phase 2 (C)	1a. Neratinib & Paclitaxel, then AC 1b. Neratinib & Paclitaxel, then ddAC	Seems to have inferior pCR rate

Chemotherapy, TH portion (cycles 1 to 4)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy, AC portion (cycles 5 to 8)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 8 cycles (TH x 4; AC x 4)

Subsequent treatment

• Surgery

References

1. I-SPY 2 neratinib: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01042379

TH-ddAC (Paclitaxel)

TH-ddAC: Taxol (Paclitaxel) & Herceptin (Trastuzumab), followed by dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2016 (I-SPY 2 neratinib)	2010-2013	Adaptively Randomized Phase 2 (C)	1a. Neratinib & Paclitaxel, then AC 1b. Neratinib & Paclitaxel, then ddAC	Seems to have inferior pCR rate

Chemotherapy, TH portion (cycles 1 to 4)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy, ddAC portion (cycles 5 to 8)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 5 to 8)

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy

21-day cycle for 4 cycles, then 14-day cycle for 4 cycles (TH x 4; ddAC x 4)

Subsequent treatment

• Surgery

References

1. I-SPY 2 neratinib: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01042379

TH-FEC & H (Docetaxel)

TH-FEC & H: Taxotere (Docetaxel) & Herceptin (Trastuzumab), followed by Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ismael et al. 2012 (HannaH)	2009-10-19 to 2010-12-01	Phase 3 (C)	TH-FEC & H (SC)	Non-inferior pCR rate
Pivot et al. 2018 (SB3-G31-BC)	2014-04 to 2015-08	Phase 3 (C)	TH-FEC & H (trastuzumab-dttb)	Equivalent bpCR rate (primary endpoint) bpCR rate: 42% vs 51.7%
Stebbing et al. 2017 (CT-P6 3.2)	2014-08-07 to 2016-05-06	Phase 3 (C)	TH-FEC & H (trastuzumab-pkrb)	Equivalent pCR rate (primary endpoint) pCR rate: 50.4% vs 46.8%

Chemotherapy, T portion (cycles 1 to 4)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Chemotherapy, FEC portion (cycles 5 to 8)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy, both portions

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 8: 6 mg/kg IV once on day 1

21-day cycle for 8 cycles (TH x 4; FEC & H x 4)

Subsequent treatment

• HannaH: Surgery
• SB3-G31-BC: Surgery, then adjuvant trastuzumab x 30 wk

References

1. HannaH: Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains dosing details in manuscript PubMed NCT00950300
   1. Update: Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. link to original article PubMed
   2. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed
2. CT-P6 3.2: Stebbing J, Baranau Y, Baryash V, Manikhas A, Moiseyenko V, Dzagnidze G, Zhavrid E, Boliukh D, Stroyakovskii D, Pikiel J, Eniu A, Komov D, Morar-Bolba G, Li RK, Rusyn A, Lee SJ, Lee SY, Esteva FJ. CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial. Lancet Oncol. 2017 Jul;18(7):917-928. Epub 2017 Jun 4. Erratum in: Lancet Oncol. 2017 Aug;18(8):e433. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. link to original article PubMed NCT02162667
   1. Update: Esteva FJ, Baranau YV, Baryash V, Manikhas A, Moiseyenko V, Dzagnidze G, Zhavrid E, Boliukh D, Stroyakovskiy D, Pikiel J, Eniu AE, Li RK, Rusyn AV, Tiangco B, Lee SJ, Lee SY, Yu SY, Stebbing J. Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial. Cancer Chemother Pharmacol. 2019 Oct;84(4):839-847. Epub 2019 Aug 19. link to original article link to PMC article PubMed
   2. Update: Stebbing J, Baranau YV, Baryash V, Manikhas A, Moiseyenko V, Dzagnidze G, Zhavrid E, Boliukh D, Pikiel J, Eniu AE, Li RK, Tiangco B, Lee SJ, Kim S. Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial. Breast Cancer Res Treat. 2021 Aug;188(3):631-640. Epub 2021 Jun 20. link to original article link to PMC article PubMed
3. SB3-G31-BC: Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. link to original article contains dosing details in manuscript PubMed NCT02149524

TH-FEC & H (Docetaxel, SC Trastuzumab)

TH-FEC & H: Taxotere (Docetaxel) & Herceptin Hylecta (Trastuzumab and hyaluronidase), followed by Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin Hylecta (Trastuzumab and hyaluronidase)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ismael et al. 2012 (HannaH)	2009-10-19 to 2010-12-01	Phase 3 (E-RT-switch-ic)	TH-FEC & H (IV)	Non-inferior pCR rate (co-primary endpoint)

Chemotherapy, T portion (cycles 1 to 4)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Chemotherapy, FEC portion (cycles 5 to 8)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy, both portions (cycles 1 to 8)

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 8 cycles (TH x 4; FEC & H x 4)

Subsequent treatment

• Surgery

References

1. HannaH: Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains dosing details in manuscript PubMed NCT00950300
   1. Update: Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. link to original article PubMed
   2. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed

TH-FEC & H (Paclitaxel)

TH-FEC & H: Taxol (Paclitaxel) & Herceptin (Trastuzumab), followed by Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2005	2001-2003	Phase 3 (E-esc)	T-FEC	Seems to have superior pCR rate (primary endpoint)

Chemotherapy, T portion (cycles 1 to 4)

• Paclitaxel (Taxol) 225 mg/m² IV continuous infusion over 24 hours, started on day 1

Chemotherapy, FEC portion (cycles 5 to 8)

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 4
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy, both portions

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, given prior to first dose of paclitaxel, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 8: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 8 cycles (TH x 4; FEC & H x 4)

Subsequent treatment

• Surgery

References

1. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article contains dosing details in manuscript PubMed
   1. Update: Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. link to original article PubMed

Neoadjuvant therapy

Docetaxel & Trastuzumab (TH)

TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)
DH: Docetaxel & Herceptin (Trastuzumab)

Regimen variant #1, 75->100 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2011 (NeoSphere)	2007-2009	Randomized Phase 2 (C)	1. Docetaxel & Pertuzumab	Not reported
			2. Pertuzumab & Trastuzumab	Not reported
			3. THP	Seems to have inferior pCR rate

Note: Docetaxel dose was only escalated if tolerated.

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycle 1: 75 mg/m² IV once on day 1
  • Cycles 2 to 4: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #2, 100 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2022 (PHEDRA)	2018-2021	Phase 3 (C)	TH & Pyrotinib	Inferior tpCR rate

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #3, 100 mg/m² q3wk docetaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence	Efficacy
Van Pelt et al. 2003	2000-2002	Phase 2	OCR: 77%

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 2 to 5: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 5: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 5 cycles

Subsequent treatment

• Surgery, then adjuvant AC-H

References

1. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. link to original article contains dosing details in abstract PubMed
2. NeoSphere: Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains dosing details in manuscript PubMed NCT00545688
   1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed
3. PEONY: Shao Z, Pang D, Yang H, Li W, Wang S, Cui S, Liao N, Wang Y, Wang C, Chang YC, Wang H, Kang SY, Seo JH, Shen K, Laohawiriyakamol S, Jiang Z, Li J, Zhou J, Althaus B, Mao Y, Eng-Wong J. Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia: The PEONY Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Mar 1;6(3):e193692. Epub 2020 Mar 12. link to original article link to PMC article contains dosing details in abstract PubMed NCT02586025
   1. Update: Huang L, Pang D, Yang H, Li W, Wang S, Cui S, Liao N, Wang Y, Wang C, Chang YC, Wang HC, Kang SY, Seo JH, Shen K, Laohawiriyakamol S, Jiang Z, Wang H, Lamour F, Song G, Curran M, Duan C, Lysbet de Haas S, Restuccia E, Shao Z. Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial. Nat Commun. 2024 Mar 9;15(1):2153. link to original article link to PMC article PubMed
4. PHEDRA: Wu J, Jiang Z, Liu Z, Yang B, Yang H, Tang J, Wang K, Liu Y, Wang H, Fu P, Zhang S, Liu Q, Wang S, Huang J, Wang C, Wang S, Wang Y, Zhen L, Zhu X, Wu F, Lin X, Zou J. Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial. BMC Med. 2022 Dec 27;20(1):498. link to original article contains dosing details in abstract link to PMC article PubMed NCT03588091

Docetaxel & Trastuzumab (TH) & Pyrotinib

TH & Pyrotinib: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pyrotinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2022 (PHEDRA)	2018-2021	Phase 3 (E-esc)	TH	Superior tpCR rate (primary endpoint) tpCR rate: 41% vs 22%

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Pyrotinib (Irene) 400 mg PO once per day
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. PHEDRA: Wu J, Jiang Z, Liu Z, Yang B, Yang H, Tang J, Wang K, Liu Y, Wang H, Fu P, Zhang S, Liu Q, Wang S, Huang J, Wang C, Wang S, Wang Y, Zhen L, Zhu X, Wu F, Lin X, Zou J. Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial. BMC Med. 2022 Dec 27;20(1):498. link to original article contains dosing details in abstract link to PMC article PubMed NCT03588091

Lapatinib & Paclitaxel (TL)

TL: Taxol (Paclitaxel) & Lapatinib

Regimen variant #1, weekly paclitaxel x 12

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (E-switch-ic)	See link	See link

Preceding treatment

• Neoadjuvant Lapatinib x 6 wk

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Lapatinib (Tykerb) 1500 mg PO once per day

28-day cycle for 3 cycles

Subsequent treatment

• Surgery, then adjuvant FEC x 3

Regimen variant #2, weekly paclitaxel x 16

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carey et al. 2015 (CALGB 40601)	2008-2012	Phase 3 (E-switch-ic)	1. TH	Not reported
			2. THL	Not reported

Note: this arm was closed early.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Lapatinib (Tykerb) 1500 mg PO once per day

28-day cycle for 4 cycles

Subsequent treatment

• Surgery; adjuvant AC x 4 or ddAC x 4, then trastuzumab for 36 weeks was recommended but not mandated

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. CALGB 40601: Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00770809
   1. Update: Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. link to original article link to PMC article PubMed

Lapatinib & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (E-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Targeted therapy

• Lapatinib (Tykerb) 1000 mg PO once per day
• Trastuzumab (Herceptin) 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22, 29, 36

6-week course

Subsequent treatment

• Neoadjuvant THL (Taxol) x 12 wk, then surgery

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed

TCH (Docetaxel)

TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lammers et al. 2018 (REFLECTIONS B327-04)	NR	Phase 3 (C)	TCH (trastuzumab-qyyp) x 6	Non-inferior pharmacokinetics (primary endpoint)

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1, given second
• Carboplatin (Paraplatin) AUC 6 IV over at least 15 minutes once on day 1, given third

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1, given first
  • Cycles 2 to 6: 6 mg/kg IV over 30 to 90 minutes once on day 1, given first

21-day cycle for 6 cycles

Subsequent treatment

• Surgery

References

1. REFLECTIONS B327-04: Lammers PE, Dank M, Masetti R, Abbas R, Hilton F, Coppola J, Jacobs I. Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer. Br J Cancer. 2018 Aug;119(3):266-273. Epub 2018 Jul 13. link to original article link to PMC article PubMed NCT02187744

TCHP (Paclitaxel)

TCHP: Taxol (Paclitaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1, standard carboplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van Ramshorst et al. 2018 (TRAIN-2)	2013-2016	Phase 3 (E-switch-ic)	FEC & HP x 3, then TCHP x 6	Did not meet primary endpoint of pCR rate

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 9: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 9: 420 mg IV once on day 1

21-day cycle for 9 cycles

Subsequent treatment

• Surgery

Regimen variant #2, split carboplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van Ramshorst et al. 2018 (TRAIN-2)	2013-2016	Phase 3 (E-switch-ic)	FEC & HP x 3, then TCHP x 6	Did not meet primary endpoint of pCR rate

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8
• Carboplatin (Paraplatin) AUC 3 IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 9: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 9: 420 mg IV once on day 1

21-day cycle for 9 cycles

Subsequent treatment

• Surgery

References

1. TRAIN-2: van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ, Mandigers CM, van Warmerdam LJ, Wesseling J, Vrancken Peeters MT, Linn SC, Sonke GS; Dutch Breast Cancer Research Group. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1630-1640. Epub 2018 Nov 6. link to original article contains dosing details in abstract PubMed NCT01996267
   1. Update: van der Voort A, van Ramshorst MS, van Werkhoven ED, Mandjes IA, Kemper I, Vulink AJ, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ, Mandigers CM, van Warmerdam LJ, Wesseling J, Vrancken Peeters MT, Linn SC, Sonke GS. Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial. JAMA Oncol. 2021 Jul 1;7(7):978-984. link to original article link to PMC article PubMed

TCHP (Docetaxel)

TCHP: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase 2 (E-RT-switch-ic)	1. FEC-THP 2. FEC & HP-THP	Not reported	Similar rates of LVSD (co-primary endpoint)
Hurvitz et al. 2017 (KRISTINE)	2014-06-25 to 2015-06-15	Phase 3 (C)	Pertuzumab & T-DM1	Superior EFS1 (secondary endpoint) (HR 0.38, 95% CI 0.20-0.74) Seems to have superior pCR rate (primary endpoint)

¹Reported efficacy for KRISTINE is based on the 2019 update.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 6: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 6: 420 mg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• TRYPHAENA: Surgery, then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)
• KRISTINE: Surgery

References

1. TRYPHAENA: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. link to original article contains dosing details in manuscript PubMed NCT00976989
   1. Update: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J, Kirk S, Cortés J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018 Jan;89:27-35. Epub 2017 Dec 8. link to original article PubMed
2. KRISTINE: Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Beckmann MW, Afenjar K, Fresco R, Helms HJ, Xu J, Lin YG, Sparano J, Slamon D. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):115-126. Epub 2017 Nov 23. link to original article contains dosing details in abstract PubMed NCT02131064
   1. Update: Hurvitz SA, Martin M, Jung KH, Huang CS, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Fasching PA, Afenjar K, Spera G, Lopez-Valverde V, Song C, Trask P, Boulet T, Sparano JA, Symmans WF, Thompson AM, Slamon D. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE Study. J Clin Oncol. 2019 Sep 1;37(25):2206-2216. Epub 2019 Jun 3. link to original article link to PMC article PubMed

TCHP (Docetaxel, SC Trastuzumab)

TCHP: Taxotere (Docetaxel), Carboplatin, Herceptin Hylecta (SC Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pérez-García et al. 2021 (PHERGain)	2017-06-26 to 2019-04-24	Randomized Phase 2 (C)	HP, then PET-adapted therapy	Non-comparative

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg SC once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 6: 420 mg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Surgery

References

1. PHERGain: Pérez-García JM, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Schmid P, Marmé F, Escrivá-de-Romani S, Calvo L, Ribelles N, Martinez N, Albacar C, Prat A, Dalenc F, Kerrou K, Colleoni M, Afonso N, Di Cosimo S, Sampayo-Cordero M, Malfettone A, Cortés J, Llombart-Cussac A; PHERGain steering committee and trial investigators. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):858-871. Epub 2021 May 18. link to original article PubMed NCT03161353
   1. Update: Pérez-García JM, Cortés J, Ruiz-Borrego M, Colleoni M, Stradella A, Bermejo B, Dalenc F, Escrivá-de-Romaní S, Calvo Martínez L, Ribelles N, Marmé F, Cortés A, Albacar C, Gebhart G, Prat A, Kerrou K, Schmid P, Braga S, Di Cosimo S, Gion M, Antonarelli G, Popa C, Szostak E, Alcalá-López D, Gener P, Rodríguez-Morató J, Mina L, Sampayo-Cordero M, Llombart-Cussac A; PHERGain Trial Investigators. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Lancet. 2024 Apr 27;403(10437):1649-1659. Epub 2024 Apr 3. link to original article contains dosing details in abstract PubMed

Paclitaxel & Trastuzumab (TH)

TH: Taxol (Paclitaxel) & Herceptin (Trastuzumab)
T-T: Taxol (Paclitaxel) & Trastuzumab

Regimen variant #1, weekly paclitaxel x 12, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in NeoALTTO had already undergone trastuzumab loading so would continue at the 2 mg/kg weekly dose.

Preceding treatment

• NeoALTTO: Neoadjvuant Trastuzumab x 6 wk

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• NeoALTTO: Surgery, then adjuvant FEC x 3

Regimen variant #2, weekly paclitaxel x 12, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (LILAC)	2013-2015	Phase 3 (C)	Paclitaxel & Trastuzumab-anns	Inconclusive whether equivalent pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant anthracycline-containing chemotherapy x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #3, weekly paclitaxel x 16

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carey et al. 2015 (CALGB 40601)	2008-2012	Phase 3 (C)	1. THL	Did not meet primary endpoint of pCR rate
			2. TL	Not reported

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant AC x 4 or ddAC x 4, then trastuzumab for 36 weeks was recommended but not mandated

Regimen variant #4, q3wk, paclitaxel 175 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (LILAC)	2013-2015	Phase 3 (C)	Paclitaxel & Trastuzumab-anns	Inconclusive whether equivalent pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant anthracycline-containing chemotherapy x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. CALGB 40601: Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00770809
   1. Update: Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. link to original article link to PMC article PubMed
3. I-SPY 2 neratinib: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01042379
4. LILAC: von Minckwitz G, Colleoni M, Kolberg HC, Morales S, Santi P, Tomasevic Z, Zhang N, Hanes V. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2018 Jul;19(7):987-998. Epub 2018 Jun 4. link to original article contains dosing details in abstract PubMed NCT01901146

THL (Paclitaxel)

THL: Taxol (Paclitaxel), Herceptin (Trastuzumab), Lapatinib

Regimen variant #1, weekly paclitaxel x 12

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (E-esc)	See link	See link

Preceding treatment

• Neoadjuvant Lapatinib & Trastuzumab x 6 wk

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) 2 mg/kg IV once per day on days 1, 8, 15, 22
• Lapatinib (Tykerb) 1000 mg PO once per day

28-day cycle for 3 cycles

Subsequent treatment

• Surgery, then adjuvant FEC x 3

Regimen variant #2, weekly paclitaxel x 16

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carey et al. 2015 (CALGB 40601)	2008-2012	Phase 3 (E-esc)	1. TH	Did not meet primary endpoint of pCR rate
			2. TL	Not reported

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22
• Lapatinib (Tykerb) 750 mg PO once per day

28-day cycle for 4 cycles

Subsequent treatment

• Surgery; adjuvant AC x 4 or ddAC x 4, then trastuzumab for 36 weeks was recommended but not mandated

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. CALGB 40601: Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00770809
   1. Update: Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. link to original article link to PMC article PubMed

THP (Docetaxel)

THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2011 (NeoSphere)	2007-2009	Randomized Phase 2 (E-RT-esc)	1. Docetaxel & Pertuzumab	Did not meet primary endpoint of pCR rate
			2. Pertuzumab & Trastuzumab	Did not meet primary endpoint of pCR rate
			3. TH	Seems to have superior pCR rate (primary endpoint)
Shao et al. 2020 (PEONY)	2016-03-14 to 2017-03-13	Phase 3 (E-esc)	TH	Superior pCR rate (primary endpoint) Superior DFS601 (secondary endpoint) DFS60: 86% vs 75% (HR 0.52, 95% CI 0.30-0.88)

¹Reported efficacy for PEONY is based on the 2024 update.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 4: 420 mg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• NeoSphere: Surgery
• PEONY: Surgery, then adjuvant FEC & H

Dose and schedule modifications

• Based on tolerability, investigators could increase docetaxel dose to 100 mg/m² IV once on day 1 in cycles 2 to 4

References

1. NeoSphere: Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains dosing details in manuscript PubMed NCT00545688
   1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed
2. PEONY: Shao Z, Pang D, Yang H, Li W, Wang S, Cui S, Liao N, Wang Y, Wang C, Chang YC, Wang H, Kang SY, Seo JH, Shen K, Laohawiriyakamol S, Jiang Z, Li J, Zhou J, Althaus B, Mao Y, Eng-Wong J. Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia: The PEONY Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Mar 1;6(3):e193692. Epub 2020 Mar 12. link to original article link to PMC article contains dosing details in abstract PubMed NCT02586025
   1. Update: Huang L, Pang D, Yang H, Li W, Wang S, Cui S, Liao N, Wang Y, Wang C, Chang YC, Wang HC, Kang SY, Seo JH, Shen K, Laohawiriyakamol S, Jiang Z, Wang H, Lamour F, Song G, Curran M, Duan C, Lysbet de Haas S, Restuccia E, Shao Z. Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial. Nat Commun. 2024 Mar 9;15(1):2153. link to original article link to PMC article PubMed

Trastuzumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Targeted therapy

• Trastuzumab (Herceptin) 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22, 29, 36

6-week course

Subsequent treatment

• Neoadjuvant TH (Paclitaxel) x 12 wk, then surgery

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed

Neoadjuvant response criteria

Clinical response rate (cRR)

Although fairly dated, some trials such as ACOSOG Z1031 make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.

References

1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. link to original article PubMed

Miller-Payne scoring system

• Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity
• Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high
• Grade 3: An estimated 30 to 90% reduction in the number of tumor cells
• Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells)
• Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma in situ may be present)

References

1. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. link to original article PubMed

Residual cancer burden (RCB)

• The RCB is calculated as follows: RCB = 1.4 (f_inv*d_prim)^0.17 + [4(1 - 0.75^LN)d_met]^0.17
  • where d_prim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, f_inv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and d_met is the diameter of the largest metastasis in an axillary lymph node.
  • The cut-off points are 1.36 and 3.28.

References

1. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. link to original article PubMed

Residual disease in breast and nodes (RDBN)

• Level 1: pCR in breast and nodes with or without in situ carcinoma
• Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.

References

1. Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. link to original article PubMed

Sataloff's classification

• Breast:
  • T-A: Total or nearly total therapeutic effect
  • T-B: Greater than 50% therapeutic effect
  • T-C: Less than 50% therapeutic effect
  • T-D: No therapeutic effect
• Lymph node:
  • N-A: Therapeutic effect but no metastasis
  • N-B: No metastasis, no therapeutic effect
  • N-C: Therapeutic effect but metastasis
  • N-D: Metastasis, no therapeutic effect

References

1. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. PubMed

Tumor response ratio

Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.

• TRR = 0: pathologic complete response (pCR)
• TRR greater than 0 up to 0.4: strong partial response
• TRR greater than 0.4 up to 1.0: weak partial response (WPR)
• TRR greater than 1.0: tumor growth

References

1. Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. link to original article PubMed

ypTNM staging

This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.

Adjuvant therapy, sequential regimens

AC-H

AC-H: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (AC x 4; H x 18)

Regimen variant #2, weekly trastuzumab

Study	Dates of enrollment	Evidence
Van Pelt et al. 2003	2000-2002	Phase 2

Preceding treatment

• Neoadjuvant TH, then surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 5 to 56)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1
  • Cycles 6 to 56: 2 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 7-day cycle for 52 cycles (AC x 4; H x 52)

References

1. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. link to original article contains dosing details in abstract PubMed
2. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

AC-TH (Paclitaxel)

AC-TH: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen variant #1, weekly paclitaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (AC x 4; TH x 4)

Regimen variant #2, weekly paclitaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Romond et al. 2005 (NCCTG N9831)	2000-2005	Phase 3 (E-RT-esc)	1. AC-T; weekly paclitaxel	Superior OS1 (secondary endpoint) OS120: 84% vs 75.2% (HR 0.63, 95% CI 0.5-0.73)
			2. AC-T-H	Might have superior DFS2 (primary endpoint)

¹Reported efficacy is based on the 2014 pooled update.
²Reported efficacy is based on the 2011 update.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 6 to 22: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 22 cycles (AC x 4; TH x 4)

Regimen variant #3, q3wk paclitaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Romond et al. 2005 (NSABP B-31)	2000-2005	Phase 3 (E-RT-esc)	1a. AC-T; weekly paclitaxel 1b. AC-T; q3wk paclitaxel	Superior OS1 (secondary endpoint) OS120: 84% vs 75.2% (HR 0.63, 95% CI 0.5-0.73) Superior DFS (primary endpoint)	Might have superior DASI score

¹Reported efficacy is based on the 2014 pooled update.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 6 to 22: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 22 cycles (AC x 4; TH x 4)

References

1. NSABP B-31: Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed NCT00004067
   1. Pooled update: Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. link to original article link to PMC article PubMed
   2. Pooled update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. Epub 2014 Oct 20. link to original article link to PMC article PubMed
   3. HRQoL analysis: Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. link to original article link to PMC article PubMed
2. NCCTG N9831: Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed NCT00005970
   1. Pooled update: Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. link to original article link to PMC article PubMed
   2. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
   3. Pooled update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. Epub 2014 Oct 20. link to original article link to PMC article PubMed
3. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddAC-ddTH (Paclitaxel)

ddAC-ddTH: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by dose-dense Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence
Dang et al. 2008	2005	Phase 2

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, ddTH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Targeted therapy, ddTH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once on day 8
  • Cycles 6 to 8: 2 mg/kg IV once per day on days 1 & 8
  • Cycles 9 to 53: 2 mg/kg IV once on day 1

Supportive therapy, both portions (cycles 1 to 8)

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy

14-day cycle for 8 cycles (ddAC x 4; ddTH x 4)

Subsequent treatment

• Trastuzumab maintenance x 44 weeks (1 year total)

References

1. Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. link to original article contains dosing details in manuscript PubMed

AC-TH (Docetaxel)

AC-TH: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (AC x 4; TH x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 7)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (AC x 4; TH x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (AC x 4; TH x 3)

Regimen variant #4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2011 (BCIRG 006)	2001-2004	Phase 3 (E-RT-esc)	1. AC-D	Superior OS (secondary endpoint)
			2. TCH	Did not meet primary endpoint of DFS

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 6 to 8: 2 mg/kg IV once per day on days 1, 8, 15
  • Cycles 9 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (AC x 4; TH x 4)

References

1. BCIRG 006: Slamon D, Eiermann W, Robert N, Pienkowski T, Martín M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00021255
2. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

AC-THP (Paclitaxel)

AC-THP: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (AC x 4; THP x 4)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

AC-THP (Docetaxel)

AC-THP: Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (AC x 4; THP x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (AC x 4; THP x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for AC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, AC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (AC x 4; THP x 3)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

ddAC-TH (Paclitaxel)

ddAC-TH: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddAC-TH (Docetaxel)

ddAC-TH: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddAC-THP (Paclitaxel)

ddAC-THP: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

ddAC-THP (Docetaxel)

ddAC-THP: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddAC portion (cycles 1 to 4)

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddAC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

CMF-H

CMF-H: Cyclophosphamide, Methotrexate, Fluorouracil, followed by Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. The protocol document reported a flat dose of oral cyclophosphamide, but this would not be consistent with any other known CMF variants; dosing below is provided as BSA-based.

Preceding treatment

• Surgery

Chemotherapy, CMF portion (cycles 1 to 6)

• Cyclophosphamide (Cytoxan) 75 to 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 500 to 600 mg/m² IV once per day on days 1 & 8

Targeted therapy, H portion (cycles 7 to 24)

• Trastuzumab (Herceptin) as follows:
  • Cycle 7: 8 mg/kg IV once on day 1
  • Cycles 8 to 24: 6 mg/kg IV once on day 1

21-day cycle for 24 cycles (CMF x 6; H x 18)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

EC-H

EC-H: Epirubicin and Cyclophosphamide, followed by Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (EC x 4; H x 18)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

EC-TH (Paclitaxel)

EC-TH: Epirubicin and Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (EC x 4; TH x 4)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

EC-TH (Docetaxel)

EC-TH: Epirubicin and Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (EC x 4; TH x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 7)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (EC x 4; TH x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (EC x 4; TH x 3)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

EC-THP (Paclitaxel)

EC-THP: Epirubicin and Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (EC x 4; THP x 4)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

EC-THP (Docetaxel)

EC-THP: Epirubicin and Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (EC x 4; THP x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (EC x 4; THP x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for EC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, EC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

21-day cycle for 22 cycles (EC x 4; THP x 3)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

ddEC-TH (Paclitaxel)

ddEC-TH: dose-dense Epirubicin and Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddEC-TH (Docetaxel)

ddEC-TH: dose-dense Epirubicin and Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, TH portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddEC-THP (Paclitaxel)

ddEC-THP: dose-dense Epirubicin and Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 8)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

ddEC-THP (Docetaxel)

ddEC-THP: dose-dense Epirubicin and Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 8)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) as follows:
  • Cycle 5: 75 mg/m² IV once on day 1
  • Cycles 6 & 7: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for ddEC are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, ddEC portion (cycles 1 to 4)

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive therapy, ddEC portion (cycles 1 to 4)

• G-CSF support (drug/dose/schedule not specified)

Chemotherapy, THP portion (cycles 5 to 7)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 5: 840 mg IV once on day 1
  • Cycles 6 to 22: 420 mg IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

FAC-TH (Paclitaxel)

FAC-TH: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 7)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; TH x 4)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FAC-TH (Docetaxel)

FAC-TH: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 7)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; TH x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 6)

• Docetaxel (Taxotere) as follows:
  • Cycle 4: 75 mg/m² IV once on day 1
  • Cycles 5 & 6: 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; TH x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 6)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; TH x 3)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FAC-THP (Paclitaxel)

FAC-THP: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 4 to 7)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion (cycles 4 to 21)

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 4: 840 mg IV once on day 1
  • Cycles 5 to 21: 420 mg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; THP x 4)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FAC-THP (Docetaxel)

FAC-THP: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 4 to 7)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 4 to 21)

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 4: 840 mg IV once on day 1
  • Cycles 5 to 21: 420 mg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; THP x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 4 to 6)

• Docetaxel (Taxotere) as follows:
  • Cycle 4: 75 mg/m² IV once on day 1
  • Cycles 5 & 6: 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 4 to 21)

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 4: 840 mg IV once on day 1
  • Cycles 5 to 21: 420 mg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; THP x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, THP portion (cycles 4 to 6)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, THP portion (cycles 4 to 21)

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 4: 840 mg IV once on day 1
  • Cycles 5 to 21: 420 mg IV once on day 1

21-day cycle for 21 cycles (FAC x 3; THP x 3)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FEC-H

FEC-H: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Herceptin (Trastuzumab)

Regimen variant #1, FEC 75

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 6)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 7 to 24)

• Trastuzumab (Herceptin) as follows:
  • Cycle 7: 8 mg/kg IV once on day 1
  • Cycles 8 to 24: 6 mg/kg IV once on day 1

21-day cycle for 24 cycles (FEC x 6; H x 18)

Regimen variant #2, FEC 100 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 4)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (FEC x 4; H x 18)

Regimen variant #3, FEC 100 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 6)

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 7 to 24)

• Trastuzumab (Herceptin) as follows:
  • Cycle 7: 8 mg/kg IV once on day 1
  • Cycles 8 to 24: 6 mg/kg IV once on day 1

21-day cycle for 24 cycles (FEC x 6; H x 18)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

FEC-TH (Paclitaxel)

FEC-TH: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 7)

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FEC x 3; TH x 4)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FEC-TH (Docetaxel)

FEC-TH: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 7)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FEC x 3; TH x 4)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 6)

• Docetaxel (Taxotere) as follows:
  • Cycle 4: 75 mg/m² IV once on day 1
  • Cycles 5 & 6: 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FEC x 3; TH x 3)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy, FEC portion (cycles 1 to 3)

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Chemotherapy, TH portion (cycles 4 to 6)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 4: 8 mg/kg IV once on day 1
  • Cycles 5 to 21: 6 mg/kg IV once on day 1

21-day cycle for 21 cycles (FEC x 3; TH x 3)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddFEC-ddTH (Docetaxel)

ddFEC-ddTH (Docetaxel): dose-dense Fluorouracil, Epirubicin, Cyclophosphamide, followed by ddTH: dose-dense Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mavroudis et al. 2015 (HORG CT/04.23)	2004-2012	Phase 3 (C)	ddFEC-ddTH; 6-months total of trastuzumab	Inconclusive whether non-inferior DFS36

Preceding treatment

• Surgery

Chemotherapy, ddFEC portion (cycles 1 to 4)

• Fluorouracil (5-FU) 700 mg/m² IV over 5 to 15 minutes once on day 1
• Epirubicin (Ellence) 75 mg/m² IV over 5 to 15 minutes once on day 1
• Cyclophosphamide (Cytoxan) 700 mg/m² IV over 30 to 60 minutes once on day 1

Supportive therapy, ddFEC portion (cycles 1 to 4)

• Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 or 480 mcg) SC once per day on days 3 to 10

Chemotherapy, ddTH portion (cycles 5 to 20)

• Docetaxel (Taxotere) as follows:
  • Cycles 5 to 8: 75 mg/m² IV over 60 minutes once on day 1

Targeted therapy, ddTH portion (cycles 5 to 20)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 6 mg/kg IV once on day 1
  • Cycles 6 to 8: 4 mg/kg IV once on day 1
  • Cycles 9 to 20: 6 mg/kg IV once on day 1

Supportive therapy, ddTH portion (cycles 5 to 20)

• Filgrastim (Neupogen) as follows:
  • Cycles 5 to 8: 5 mcg/kg (rounded to 300 or 480 mcg) SC once per day on days 3 to 10

14-day cycle for 8 cycles, then 21-day cycle for 12 cycles (1 year total)

References

1. HORG CT/04.23: Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. link to original article contains dosing details in manuscript PubMed NCT00615602

FEC-THP (Paclitaxel)

FEC-THP: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Protocol

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC dosing and number of cycles are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, FEC portion

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 to 4 cycles

Chemotherapy, THP portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy, THP portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 18: 420 mg IV once on day 1

21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

FEC-THP (Docetaxel)

FEC-THP: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Protocol variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC dosing and number of cycles are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, FEC portion

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 to 4 cycles

Chemotherapy, THP portion

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1

Targeted therapy, THP portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 18: 420 mg IV once on day 1

21-day cycle for 18 cycles (1 year)

Protocol variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC dosing and number of cycles are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, FEC portion

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 to 4 cycles

Chemotherapy, THP portion

• Docetaxel (Taxotere) as follows:
  • Cycle 1: 75 mg/m² IV once on day 1
  • Cycles 2 & 3: 100 mg/m² IV once on day 1

Targeted therapy, THP portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 18: 420 mg IV once on day 1

21-day cycle for 18 cycles (1 year)

Protocol variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)
Krop et al. 2021 (KAITLIN)	2014-01 to 2015-06	Phase 3 (C)	1a. AC-KP 1b. ddAC-KP 1c. EC-KP 1d. ddEC-KP 1e. FEC-KP	Did not meet primary endpoint of IDFS

¹Reported efficacy for APHINITY is based on the 2021 update.
Note that ranges for FEC dosing and number of cycles are given in the protocol, replicated here; KAITLIN only allowed up to 100 mg/m² of epirubicin per cycle.

Preceding treatment

• Surgery

Chemotherapy, FEC portion

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 to 4 cycles

Chemotherapy, THP portion

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 3: 100 mg/m² IV once on day 1

Targeted therapy, THP portion

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 18: 420 mg IV once on day 1

21-day cycle for 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022 Feb 10;40(5):438-448. Epub 2021 Dec 10. link to original article contains dosing details in supplement link to PMC article PubMed NCT01966471

T-H (Docetaxel)

T-H: Taxotere (Docetaxel) followed by Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, T portion (cycles 1 to 4)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (T x 4; H x 18)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

T-H (Paclitaxel)

T-H: Taxol (Paclitaxel) followed by Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, T portion (cycles 1 to 12)

• Paclitaxel (Taxol) 80 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 13 to 30)

• Trastuzumab (Herceptin) as follows:
  • Cycle 13: 8 mg/kg IV once on day 1
  • Cycles 14 to 30: 6 mg/kg IV once on day 1

7-day cycle for 12 cycles, then 21-day cycle for 18 cycles (T x 12; H x 18)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

TC-H (Docetaxel)

TC-H: Taxotere (Docetaxel) & Cyclophosphamide, followed by Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

• Surgery

Chemotherapy, TC portion (cycles 1 to 4)

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Targeted therapy, H portion (cycles 5 to 22)

• Trastuzumab (Herceptin) as follows:
  • Cycle 5: 8 mg/kg IV once on day 1
  • Cycles 6 to 22: 6 mg/kg IV once on day 1

21-day cycle for 22 cycles (TC x 4; H x 18)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

TH-FEC (Docetaxel)

TH-FEC: Taxotere (Docetaxel) & Herceptin (Trastuzumab), followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2006 (FinHer)	2000-2003	Phase 3 (E-esc)	1. D-FEC 2. V-FEC	Superior RFS (primary endpoint) Median RFS: NYR vs NYR (HR 0.42, 95% CI 0.21-0.83)
			3. VH-FEC	Not reported

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Regimen variant #2, 600/75/600 x 3

Study	Dates of enrollment	Evidence
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized part of phase 3 RCT

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 80 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 & 3: 6 mg/kg IV once on day 1

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Subsequent treatment

• Trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #3

Study	Dates of enrollment	Evidence
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized part of phase 3 RCT

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 80 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Subsequent treatment

• Trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #4

Study	Dates of enrollment	Evidence
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized part of phase 3 RCT

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 & 3: 6 mg/kg IV once on day 1

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Subsequent treatment

• Trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #5

Study	Dates of enrollment	Evidence
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized part of phase 3 RCT

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Subsequent treatment

• Trastuzumab maintenance for a total of 1 year versus no further treatment

References

1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains dosing details in manuscript PubMed ISRCTN76560285
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. link to original article PubMed
2. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00593697

TH-FEC (Docetaxel, SC Trastuzumab)

TH-FEC: Taxotere (Docetaxel) & Herceptin Hylecta (Trastuzumab and hyaluronidase), followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen variant #1, 80 x 3, q3wk trastuzumab

Study	Dates of enrollment	Evidence
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized part of phase 3 RCT

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 80 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Subsequent treatment

• trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #2, 100 x 3, q3wk trastuzumab

Study	Dates of enrollment	Evidence
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized part of phase 3 RCT

Preceding treatment

• Surgery

Chemotherapy, TH portion (cycles 1 to 3)

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy, TH portion (cycles 1 to 3)

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (TH x 3; FEC x 3)

Subsequent treatment

• trastuzumab maintenance for a total of 1 year versus no further treatment

References

1. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00593697

VH-FEC

VH-FEC: Vinorelbine & Herceptin (Trastuzumab), followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2006 (FinHer)	2000-2003	Phase 3 (E-esc)	1. D-FEC 2. V-FEC	Superior RFS (primary endpoint) Median RFS: NYR vs NYR (HR 0.42, 95% CI 0.21-0.83)
			3. TH-FEC	Not reported

Preceding treatment

• Surgery

Chemotherapy, VH portion (cycles 1 to 3)

• Vinorelbine (Navelbine) as follows:
  • Cycles 1 & 2: 25 mg/m² IV over 5 to 10 minutes once per day on days 1, 8, 15
  • Cycle 3: 25 mg/m² IV over 5 to 10 minutes once per day on days 1 & 8

Targeted therapy, VH portion (cycles 1 to 3)

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy, FEC portion (cycles 4 to 6)

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles (VH x 3; FEC x 3)

References

1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains dosing details in manuscript PubMed ISRCTN76560285
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. link to original article PubMed

Adjuvant therapy

Docetaxel & Trastuzumab (TH)

TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1, 75 x 4, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 12 mo	Inconclusive whether non-inferior DFS

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk) for a total of 1 year

Regimen variant #2, 75 x 4, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase 3 (C)	1. TH-L 2. THL (Taxotere) 3. TL (Docetaxel)	Did not meet primary endpoint of DFS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then adjuvant anthracycline-based chemotherapy

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk) for a total of 1 year

References

1. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00490139
   1. Update: Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. Epub 2021 Mar 23. link to original article link to PMC article PubMed
2. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in manuscript PubMed NCT01104935

CMF & H

CMF & H: Cyclophosphamide, Methotrexate, Fluorouracil, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. The protocol document reported a flat dose of oral cyclophosphamide, but this would not be consistent with any other known CMF variants; dosing below is provided as BSA-based.

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 75 to 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) as follows:
  • Cycles 1 to 6: 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) as follows:
  • Cycles 1 to 6: 500 to 600 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1

21-day cycle for 18 cycles (1 year)

References

1. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

FEC

FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil

Regimen variant #1, 500/100/500 x 3 ("FEC 100")

Study	Dates of enrollment	Evidence
Baselga et al. 2012 (NeoALTTO)	2008-2010	Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Lapatinib or Lapatinib & Trastuzumab or Trastuzumab maintenance, according to initial randomization

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in manuscript PubMed NCT01104935

FEC & H

Regimen

Study	Dates of enrollment	Evidence
Gianni et al. 2011 (NeoSphere)	2007-2009	Non-randomized part of phase 2 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant Docetaxel & Pertuzumab versus THP (Docetaxel) versus pertuzumab & trastuzumab versus TH (Docetaxel), then surgery

Chemotherapy

• Fluorouracil (5-FU) as follows:
  • Cycles 1 to 3: 600 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 1 to 3: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 3: 600 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycle for 18 cycles

Subsequent treatment

• NeoSphere, ER-positive patients: Radiotherapy and/or hormone therapy "per local guidelines"

References

1. NeoSphere: Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains dosing details in manuscript PubMed NCT00545688
   1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed

Lapatinib & Trastuzumab

L+T: Lapatinib & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase 3 (E-esc)	1. Lapatinib	Did not meet primary endpoint of DFS
			2. Trastuzumab	Might have superior DFS1 (HR 0.86, 95% CI 0.74-1.00)
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (E-esc)	See link	See link

¹Reported efficacy is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• NeoALTTO: Surgery, then adjuvant FEC x 3

Targeted therapy

• Lapatinib (Tykerb) 1000 mg PO once per day
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 to 12: 6 mg/kg IV over 30 minutes once on day 1

21-day cycle for 12 cycles (34-week course)

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00490139
   1. Update: Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. Epub 2021 Mar 23. link to original article link to PMC article PubMed

Neratinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chan et al. 2016 (ExteNET)	2009-07-09 to 2011-10-24	Phase 3 (E-RT-esc)	Placebo	Superior iDFS1 (primary endpoint) iDFS60: 90% vs 88% (HR 0.73, 95% CI 0.57-0.92) Did not meet secondary endpoint of OS2 OS84: 90.1% vs 90.2% (HR 0.95, 95% CI 0.75-1.21)

¹Reported efficacy is based on the 2017 update.
²Reported efficacy is based on the 2023 update.

Preceding treatment

• Surgery, then trastuzumab-containing chemotherapy or trastuzumab-containing chemotherapy, then surgery (neoadjuvant or adjuvant)

Targeted therapy

• Neratinib (Nerlynx) 240 mg PO once per day, taken with food

Supportive therapy

• (per FDA package insert)
• Loperamide (Imodium) as follows:
  • Weeks 1 & 2: 4 mg PO three times per day
  • Weeks 3 to 8: 4 mg PO twice per day
  • Weeks 9 to 52: 4 mg PO as needed for diarrhea, not to exceed 16 mg/d

12-month course

References

1. ExteNET: Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-77. Epub 2016 Feb 10. link to original article contains dosing details in manuscript PubMed NCT00878709
   1. Update: Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1688-1700. Epub 2017 Nov 13. link to original article PubMed
   2. HRQoL analysis: Delaloge S, Cella D, Ye Y, Buyse M, Chan A, Barrios CH, Holmes FA, Mansi J, Iwata H, Ejlertsen B, Moy B, Chia SKL, Gnant M, Smichkoska S, Ciceniene A, Martinez N, Filipović S, Ben-Baruch NE, Joy AA, Langkjer ST, Senecal F, de Boer RH, Moran S, Yao B, Bryce R, Auerbach A, Fallowfield L, Martin M. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 Apr 1;30(4):567-574. link to original article PubMed
   3. Subgroup analysis: Iwata H, Masuda N, Kim SB, Inoue K, Rai Y, Fujita T, Chiu J, Ohtani S, Takahashi M, Miyaki T, Lu YS, Xu B, Yap YS, Bustam A, Yao B, Zhang B, Bryce R, Chan A. Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer. Future Oncol. 2019 Jul;15(21):2489-2501. Epub 2019 May 29. link to original article PubMed
   4. Subgroup analysis: Chan A, Moy B, Mansi J, Ejlertsen B, Holmes FA, Chia S, Iwata H, Gnant M, Loibl S, Barrios CH, Somali I, Smichkoska S, Martinez N, Alonso MG, Link JS, Mayer IA, Cold S, Murillo SM, Senecal F, Inoue K, Ruiz-Borrego M, Hui R, Denduluri N, Patt D, Rugo HS, Johnston SRD, Bryce R, Zhang B, Xu F, Wong A, Martin M; ExteNET Study Group. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clin Breast Cancer. 2021 Feb;21(1):80-91.e7. Epub 2020 Oct 6. link to original article PubMed
   5. Update: Holmes FA, Moy B, Delaloge S, Chia SKL, Ejlertsen B, Mansi J, Iwata H, Gnant M, Buyse M, Barrios CH, Silovski T, Šeparović R, Bashford A, Zotano AG, Denduluri N, Patt D, Gokmen E, Gore I, Smith JW 2nd, Loibl S, Masuda N, Tomašević Z, Petráková K, DiPrimeo D, Wong A, Martin M, Chan A; ExteNET Study Group. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur J Cancer. 2023 May;184:48-59. Epub 2023 Feb 10. link to original article PubMed

Paclitaxel & Trastuzumab (TH)

TH: Taxol (Paclitaxel) & Herceptin (Trastuzumab)
PH: Paclitaxel & Herceptin (Trastuzumab)

Regimen variant #1, weekly paclitaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence
Tolaney et al. 2015 (APT)	2007-10-29 to 2010-09-03	Phase 2

Preceding treatment

• Surgery

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 18: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 18 cycles (1 year)

Regimen variant #2, weekly paclitaxel, weekly then q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tolaney et al. 2015 (APT)	2007-10-29 to 2010-09-03	Phase 2
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase 3 (C)	1. TH-L (Paclitaxel) 2. THL (Paclitaxel) 3. TL (Paclitaxel)	Did not meet primary endpoint of DFS

Preceding treatment

• APT: Surgery
• ALTTO: Surgery, then adjuvant anthracycline-based chemotherapy

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15
  • Cycles 5 to 18: 6 mg/kg IV once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #3, weekly paclitaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 12 mo	Inconclusive whether non-inferior DFS

Preceding treatment

• Surgery

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1

21-day cycle for 18 cycles (1 year)

References

1. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article does not contain dosing details link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article PubMed
2. APT: Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan 8;372(2):134-41. Erratum in: N Engl J Med. 2015 Nov 12;373(20):1989. link to original article link to PMC article PubMed NCT00542451
   1. Update: Tolaney SM, Guo H, Pernas S, Barry WT, Dillon DA, Ritterhouse L, Schneider BP, Shen F, Fuhrman K, Baltay M, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis MJ, Shapira I, Wolff AC, Carey LA, Overmoyer B, Partridge AH, Hudis CA, Krop IE, Burstein HJ, Winer EP. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol. 2019 Aug 1;37(22):1868-1875. Epub 2019 Apr 2. link to original article link to PMC article PubMed NCT00542451
   2. Update: Tolaney SM, Tarantino P, Graham N, Tayob N, Parè L, Villacampa G, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis MJ, Shapira I, Wolff AC, Carey LA, Barroso-Sousa R, Villagrasa P, DeMeo M, DiLullo M, Zanudo JGT, Weiss J, Wagle N, Partridge AH, Waks AG, Hudis CA, Krop IE, Burstein HJ, Prat A, Winer EP. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023 Mar;24(3):273-285. link to original article PubMed
3. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00490139
   1. Update: Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. Epub 2021 Mar 23. link to original article link to PMC article PubMed
4. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in supplement PubMed NCT01104935

Pertuzumab and Trastuzumab hyaluronidase monotherapy

Regimen

Study	Dates of enrollment	Evidence
Tan et al. 2021 (FeDeriCa)	2018-06-14 to 2018-12-24	Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant AC-THP (Phesgo) or ddAC-THP (Phesgo), then surgery

Targeted therapy

• Pertuzumab and Trastuzumab hyaluronidase (Phesgo) 600/600 SC once on day 1

21-day cycle for 14 cycles (42 weeks)

References

1. FeDeriCa: Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga JY, Jung KH, Schem C, Hogea A, Badovinac Crnjevic T, Heeson S, Shivhare M, Kirschbrown WP, Restuccia E, Jackisch C; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021 Jan;22(1):85-97. Epub 2020 Dec 21. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. link to original article PubMed NCT03493854

TCH (Docetaxel)

TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)
TCbH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen variant #1, 60/5

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Note: This was suggested as an "acceptable" dose for elderly patients, given immature safety results of BCIRG 006.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 60 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 5 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15
  • Cycles 7 to 18: 6 mg/kg IV once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #2, 75/6, capped carboplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (C)	1a. AC-THP (Paclitaxel) 1b. AC-THP (Docetaxel) 1c. ddAC-THP (Paclitaxel) 1c. ddAC-THP (Docetaxel) 1e. EC-THP (Paclitaxel) 1f. EC-THP (Docetaxel) 1g. ddEC-THP (Paclitaxel) 1h. ddEC-THP (Docetaxel) 1i. FAC-THP (Paclitaxel) 1j. FAC-THP (Docetaxel) 1k. FEC-THP (Paclitaxel) 1l. FEC-THP (Docetaxel) 1m. TCHP (Docetaxel)	Inferior IDFS1

¹Reported efficacy is based on the 2021 update.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 (maximum dose of 900 mg) IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

Regimen variant #3, 75/6, no cap

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2011 (BCIRG 006)	2001-2004	Phase 3 (E-RT-esc)	1. AC-D	Seems to have superior OS (secondary endpoint)
			2. AC-TH	Did not meet primary endpoint of DFS
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase 3 (C)	1. TCL 2. TCH-L 3. TCHL	Did not meet primary endpoint of DFS
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (C)	Trastuzumab x 1 y	Inconclusive whether non-inferior DFS (primary endpoint)

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15
  • Cycles 7 to 18: 6 mg/kg IV once on day 1

Supportive therapy

• ALTTO: G-CSF use is mandatory (details not provided)

21-day cycle for 18 cycles (1 year)

References

1. BCIRG 006: Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article PubMed NCT00021255
2. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
3. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00490139
   1. Update: Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. Epub 2021 Mar 23. link to original article link to PMC article PubMed
4. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in manuscript PubMed NCT01104935

TCHP (Docetaxel)

TCHP: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase 3 (E-RT-esc)	1a. AC-TH (Paclitaxel) 1b. AC-TH (Docetaxel) 1c. ddAC-TH (Paclitaxel) 1d. ddAC-TH (Docetaxel) 1e. EC-TH (Paclitaxel) 1f. EC-TH (Docetaxel) 1g. ddEC-TH (Paclitaxel) 1h. ddEC-TH (Docetaxel) 1i. FAC-TH (Paclitaxel) 1j. FAC-TH (Docetaxel) 1k. FEC-TH (Paclitaxel) 1l. FEC-TH (Docetaxel) 1m. TCH (Taxotere)	Superior IDFS1 (primary endpoint) IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy is based on the 2021 update.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 (maximum dose: 900 mg) IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 18: 420 mg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

TCyH (Docetaxel)

TCyH: Taxotere (Docetaxel), Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence
Jones et al. 2013 (US Oncology 06-038)	2007-2009	Phase 2

Preceding treatment

• Surgery, within 84 days

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 4: 75 mg/m² IV over 60 minutes once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV over 15 to 30 minutes once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 to 60 minutes once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV over 30 to 60 minutes once per day on days 1, 8, 15
  • Cycles 6 to 18: 6 mg/kg IV once on day 1

Supportive therapy

• Use of Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) was allowed.
• Prophylactic antibiotics were not recommended.

21-day cycle for 18 cycles

References

1. US Oncology 06-038: Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MA, Brooks BD, Portillo RM, Vukelja SJ, Steinberg MS, Stokoe C, Crockett MW, Wang Y, Asmar L, Robert NJ, O'Shaughnessy J. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013 Oct;14(11):1121-8. Epub 2013 Sep 2. link to original article contains dosing details in manuscript PubMed NCT00493649
2. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in manuscript PubMed NCT01104935

Trastuzumab monotherapy

Regimen variant #1, 6 mo course

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase 3 (E-de-esc)	Trastuzumab x 12 mo	Non-inferior DFS (primary endpoint) DFS48: 89.4% vs 89.8% (HR 1.07, 90% CI 0.93-1.24)

Preceding treatment

• Not explicitly specified (pragmatic trial)

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 onwards: 6 mg/kg IV over 90 minutes once on day 1

21-day cycle for 9 cycles (6 months)

Regimen variant #2, 30-week course, q3wk

Study	Dates of enrollment	Evidence
Pivot et al. 2018 (SB3-G31-BC)	2014-04 to 2015-08	Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant TH-FEC & H, then surgery

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV over 30 minutes once on day 1

21-day cycle for 10 cycles (30-week course)

Regimen variant #3, 34-week course, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase 3 (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then adjuvant FEC x 3

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 to 12: 6 mg/kg IV over 30 minutes once on day 1

21-day cycle for 12 cycles (34-week course)

Regimen variant #4, 42-week course, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (KATHERINE)	2013-2015	Phase 3 (C)	T-DM1	Inferior IDFS

Note: the loading dose in cycle 1 was only used if it had been more than 6 weeks since any preceding dose of trastuzumab.

Preceding treatment

• Surgery, with residual invasive disease

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 14: 6 mg/kg IV once on day 1

21-day cycle for 14 cycles

Regimen variant #5, 1-year total course, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2005 (HERA)	2001-2005	Phase 3 (E-RT-esc)	1. No trastuzumab after (neo-)adjuvant chemotherapy	Superior OS1 (secondary endpoint) OS144: 79% vs 73% (HR 0.74, 95% CI 0.64-0.86)
			2. Trastuzumab x 2 y	Did not meet primary endpoint of DFS
Gianni et al. 2010 (NOAH)	2002-2005	Phase 3 (E-esc)	See link	See link
Pivot et al. 2013 (PHARE)	2006-2010	Phase 3 (C)	Trastuzumab x 6 mo	Inconclusive whether non-inferior DFS
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase 3 (C)	1. Lapatinib 2. T-L	Did not meet primary endpoint of DFS
			3. Lapatinib & Trastuzumab	Might have inferior DFS2
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase 3 (C)	Trastuzumab x 6 mo	Non-inferior DFS
Conte et al. 2018 (Short-HER)	2007-NR	Phase 3 (C)	Trastuzumab x 9 wks	Inconclusive whether non-inferior DFS
Joensuu et al. 2018 (SOLD)	2008-2014	Phase 3 (C)	No further treatment	Inconclusive whether non-inferior DFS
Sawaki et al. 2020 (RESPECT)	2009-10 to 2014-11	Randomized (E-de-esc)	1a. AC-H 1b. CMF & H 1c. CMF-H 1d. EC-H 1e. FEC-H 1f. T-H (Paclitaxel) 1g. T-H (Docetaxel) 1h. TC-H 1i. TCH 1j. TH (Paclitaxel) 1k. TH (Docetaxel)	Inconclusive whether non-inferior DFS (primary endpoint)

¹Reported efficacy for HERA is based on the 2017 update.
²Reported efficacy for ALTTO is based on the 2021 update.
Note: for patients already receiving trastuzumab prior to transitioning to monotherapy, re-loading is not necessary.

Preceding treatment

• HERA: surgery, then at least four cycles of an approved adjuvant chemotherapy regimen or at least four cycles of an approved neoadjuvant chemotherapy regimen, then surgery
• PERSEPHONE: Not explicitly specified (pragmatic trial)
• SOLD: Surgery, then adjuvant TH-FEC or TH-FEC (SC)
• Short-HER: Surgery, then adjuvant AC x 4 or EC x 4, then adjuvant TH (Paclitaxel) or TH (Docetaxel)
• RESPECT: Surgery

Targeted therapy

• Trastuzumab (Herceptin) as follows (see note):
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 to 18: 6 mg/kg IV over 90 minutes once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #6, 2-year course

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2005 (HERA)	2001-2005	Phase 3 (E-RT-esc)	1. No trastuzumab after (neo-)adjuvant chemotherapy	Not reported
			2. Trastuzumab x 1 y	Did not meet primary endpoint of DFS

Preceding treatment

• HERA: surgery, then at least four cycles of an approved adjuvant chemotherapy regimen or at least four cycles of an approved neoadjuvant chemotherapy regimen, then surgery

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 to 35: 6 mg/kg IV over 90 minutes once on day 1

21-day cycle for 35 cycles (2 years)

References

1. HERA: Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. link to original article contains dosing details in manuscript link to data supplement PubMed NCT00045032
   1. Update: Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. link to original article contains dosing details in manuscript PubMed
   2. Update: Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. Epub 2011 Feb 25. link to original article contains dosing details in manuscript PubMed
   3. Update: Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, Jackisch C, Cameron D, Weber HA, Heinzmann D, Dal Lago L, McFadden E, Dowsett M, Untch M, Gianni L, Bell R, Köhne CH, Vindevoghel A, Andersson M, Brunt AM, Otero-Reyes D, Song S, Smith I, Leyland-Jones B, Baselga J; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021-8. Epub 2013 Jul 18. link to original article PubMed
   4. Update: Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, McFadden E, Leyland-Jones B, Bell R, Dowsett M, Jackisch C; Herceptin Adjuvant (HERA) Trial Study Team. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017 Mar 25;389(10075):1195-1205. Epub 2017 Feb 17. link to original article link to PMC article PubMed
2. NOAH: Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 30;375(9712):377-84. link to original article contains dosing details in manuscript PubMed ISRCTN86043495
   1. Update: Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, Moliterni A, Vazquez F, Byakhov MJ, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Magazzù D, Heinzmann D, Steinseifer J, Valagussa P, Baselga J. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014 May;15(6):640-7. Epub 2014 Mar 20. Erratum in: Lancet Oncol. 2018 Dec;19(12):e667. link to original article PubMed
3. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
4. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article PubMed
5. PHARE: Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espié M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Tubiana-Mathieu N, Cany L, Catala S, Khayat D, Pauporté I, Kramar A; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013 Jul;14(8):741-8. Epub 2013 Jun 11. link to original article PubMed NCT00381901
   1. Update: Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espié M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporté I, Faure-Mercier C, Paget-Bailly S, Henriques J, Grouin JM; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019 Jun 29;393(10191):2591-2598. Epub 2019 Jun 6. link to original article PubMed
6. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00490139
   1. Update: Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. Epub 2021 Mar 23. link to original article link to PMC article PubMed
7. SB3-G31-BC: Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. link to original article contains dosing details in manuscript PubMed NCT02149524
8. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00593697
9. Short-HER: Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, Piacentini F, Cavanna L, Giotta F, Aieta M, Gebbia V, Molino A, Musolino A, Ferro A, Maltoni R, Danese S, Zamagni C, Rimanti A, Cagossi K, Russo A, Pronzato P, Giovanardi F, Moretti G, Lombardo L, Schirone A, Beano A, Amaducci L, Bajardi EA, Vicini R, Balduzzi S, D'Amico R, Guarneri V; Reader study level-I and level-II Groups. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Ann Oncol. 2018 Dec 1;29(12):2328-2333. link to original article contains dosing details in manuscript PubMed NCT00629278
   1. Update: Conte P, Bisagni G, Piacentini F, Sarti S, Minichillo S, Anselmi E, Aieta M, Gebbia V, Schirone A, Musolino A, Garrone O, Beano A, Rimanti A, Giotta F, Turletti A, Miglietta F, Dieci MV, Vicini R, Balduzzi S, D'Amico R, Guarneri V. Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial. J Clin Oncol. 2023 Nov 10;41(32):4976-4981. Epub 2023 Sep 25. link to original article PubMed
10. KATHERINE: von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. Epub 2018 Dec 5. link to original article contains dosing details in manuscript PubMed NCT01772472
11. PERSEPHONE: Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019 Jun 29;393(10191):2599-2612. Epub 2019 Jun 6. link to original article contains dosing details in abstract link to PMC article PubMed NCT00712140
12. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains dosing details in manuscript PubMed NCT01104935

Trastuzumab and hyaluronidase monotherapy

Regimen variant #1, 6 mos

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase 3 (E-de-esc)	Trastuzumab x 12 mo	Non-inferior DFS (primary endpoint) DFS48: 89.4% vs 89.8% (HR 1.07, 90% CI 0.93-1.24)

Preceding treatment

• Not explicitly specified (pragmatic trial)

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 9 cycles (6 months)

Regimen variant #2, 12 mos

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase 3 (C)	Trastuzumab x 6 mo	Non-inferior DFS
Joensuu et al. 2018 (SOLD)	2008-2014	Phase 3 (C)	No further treatment	Inconclusive whether non-inferior DFS

Preceding treatment

• SOLD: Surgery, then adjuvant TH-FEC or TH-FEC (SC)
• PERSEPHONE: Not explicitly specified (pragmatic trial)

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 18 cycles (1 year)

References

1. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00593697
2. PERSEPHONE: Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019 Jun 29;393(10191):2599-2612. Epub 2019 Jun 6. link to original article contains dosing details in abstract link to PMC article PubMed NCT00712140

Trastuzumab emtansine monotherapy

T-DM1: Trastuzumab-DM1 (Trastuzumab emtansine)

Example orders

• Example orders for trastuzumab emtansine (Kadcyla) in breast cancer

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (KATHERINE)	2013-2015	Phase 3 (E-RT-switch-ic)	Trastuzumab	Superior IDFS (primary endpoint) IDFS36: 88% vs 77% (HR 0.50, 95% CI 0.39-0.64)

Preceding treatment

• Surgery, with residual invasive disease

Antibody-drug conjugate therapy

• Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycle for 14 cycles

References

1. KATHERINE: von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. Epub 2018 Dec 5. link to original article contains dosing details in manuscript PubMed NCT01772472
2. CompassHER2 RD: NCT04457596

Metastatic or unresectable disease, first-line

Note: some patients in these trials were pre-treated with non-HER2-targeted therapies.

ACH

ACH: Adriamycin (Doxorubicin), Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2001	1995-1997	Phase 3 (E-RT-esc)	1a. AC 1b. EC	Seems to have superior OS (secondary endpoint) Median OS: 25.1 vs 20.3 mo Superior TTP (co-primary endpoint) Median TTP: 7.4 vs 4.6 mo

Note: This is not commonly used; here for reference purposes only.

Prior treatment criteria

• Slamon et al. 2001: No previous anthracycline exposure

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/mg² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/mg² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycles

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article contains dosing details in manuscript PubMed

Capecitabine, Bevacizumab, Trastuzumab

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Martín et al. 2012 (MO21926)	2008-2010	Phase 2	ORR: 73% (95% CI 62-82)

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. MO21926: Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V, Scotto N, Mitchell L, Tjulandin S. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17(4):469-75. Epub 2012 Mar 30. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00811135

Capecitabine & Lapatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase 3 (E-switch-ic)	Capecitabine & Trastuzumab	Did not meet primary endpoint of CNS metastases as first site of relapse

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Lapatinib (Tykerb) 1250 mg PO once per day on days 1 to 21

21-day cycles

References

1. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article PubMed NCT00820222

Capecitabine & Trastuzumab (XH)

XH: Xeloda (Capecitabine) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase 3 (C)	Capecitabine & Lapatanib	Did not meet primary endpoint of CNS metastases as first site of relapse

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article contains dosing details in abstract PubMed NCT00820222

Carboplatin & Paclitaxel (CP) & Trastuzumab

TPC: Trastuzumab, Paclitaxel, Carboplatin
TCH: Taxol (Paclitaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen variant #1, weekly

Study	Dates of enrollment	Evidence
Perez et al. 2005 (NCCTG 983252)	1999-04 to 2003-07	Phase 2

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15, 22

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15
• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15

28-day cycle for 6 cycles

Subsequent treatment

• Trastuzumab maintenance (weekly)

Regimen variant #2, weekly T, q3wk PC

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2006	1998-2002	Phase 3 (E-esc)	TP	Superior PFS (secondary endpoint) Median PFS: 10.7 vs 7.1 mo (HR 0.66, 95% CI 0.59-0.73) Seems to have superior ORR (primary endpoint)

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 2
• Carboplatin (Paraplatin) AUC 6 IV once on day 2

21-day cycle for at least 6 cycles

Subsequent treatment

• Trastuzumab maintenance (weekly)

Regimen variant #3, q3wk

Study	Dates of enrollment	Evidence
Perez et al. 2005 (NCCTG 983252)	1999-04 to 2003-07	Phase 2

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 8: 6 mg/kg IV once on day 1

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk)

References

1. NCCTG 983252: Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. link to original article PubMed
2. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article contains dosing details in manuscript PubMed

Docetaxel & Trastuzumab (TH)

TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)
HT: Herceptin (Trastuzumab) & Taxotere (Docetaxel)
H+D: Herceptin (Trastuzumab) & Docetaxel

Regimen variant #1, 35 mg/m² docetaxel, 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Esteva et al. 2002	NR	Phase 2
Burstein et al. 2007 (TRAVIOTA)	2001-2003	Phase 3 (E-switch-ic)	VH	Might have inferior TTP (secondary endpoint) Median TTP: 6 vs 8.5 mo

Note: Esteva et al. 2002 described the day before the start of a cycle as "day 0," which is not the typical convention, so day -1 is being used instead.

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

Targeted therapy

• Trastuzumab (Herceptin) given second as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day -1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15

Supportive therapy

• Dexamethasone (Decadron) 4 mg PO every 12 hours x 3 doses on cycles 1 & 2, starting the night prior to docetaxel. Patients who did not have "hypersensitivity reactions and no significant fluid retention during the first 8 weeks" received 4 mg PO twice per day on day 1 for at least the next two cycles. Patients who "remained free of fluid retention after 8 additional weeks" then received 4 mg PO once on day 1 prior to docetaxel in subsequent cycles.

28-day cycles

Regimen variant #2, 60 mg/m² q3wk docetaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Inoue et al. 2009 (JO17360)	2004-2008	Phase 3 (C)	H	Seems to have superior OS (co-primary endpoint) Median OS: NYR vs NYR (HR 0.37, 95% CI 0.14-0.97)

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #3, 75 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hurvitz et al. 2013 (TDM4450g)	2008-2009	Randomized Phase 2 (C)	T-DM1	Seems to have inferior PFS
Baselga et al. 2011 (CLEOPATRA)	2008-2010	Phase 3 (C)	THP	Inferior OS1
Gelmon et al. 2015 (NCIC-CTG MA.31)	2008-2011	Phase 3 (C)	1a. TL (Docetaxel) 1b. Lapatinib & Paclitaxel	Superior PFS (primary endpoint)
Perez et al. 2016 (MARIANNE)	2010-2012	Phase 3 (C)	1. T-DM1	Non-inferior PFS
			2. Pertuzumab & T-DM1	Non-inferior PFS
Hugo et al. 2017 (HERITAGE)	2012-12-10 to 2015-08-05	Phase 3 (C)	1a. Docetaxel & Trastuzumab-dkst 1b. Paclitaxel & Trastuzumab-dkst	Equivalent ORR24w (primary endpoint) ORR24w: 64% vs 69.6%
Xu et al. 2021 (HLX02-BC01)	2016-11-11 to 2019-07-10	Phase 3 (C)	Docetaxel & Trastuzumab-strf	Equivalent ORR24w (primary endpoint) ORR24w: 71.4% vs 71.3%
Ma et al. 2023 (PHILA)	2019-05-06 to 2022-01-17	Phase 3 (C)	TH & Pyrotinib	Inferior PFS

¹Reported efficacy for CLEOPATRA is based on the 2020 update.
Note: Dose of docetaxel in TDM4450g and MARIANNE was per investigator's discretion. CLEOPATRA has an unusual schedule with both medications being given on day 2 of cycle 1, due to this regimen being the control arm, in which patients in one arm received a placebo instead of pertuzumab on day 1. It is reasonable to assume that in practice, drugs in this regimen will be given on day 1 from the beginning.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 2
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for at least 6 cycles

Subsequent treatment

• CLEOPATRA, if it is decided to no longer administer docetaxel with this regimen: patients could continue to receive trastuzumab maintenance
• NCIC-CTG MA.31: Trastuzumab maintenance, after 8 cycles

Regimen variant #4, 100 mg/m² q3wk docetaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Marty et al. 2005 (M77001)	2000-2002	Randomized Phase 2 (E-esc)	Docetaxel	Seems to have superior OS (secondary endpoint) Superior ORR (primary endpoint)
Valero et al. 2010 (BCIRG 007)	2001-2004	Phase 3 (C)	TCH	Did not meet primary endpoint of TTP

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15
  • Cycles 2 to 8: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15

Supportive therapy

• Dexamethasone (Decadron) 8 mg (or equivalent) PO twice per day x 6 doses, starting the night prior to docetaxel
• "Antiemetic premedication was mandatory" (no additional details given).

21-day cycle for 6 cycles (M77001; see note) or 8 cycles (BCIRG 007)

Subsequent treatment

• M77001: Patients could receive docetaxel beyond six cycles at the discretion of the investigator. Otherwise, patients proceeded to trastuzumab maintenance.
• BCIRG 007: Trastuzumab maintenance

Regimen variant #5, 100 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Andersson et al. 2010 (HERNATA)	2004-2008	Phase 3 (C)	VH	Did not meet primary endpoint of TTP
Gianni et al. 2013 (AVAREL)	2006-2010	Randomized Phase 2 (C)	BTH	Might have inferior PFS
Hurvitz et al. 2013 (TDM4450g)	2008-2009	Randomized Phase 2 (C)	T-DM1	Seems to have inferior PFS
Perez et al. 2016 (MARIANNE)	2010-2012	Phase 3 (E-esc)	1. T-DM1	Non-inferior PFS (primary endpoint)
			2. Pertuzumab & T-DM1	Non-inferior PFS (primary endpoint)

Note: In HERNATA, the day of docetaxel and trastuzumab were reversed in cycle 1. Dose of docetaxel in TDM4450g and MARIANNE was per investigator's discretion.

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1 (see note)

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 2 (see note)
  • Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1

21-day cycles

References

1. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002 Apr 1;20(7):1800-8. link to original article contains dosing details in manuscript PubMed
2. M77001: Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains dosing details in manuscript PubMed
3. TRAVIOTA: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. Epub 2007 Aug 20. link to original article PubMed NCT00146549
4. JO17360: Inoue K, Nakagami K, Mizutani M, Hozumi Y, Fujiwara Y, Masuda N, Tsukamoto F, Saito M, Miura S, Eguchi K, Shinkai T, Ando M, Watanabe T, Masuda N, Ohashi Y, Sano M, Noguchi S. Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group. Breast Cancer Res Treat. 2010 Jan;119(1):127-36. Epub 2009 Aug 19. link to original article contains dosing details in abstract PubMed
5. BCIRG 007: Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains dosing details in manuscript PubMed NCT00047255
6. HERNATA: Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. Epub 2010 Dec 13. link to original article contains dosing details in manuscript PubMed NCT00430001
7. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. HRQoL analysis: Cortés J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. Epub 2013 Jul 17. link to original article PubMed
   3. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article link to PMC article PubMed
   4. Update: Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. link to original article PubMed
8. TDM4450g: Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. link to original article contains dosing details in manuscript PubMed NCT00679341
9. AVAREL: Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013 May 10;31(14):1719-25. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT00391092
10. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article contains dosing details in manuscript PubMed NCT00667251
11. HERITAGE: Rugo HS, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J, Sharma R, Baczkowski M, Kothekar M, Loganathan S, Manikhas A, Bondarenko I, Mukhametshina G, Nemsadze G, Parra JD, Abesamis-Tiambeng ML, Baramidze K, Akewanlop C, Vynnychenko I, Sriuranpong V, Mamillapalli G, Ray S, Yanez Ruiz EP, Pennella E; Heritage Study Investigators. Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA. 2017 Jan 3;317(1):37-47. link to original article PubMed NCT02472964
    1. Update: Rugo HS, Pennella EJ, Gopalakrishnan U, Hernandez-Bronchud M, Herson J, Koch HF, Loganathan S, Deodhar S, Marwah A, Manikhas A, Bondarenko I, Mukhametshina G, Nemsadze G, Parra JD, Abesamis-Tiambeng MLT, Baramidze K, Akewanlop C, Vynnychenko I, Sriuranpong V, Mamillapalli G, Roy S, Yanez Ruiz EP, Barve A, Fuentes-Alburo A, Waller CF. Final overall survival analysis of the phase 3 HERITAGE study demonstrates equivalence of trastuzumab-dkst to trastuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2021 Jul;188(2):369-377. Epub 2021 Jun 14. link to original article link to PMC article PubMed
12. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01120184
    1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed
13. PUFFIN: Xu B, Li W, Zhang Q, Shao Z, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhang H, Lei G, Restuccia E. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2020 Aug;182(3):689-697. Epub 2020 Jun 20. link to original article link to PMC article PubMed NCT02896855
    1. Update: Xu B, Li W, Zhang Q, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhu H, Siddiqui A, Macharia H, Knott A. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): final analysis of a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2023 Feb;197(3):503-513. Epub 2022 Dec 4. link to original article link to PMC article PubMed
14. HLX02-BC01: Xu B, Zhang Q, Sun T, Li W, Teng Y, Hu X, Bondarenko I, Adamchuk H, Zhang L, Trukhin D, Wang S, Zheng H, Tong Z, Shparyk Y, Wang Q; HLX02-BC01 Investigators. Efficacy, Safety, and Immunogenicity of HLX02 Compared with Reference Trastuzumab in Patients with Recurrent or Metastatic HER2-Positive Breast Cancer: A Randomized Phase III Equivalence Trial. BioDrugs. 2021 May;35(3):337-350. Epub 2021 Apr 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03084237
15. PHILA: Ma F, Yan M, Li W, Ouyang Q, Tong Z, Teng Y, Wang Y, Wang S, Geng C, Luo T, Zhong J, Zhang Q, Liu Q, Zeng X, Sun T, Mo Q, Liu H, Cheng Y, Cheng J, Wang X, Nie J, Yang J, Wu X, Wang X, Li H, Ye C, Dong F, Wu S, Zhu X, Xu B; PHILA Investigators. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial. BMJ. 2023 Oct 31;383:e076065. Erratum in: BMJ. 2023 Nov 16;383:p2665. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03863223

Docetaxel & Trastuzumab (TH) & Pyrotinib

TH & Pyrotinib: Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ma et al. 2023 (PHILA)	2019-05-06 to 2022-01-17	Phase 3 (E-esc)	TH	Superior PFS (primary endpoint) Median PFS: 24.3 vs 10.4 mo (HR 0.41, 95% CI 0.32-0.53)

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Pyrotinib (Irene) 400 mg PO once per day on days 1 to 21
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 2
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for at least 6 cycles

References

1. PHILA: Ma F, Yan M, Li W, Ouyang Q, Tong Z, Teng Y, Wang Y, Wang S, Geng C, Luo T, Zhong J, Zhang Q, Liu Q, Zeng X, Sun T, Mo Q, Liu H, Cheng Y, Cheng J, Wang X, Nie J, Yang J, Wu X, Wang X, Li H, Ye C, Dong F, Wu S, Zhu X, Xu B; PHILA Investigators. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial. BMJ. 2023 Oct 31;383:e076065. Erratum in: BMJ. 2023 Nov 16;383:p2665. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03863223

ECH

ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2001	1995-1997	Phase 3 (E-RT-esc)	1a. AC 1b. EC	Seems to have superior OS (secondary endpoint) Median OS: 25.1 vs 20.3 mo Superior TTP (co-primary endpoint) Median TTP: 7.4 vs 4.6 mo

Note: This is not commonly used; here for reference purposes only.

Prior treatment criteria

• Slamon et al. 2001: No previous anthracycline exposure

Chemotherapy

• Epirubicin (Ellence) 75 mg/mg² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/mg² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycles

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article contains dosing details in manuscript PubMed

Lapatinib & Paclitaxel (TL)

TL: Taxol (Paclitaxel) & Lapatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Guan et al. 2013 (EGF104535)	2006-2009	Phase 3 (E-esc)	Paclitaxel	Superior OS (primary endpoint) Median OS: 27.8 vs 20.5 mo (HR 0.74, 95% CI 0.58-0.94)

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Lapatinib (Tykerb) 1500 mg PO once per day on days 1 to 28

28-day cycles

References

1. EGF104535: Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z, Lorvidhaya V, Jiang Z, Yang J, Makhson A, Leung WL, Russo MW, Newstat B, Wang L, Chen G, Oliva C, Gomez H. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. J Clin Oncol. 2013 Jun 1;31(16):1947-53. Epub 2013 Mar 18. link to original article contains dosing details in manuscript PubMed NCT00281658
2. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article PubMed NCT00667251

Paclitaxel & Trastuzumab (TH)

TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)
TP: Trastuzumab, Paclitaxel

Regimen variant #1, weekly paclitaxel (80 mg/m²), weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Seidman et al. 2008 (CALGB 9840)	1998-NR	Phase 3 (E-switch-ic)	TH; q3wk paclitaxel	Superior ORR (primary endpoint) ORR: 42% vs 29% (OR 1.75) Superior OS (secondary endpoint) Median OS: 24 vs 12 mo (HR 0.78, 95% CI 0.65-0.94)
Burstein et al. 2007 (TRAVIOTA)	2001-2003	Phase 3 (E-switch-ic)	VH	Might have inferior TTP (secondary endpoint)
Baselga et al. 2014 (STM01-102)	2006-2009	Phase 3 (C)	MTP	Did not meet primary endpoint of PFS
Perez et al. 2016 (MARIANNE)	2010-2012	Phase 3 (C)	1. T-DM1	Non-inferior PFS
			2. Pertuzumab & T-DM1	Non-inferior PFS
Hugo et al. 2017 (HERITAGE)	2012-12-10 to 2015-08-05	Phase 3 (C)	1a. Docetaxel & Trastuzumab-dkst 1b. Paclitaxel & Trastuzumab-dkst	Equivalent ORR24w (primary endpoint) ORR24w: 64% vs 69.6%

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, weekly paclitaxel (80 mg/m²), q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hugo et al. 2017 (HERITAGE)	2012-12-10 to 2015-08-05	Phase 3 (C)	1a. Docetaxel & Trastuzumab-dkst 1b. Paclitaxel & Trastuzumab-dkst	Equivalent ORR24w (primary endpoint) ORR24w: 64% vs 69.6%

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 60 minutes once on day 1

21-day cycles

Regimen variant #3, weekly paclitaxel (90 mg/m²)

Study	Dates of enrollment	Evidence
Seidman et al. 2001	NR	Phase 2

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 0, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #4, paclitaxel 3 weeks out of 4, 6 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gelmon et al. 2015 (NCIC-CTG MA.31)	2008-2011	Phase 3 (C)	1a. TL (Docetaxel) 1b. Lapatinib & Paclitaxel	Superior PFS (primary endpoint)

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycle for 6 cycles

Subsequent treatment

• Trastuzumab maintenance

Regimen variant #5, paclitaxel 3 weeks out of 4, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hurvitz et al. 2015 (BOLERO-1)	2009-2012	Phase 3 (C)	TH & Everolimus	Did not meet primary endpoint of PFS
Awada et al. 2016 (NEfERT-T)	2009-2014	Phase 3 (C)	Neratinib & Paclitaxel	Did not meet primary endpoint of PFS
Pegram et al. 2018 (REFLECTIONS B327-02)	2014-04-04 to 2016-01-22	Phase 3 (C)	Paclitaxel & Trastuzumab-bvzr	Equivalent ORR (primary endpoint) ORR: 66.5% vs 62.5%

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #6, q3wk paclitaxel, weekly trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2001	1995-1997	Phase 3 (E-RT-esc)	Paclitaxel	Seems to have superior OS (secondary endpoint) Median OS: 25.1 vs 20.3 mo Superior TTP (co-primary endpoint) Median TTP: 7.4 vs 4.6 mo
Robert et al. 2006	1998-2002	Phase 3 (C)	TPC	Inferior PFS
Seidman et al. 2008 (CALGB 9840)	1998-NR	Phase 3 (C)	TH; weekly paclitaxel (80 mg/m2)	Inferior OS

Prior treatment criteria

• Slamon et al. 2001: Previous anthracycline exposure

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6: 175 mg/m² IV once on day 2
  • Cycle 7 onwards: continued at investigator's discretion

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for at least 6 cycles

Regimen variant #7, q3wk paclitaxel, q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Alexeev et al. 2020 (BCD-022-02)	2012-10 to 2017-12	Phase 3 (C)	TH (biosimilar trastuzumab)	Equivalent ORR (primary endpoint) ORR: 43.6% vs 49.6%

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6: 175 mg/m² IV once on day 2

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
2. Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001 May 15;19(10):2587-95. link to original article PubMed
3. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article PubMed
4. TRAVIOTA: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. Epub 2007 Aug 20. link to original article PubMed NCT00146549
5. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
6. STM01-102: Baselga J, Manikhas A, Cortés J, Llombart A, Roman L, Semiglazov VF, Byakhov M, Lokanatha D, Forenza S, Goldfarb RH, Matera J, Azarnia N, Hudis CA, Rozencweig M. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol. 2014 Mar;25(3):592-8. Epub 2014 Jan 8. link to original article link to PMC article contains dosing details in abstract PubMed NCT00294996
7. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article contains dosing details in manuscript PubMed NCT00667251
8. BOLERO-1: Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816-29. Epub 2015 Jun 16. link to original article PubMed NCT00876395
9. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01120184
   1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed
10. NEfERT-T: Awada A, Colomer R, Inoue K, Bondarenko I, Badwe RA, Demetriou G, Lee SC, Mehta AO, Kim SB, Bachelot T, Goswami C, Deo S, Bose R, Wong A, Xu F, Yao B, Bryce R, Carey LA. neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: The NEfERT-T randomized clinical trial. JAMA Oncol. 2016 Dec 1;2(12):1557-1564. link to original article contains dosing details in manuscript PubMed NCT00915018
11. HERITAGE: Rugo HS, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J, Sharma R, Baczkowski M, Kothekar M, Loganathan S, Manikhas A, Bondarenko I, Mukhametshina G, Nemsadze G, Parra JD, Abesamis-Tiambeng ML, Baramidze K, Akewanlop C, Vynnychenko I, Sriuranpong V, Mamillapalli G, Ray S, Yanez Ruiz EP, Pennella E; Heritage Study Investigators. Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA. 2017 Jan 3;317(1):37-47. link to original article PubMed NCT02472964
    1. Update: Rugo HS, Pennella EJ, Gopalakrishnan U, Hernandez-Bronchud M, Herson J, Koch HF, Loganathan S, Deodhar S, Marwah A, Manikhas A, Bondarenko I, Mukhametshina G, Nemsadze G, Parra JD, Abesamis-Tiambeng MLT, Baramidze K, Akewanlop C, Vynnychenko I, Sriuranpong V, Mamillapalli G, Roy S, Yanez Ruiz EP, Barve A, Fuentes-Alburo A, Waller CF. Final overall survival analysis of the phase 3 HERITAGE study demonstrates equivalence of trastuzumab-dkst to trastuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2021 Jul;188(2):369-377. Epub 2021 Jun 14. link to original article link to PMC article PubMed
12. REFLECTIONS B327-02: Pegram MD, Bondarenko I, Zorzetto MMC, Hingmire S, Iwase H, Krivorotko PV, Lee KS, Li RK, Pikiel J, Aggarwal R, Ewesuedo R, Freyman A, Li R, Vana A, Yin D, Zacharchuk C, Tan-Chiu E. PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study. Br J Cancer. 2019 Jan;120(2):172-182. Epub 2018 Dec 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01989676
    1. Update: Li RK, Tokunaga E, Adamchuk H, Vladimirov V, Yanez E, Lee KS, Bondarenko I, Vana A, Hilton F, Ishikawa T, Tajima K, Lipatov O. Long-Term Safety and Effectiveness of PF-05280014 (a Trastuzumab Biosimilar) Treatment in Patients with HER2-Positive Metastatic Breast Cancer: Updated Results of a Randomized, Double-Blind Study. BioDrugs. 2022 Jan;36(1):55-69. Epub 2022 Feb 8. link to original article link to PMC article PubMed
13. BCD-022-02: Alexeev SM, Khorinko AV, Mukhametshina GZ, Shelepen KG, Burdaeva ON, Kulik SA, Satheesh CT, Srivastava K, Vikranth M, Kryukov F, Paltusova AN, Shustova MS, Ivanov RA. Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab. BMC Cancer. 2020 Aug 20;20(1):783. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01764022

nab-Paclitaxel & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence
Mirtsching et al. 2011	2005-2006	Phase 2

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV over 30 minutes once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15, 22

28-day cycles

References

1. Mirtsching B, Cosgriff T, Harker G, Keaton M, Chidiac T, Min M. A phase II study of weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab in metastatic breast cancer. Clin Breast Cancer. 2011 Apr;11(2):121-8. Epub 2011 Apr 11. link to original article contains dosing details in manuscript PubMed

Pertuzumab & T-DM1

Pertuzumab & T-DM1: Pertuzumab & Trastuzumab-DM1 (Trastuzumab emtansine)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Perez et al. 2016 (MARIANNE)	2010-2012	Phase 3 (E-esc)	1. T-DM1	Non-inferior PFS (primary endpoint) Median PFS: 15.2 vs 14.1 mo
			2a. TH (Docetaxel) 2b. TH (Paclitaxel)	Non-inferior PFS (primary endpoint) Median PFS: 15.2 vs 13.7 mo

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

Antibody-drug conjugate therapy

• Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

References

1. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01120184
   1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed

TCH (Docetaxel)

TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Valero et al. 2011 (BCIRG 007)	2001-2004	Phase 3 (E-esc)	TH	Did not meet primary endpoint of TTP Median TTP: 10.4 vs 11.1 mo (HR 1.09, 95% CI 0.83-1.44)

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 8: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 8 cycles

Subsequent treatment

• Trastuzumab maintenance

References

1. BCIRG 007: Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains dosing details in manuscript PubMed NCT00047255

THP (Docetaxel)

THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2011 (CLEOPATRA)	2008-2010	Phase 3 (E-RT-esc)	Docetaxel & Trastuzumab	Superior PFS (primary endpoint) Median PFS: 18.5 vs 12.4 mo (HR 0.62, 95% CI 0.51-0.75) Superior OS1 (secondary endpoint) Median OS: 57.1 vs 40.8 mo (HR 0.69, 95% CI 0.58-0.82)
Xu et al. 2020 (PUFFIN)	2016-09-13 to 2017-09-28	Phase 3 (E-esc)	Docetaxel & Trastuzumab	Superior PFS2 (primary endpoint) Median PFS: 16.5 vs 12.5 mo (HR 0.60, 95% CI 0.45-0.81) Might have superior OS2 (secondary endpoint) Median OS: NYR vs NYR (HR 0.68, 95% CI 0.45-1.03)

¹Reported efficacy for CLEOPATRA is based on the 2020 update.
²Reported efficacy for PUFFIN is based on the 2022 update.

Chemotherapy

• Docetaxel (Taxotere) given third as follows:
  • Cycle 1: 75 mg/m² IV once on day 2
  • Cycle 2 onwards: 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 2
  • Cycle 2 onwards: 6 mg/kg IV over 30 to 90 minutes once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV over 60 minutes once on day 1
  • Cycle 2 onwards: 420 mg IV over 30 to 60 minutes once on day 1

21-day cycle for at least 6 cycles

Subsequent treatment

• CLEOPATRA, if it is decided to no longer administer docetaxel: patients could continue to receive pertuzumab & trastuzumab maintenance.

References

1. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. HRQoL analysis: Cortés J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. Epub 2013 Jul 17. link to original article PubMed
   3. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article link to PMC article PubMed
   4. Update: Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. link to original article PubMed
2. PUFFIN: Xu B, Li W, Zhang Q, Shao Z, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhang H, Lei G, Restuccia E. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2020 Aug;182(3):689-697. Epub 2020 Jun 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02896855
   1. Update: Xu B, Li W, Zhang Q, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhu H, Siddiqui A, Macharia H, Knott A. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): final analysis of a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2023 Feb;197(3):503-513. Epub 2022 Dec 4. link to original article link to PMC article PubMed
3. HERB TEA: UMIN000030783

Trastuzumab monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pagani et al. 2017 (SAKK 22/99)	1999-2013	Phase 3 (C)	Chemotherapy & Trastuzumab	Did not meet primary endpoint of TTP

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1
  • Cycle 2 onwards: 2 mg/kg IV once on day 1

7-day cycles

Regimen variant #2, flat dose

Historic variant

Study	Dates of enrollment	Evidence
Baselga et al. 1996	NR	Phase 2

Note: this variant is of historical interest, only.

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 250 mg IV once on day 1
  • Cycles 2 to 11: 100 mg IV once on day 1

7-day cycle for 11 cycles

References

1. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996 Mar;14(3):737-44. link to original article PubMed
2. SAKK 22/99: Pagani O, Klingbiel D, Ruhstaller T, Nolè F, Eppenberger S, Oehlschlegel C, Bernhard J, Brauchli P, Hess D, Mamot C, Munzone E, Pestalozzi B, Rabaglio M, Aebi S, Ribi K, Rochlitz C, Rothgiesser K, Thürlimann B, von Moos R, Zaman K, Goldhirsch A; Swiss Group for Clinical Cancer Research. Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99. Ann Oncol. 2017 Feb 1;28(2):305-312. link to original article contains dosing details in manuscript PubMed NCT00004935

Trastuzumab emtansine monotherapy

T-DM1: Trastuzumab-DM1 (Trastuzumab emtansine)

Example orders

• Example orders for trastuzumab emtansine (Kadcyla) in breast cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hurvitz et al. 2013 (TDM4450g)	2008-2009	Randomized Phase 2 (E-switch-ooc)	TH	Seems to have superior PFS (co-primary endpoint) Median PFS: 14.2 vs 9.2 mo (HR 0.59, 95% CI 0.36-0.97)
Perez et al. 2016 (MARIANNE)	2010-2012	Phase 3 (E-de-esc)	1. T-DM1 & Pertuzumab	Non-inferior PFS (primary endpoint)
			2a. TH (Docetaxel) 2b. TH (Paclitaxel)	Non-inferior PFS (primary endpoint)

Antibody-drug conjugate therapy

• Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

References

1. TDM4450g: Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. link to original article contains dosing details in manuscript PubMed NCT00679341
2. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01120184
   1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed

Vinorelbine & Trastuzumab (VH)

VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen variant #1, vinorelbine 25 mg/m², weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Burstein et al. 2007 (TRAVIOTA)	2001-2003	Phase 3 (E-switch-ic)	1a. TH (Docetaxel) 1b. TH (Paclitaxel)	Might have superior TTP (primary endpoint)

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1
  • Cycle 2 onwards: 2 mg/kg IV once on day 1

7-day cycles

Regimen variant #2, vinorelbine 30 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Andersson et al. 2010 (HERNATA)	2004-2008	Phase 3 (E-switch-ic)	TH (Docetaxel)	Did not meet primary endpoint of TTP

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #3, vinorelbine 35 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Andersson et al. 2010 (HERNATA)	2004-2008	Phase 3 (E-switch-ic)	TH (Docetaxel)	Did not meet primary endpoint of TTP

Chemotherapy

• Vinorelbine (Navelbine) 35 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1

21-day cycles

References

1. TRAVIOTA: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. Epub 2007 Aug 20. link to original article PubMed NCT00146549
2. HERNATA: Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. Epub 2010 Dec 13. link to original article contains dosing details in manuscript PubMed NCT00430001

Metastatic or unresectable disease, subsequent lines

Capecitabine & Lapatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Geyer et al. 2006 (EGF100151)	2004-03-29 to 2005-11-15	Phase 3 (E-RT-esc)	Capecitabine	Superior TTP1 (primary endpoint) (HR 0.57, 95% CI 0.43-0.77) Did not meet secondary endpoint of OS Median OS: 75 vs 64.7 weeks (HR 0.87, 95% CI 0.71-1.08)
Verma et al. 2012 (EMILIA)	2009-2011	Phase 3 (C)	T-DM1	Inferior OS
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase 3 (E-switch-ic)	Capecitabine & Trastuzumab	Did not meet primary endpoint of CNS metastases as first site of relapse
Saura et al. 2020 (NALA)	2013-2017	Phase 3 (C)	Capecitabine & Neratinib	Inferior PFS
Xu et al. 2021 (PHOEBE)	2017-07-31 to 2018-10-30	Phase 3 (C)	Capecitabine & Pyrotinib	Inferior PFS
André et al. 2023 (DESTINY-Breast02)	2018-09-06 to 2020-12-31	Phase 3 (C)	T-DXd	Inferior PFS

¹Reported efficacy for PFS for EGF100151 is based on the 2008 update.
²Reported efficacy for OS for EGF100151 is based on the 2010 update.
Note: the primary endpoint of CEREBEL was incidence of CNS as site of first relapse; this was very low in both arms, with no statistically significant difference.

Prior treatment criteria

• EGF100151: an anthracycline, a taxane, and trastuzumab
• EMILIA, PHOEBE, DESTINY-Breast02: trastuzumab and a taxane
• CEREBEL: prior anthracycline and/or taxanes
• NALA: 2 or more previous HER2-directed therapies in the metastatic setting

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Lapatinib (Tykerb) 1250 mg PO once per day on days 1 to 21

21-day cycles

References

1. EGF100151: Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. link to original article contains dosing details in abstract PubMed NCT00078572
   1. Update: Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43. Epub 2008 Jan 11. link to original article PubMed
   2. Update: Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924-34. Epub 2010 Aug 24. link to original article link to PMC article PubMed
2. EMILIA: Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00829166
   1. PRO analysis: Welslau M, Diéras V, Sohn JH, Hurvitz SA, Lalla D, Fang L, Althaus B, Guardino E, Miles D. Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer. 2014 Mar 1;120(5):642-51. Epub 2013 Nov 12. link to original article PubMed
   2. Update: Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):732-742. Epub 2017 May 16. link to original article link to PMC article PubMed
3. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article PubMed NCT00820222
4. NALA: Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. Epub 2020 Jul 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT01808573
5. PHOEBE: Xu B, Yan M, Ma F, Hu X, Feng J, Ouyang Q, Tong Z, Li H, Zhang Q, Sun T, Wang X, Yin Y, Cheng Y, Li W, Gu Y, Chen Q, Liu J, Cheng J, Geng C, Qin S, Wang S, Lu J, Shen K, Liu Q, Wang X, Wang H, Luo T, Yang J, Wu Y, Yu Z, Zhu X, Chen C, Zou J; PHOEBE Investigators. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Mar;22(3):351-360. Epub 2021 Feb 11. link to original article contains dosing details in abstract PubMed NCT03080805
6. DESTINY-Breast02: André F, Hee Park Y, Kim SB, Takano T, Im SA, Borges G, Lima JP, Aksoy S, Gavila Gregori J, De Laurentiis M, Bianchini G, Roylance R, Miyoshi Y, Armstrong A, Sinha R, Ruiz Borrego M, Lim E, Ettl J, Yerushalmi R, Zagouri F, Duhoux FP, Fehm T, Gambhire D, Cathcart J, Wu C, Chu C, Egorov A, Krop I. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773-1785. Epub 2023 Apr 20. link to original article contains dosing details in abstract PubMed NCT03523585
   1. PRO analysis: Fehm T, Cottone F, Dunton K, André F, Krop I, Park YH, De Laurentiis M, Miyoshi Y, Armstrong A, Borrego MR, Yerushalmi R, Duhoux FP, Takano T, Lu W, Egorov A, Kim SB. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024 May;25(5):614-625. link to original article PubMed

Capecitabine & Margetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (E-RT-switch-ic)	1a. Eribulin & Trastuzumab 1b. Gemcitabine & Trastuzumab 1c. VH 1d. XH	Seems to have superior PFS (primary endpoint) Median PFS: 6 vs 5 mo (HR 0.76, 95% CI 0.59-0.98) Did not meet secondary endpoint of OS1 Median OS: 21.6 vs 21.9 mo (HR 0.95, 95% CI 0.77-1.17)

¹Reported efficacy is based on the 2022 update.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article PubMed

Capecitabine & Neratinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Saura et al. 2014 (3144A1-2206)	2008-NR	Phase 1/2		ORR: 64%
Saura et al. 2020 (NALA)	2013-2017	Phase 3 (E-RT-switch-ic)	Capecitabine & Lapatinib	Superior PFS (primary endpoint) Median PFS: 8.8 vs 6.6 mo (HR 0.76, 95% CI 0.63-0.93)

Chemotherapy

• Capecitabine (Xeloda) 750 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Neratinib (Nerlynx) 240 mg PO once per day on days 1 to 21

21-day cycles

References

1. 3144A1-2206: Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, Kiger C, Germa C, Wang K, Martin M, Baselga J, Kim SB. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2014 Nov 10;32(32):3626-33. Epub 2014 Oct 6. link to original article contains dosing details in manuscript PubMed NCT00741260
2. NALA: Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. Epub 2020 Jul 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT01808573

Capecitabine & Pyrotinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Xu et al. 2021 (PHOEBE)	2017-07-31 to 2018-10-30	Phase 3 (E-switch-ic)	Capecitabine & Lapatinib	Superior PFS (primary endpoint) Median PFS: 12.5 vs 6.8 mo (HR 0.39, 95% CI 0.27-0.56)

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Pyrotinib (Irene) 400 mg PO once per day on days 1 to 21

21-day cycles

References

1. PHOEBE: Xu B, Yan M, Ma F, Hu X, Feng J, Ouyang Q, Tong Z, Li H, Zhang Q, Sun T, Wang X, Yin Y, Cheng Y, Li W, Gu Y, Chen Q, Liu J, Cheng J, Geng C, Qin S, Wang S, Lu J, Shen K, Liu Q, Wang X, Wang H, Luo T, Yang J, Wu Y, Yu Z, Zhu X, Chen C, Zou J; PHOEBE Investigators. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Mar;22(3):351-360. Epub 2021 Feb 11. link to original article contains dosing details in abstract PubMed NCT03080805

Capecitabine & Trastuzumab (XH)

XH: Xeloda (Capecitabine) & Herceptin (Trastuzumab)

Regimen variant #1, 2000/6, with loading dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (C)	1a. Capecitabine & Margetuximab 1b. Eribulin & Margetuximab 1c. Gemcitabine & Margetuximab 1d. Vinorelbine & Margetuximab	Seems to have inferior PFS
Murthy et al. 2019 (HER2CLIMB)	2016-2019	Phase 3 (C)	XH & Tucatinib	Inferior OS

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 2500/6, with loading dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bartsch et al. 2007	2004-2006	Phase 2
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase 3 (C)	Capecitabine & Lapatanib	Did not meet primary endpoint of CNS metastases as first site of relapse
Urruticoechea et al. 2017 (PHEREXA)	2010-2013	Phase 3 (C)	XHP	Might have inferior PFS
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS
André et al. 2023 (DESTINY-Breast02)	2018-09-06 to 2020-12-31	Phase 3 (C)	T-DXd	Inferior PFS

Note: the only difference between this and the next variant is the use of a loading dose of trastuzumab. The primary endpoint of CEREBEL was incidence of CNS as site of first relapse; this was very low in both arms, with no statistically significant difference.

Prior treatment criteria

• Bartsch et al. 2007: anthracycline and docetaxel or vinorelbine failure and prior trastuzumab exposure
• CEREBEL: prior anthracycline and/or taxanes
• PHEREXA: taxane
• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.
• DESTINY-Breast02: trastuzumab and a taxane

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, 2500/6, no loading dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2009 (GBG 26/BIG 3-05)	2003-NR	Phase 3 (E-esc)	Capecitabine	Seems to have superior TTP (primary endpoint) Median TTP: 8.2 vs 5.6 mo (HR 0.69, 95% CI 0.48-0.97)

Note: This was a continuation of trastuzumab so there is no loading dose.

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycles

References

1. Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, Gnant M, Zielinski CC, Steger GG. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. Epub 2007 Aug 6. link to original article contains dosing details in manuscript PubMed
2. GBG 26/BIG 3-05: von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. link to original article contains dosing details in manuscript PubMed NCT00148876
   1. Update: von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. link to original article PubMed
3. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article contains dosing details in abstract PubMed NCT00820222
4. PHEREXA: Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol. 2017 Sep 10;35(26):3030-3038. Epub 2017 Apr 24. link to original article contains dosing details in manuscript PubMed NCT01026142
5. HER2CLIMB: Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. link to original article contains dosing details in manuscript PubMed NCT02614794
   1. Subgroup analysis: Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. link to original article link to PMC article PubMed
   2. Update: Curigliano G, Mueller V, Borges V, Hamilton E, Hurvitz S, Loi S, Murthy R, Okines A, Paplomata E, Cameron D, Carey LA, Gelmon K, Hortobagyi GN, Krop I, Loibl S, Pegram M, Slamon D, Ramos J, Feng W, Winer E. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022 Mar;33(3):321-329. Epub 2021 Dec 23. link to original article PubMed
6. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article linnk to PMC article PubMed
7. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202
8. DESTINY-Breast02: André F, Hee Park Y, Kim SB, Takano T, Im SA, Borges G, Lima JP, Aksoy S, Gavila Gregori J, De Laurentiis M, Bianchini G, Roylance R, Miyoshi Y, Armstrong A, Sinha R, Ruiz Borrego M, Lim E, Ettl J, Yerushalmi R, Zagouri F, Duhoux FP, Fehm T, Gambhire D, Cathcart J, Wu C, Chu C, Egorov A, Krop I. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773-1785. Epub 2023 Apr 20. link to original article contains dosing details in abstract PubMed NCT03523585
   1. PRO analysis: Fehm T, Cottone F, Dunton K, André F, Krop I, Park YH, De Laurentiis M, Miyoshi Y, Armstrong A, Borrego MR, Yerushalmi R, Duhoux FP, Takano T, Lu W, Egorov A, Kim SB. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024 May;25(5):614-625. link to original article PubMed

Capecitabine & Trastuzumab (XH) & Tucatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Murthy et al. 2019 (HER2CLIMB)	2016-2019	Phase 3 (E-RT-esc)	XH	Superior PFS1 (primary endpoint) Median PFS: 7.6 vs 4.9 mo (HR 0.57, 95% CI 0.47-0.70) Superior OS1 (secondary endpoint) Median OS: 24.7 vs 19.2 mo (HR 0.73, 95% CI 0.59-0.90)

¹Reported efficacy is based on the 2021 update.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Tucatinib (Tukysa) 300 mg PO twice per day on days 1 to 21
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. HER2CLIMB: Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. link to original article contains dosing details in manuscript PubMed NCT02614794
   1. Subgroup analysis: Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. link to original article link to PMC article PubMed
   2. Update: Curigliano G, Mueller V, Borges V, Hamilton E, Hurvitz S, Loi S, Murthy R, Okines A, Paplomata E, Cameron D, Carey LA, Gelmon K, Hortobagyi GN, Krop I, Loibl S, Pegram M, Slamon D, Ramos J, Feng W, Winer E. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022 Mar;33(3):321-329. Epub 2021 Dec 23. link to original article PubMed

Docetaxel & Trastuzumab (TH)

TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1, 60 mg/m² docetaxel

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Prior treatment criteria

• History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 75 mg/m² docetaxel

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Prior treatment criteria

• History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

EHP

EHP: Eribulin, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Eribulin & Margetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (E-RT-switch-ic)	1a. Eribulin & Trastuzumab 1b. Gemcitabine & Trastuzumab 1c. VH 1d. XH	Seems to have superior PFS (primary endpoint) Median PFS: 6 vs 5 mo (HR 0.76, 95% CI 0.59-0.98) Did not meet secondary endpoint of OS1 Median OS: 21.6 vs 21.9 mo (HR 0.95, 95% CI 0.77-1.17)

¹Reported efficacy is based on the 2022 update.

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article link to PMC article PubMed

Eribulin & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (C)	1a. Capecitabine & Margetuximab 1b. Eribulin & Margetuximab 1c. Gemcitabine & Margetuximab 1d. Vinorelbine & Margetuximab	Seems to have inferior PFS
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article PubMed
2. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Gemcitabine & Margetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (E-RT-switch-ic)	1a. Eribulin & Trastuzumab 1b. Gemcitabine & Trastuzumab 1c. VH 1d. XH	Seems to have superior PFS (primary endpoint) Median PFS: 6 vs 5 mo (HR 0.76, 95% CI 0.59-0.98) Did not meet secondary endpoint of OS1 Median OS: 21.6 vs 21.9 mo (HR 0.95, 95% CI 0.77-1.17)

¹Reported efficacy is based on the 2022 update.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article PubMed

Gemcitabine & Trastuzumab

Regimen variant #1, 1000/q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (C)	1a. Capecitabine & Margetuximab 1b. Eribulin & Margetuximab 1c. Gemcitabine & Margetuximab 1d. Vinorelbine & Margetuximab	Seems to have inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 1200/q3wk trastuzumab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, weekly trastuzumab

Study	Dates of enrollment	Evidence
O'Shaughnessy et al. 2004	1999-04 to 2001-07	Phase 2

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycles

References

1. O'Shaughnessy JA, Vukelja S, Marsland T, Kimmel G, Ratnam S, Pippen JE. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer. 2004 Jun;5(2):142-7. link to original article contains dosing details in abstract PubMed
2. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article PubMed
3. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

GHP

GHP: Gemcitabine, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Lapatinib & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Blackwell et al. 2010 (EGF104900)	2005-11 to 2006-11	Phase 3 (E-esc)	Lapatinib	Superior PFS1 (primary endpoint) Median PFS: 11.1 vs 8.1 weeks (HR 0.74, 95% CI 0.58-0.94) Seems to have superior OS1 (secondary endpoint) Median OS: 14 vs 9.5 mo (HR 0.74, 95% CI 0.57-0.97)

¹Reported efficacy is based on the 2012 update.

Targeted therapy

• Lapatinib (Tykerb) 1000 mg PO once per day on days 1 to 7
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1,
  • Cycle 2 onwards: 2 mg/kg IV once on day 1

7-day cycles

References

1. EGF104900: Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. Epub 2010 Feb 1. link to original article contains dosing details in manuscript PubMed NCT00320385
   1. Update: Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. Epub 2012 Jun 11. link to original article PubMed

Paclitaxel & Trastuzumab (TH)

TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Paclitaxel, Pertuzumab, Trastuzumab emtansine

Regimen variant #1, q3wk T-DM1

Study	Dates of enrollment	Evidence
Krop et al. 2016 (TDM4652g)	2009-NR	Phase 1b/2a

Note: this is the MTD.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

Antibody-drug conjugate therapy

• Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, weekly T-DM1

Study	Dates of enrollment	Evidence
Krop et al. 2016 (TDM4652g)	2009-NR	Phase 1b/2a

Note: this is the MTD.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

Antibody-drug conjugate therapy

• Trastuzumab emtansine (Kadcyla) 2.4 mg/kg IV once per day on days 1, 8, 15

21-day cycles

References

1. TDM4652g: Krop IE, Modi S, LoRusso PM, Pegram M, Guardino E, Althaus B, Lu D, Strasak A, Elias A. Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res. 2016 Mar 15;18(1):34. link to original article link to PMC article contains dosing details in abstract PubMed

nab-Paclitaxel & Trastuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 220 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

nab-Paclitaxel, Pertuzumab, Trastuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 220 mg/m² IV once on day 1

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m² IV once on day 1

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Pertuzumab & Trastuzumab

Regimen variant #1, q3wk trastuzumab

Study	Dates of enrollment	Evidence
Baselga et al. 2010 (NCI-P6660)	2005-NR	Phase 2

Targeted therapy

• Pertuzumab (Perjeta) as follows, given second:
  • Cycle 1: 840 mg IV once on day 2
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Loading dose: 8 mg/kg IV once on day -28 (that is, 28 days before the start of cycle 1)
  • Cycle 1 onwards: 6 mg/kg IV once on day 1, given first

21-day cycle for 8 cycles Treatment can be continued if there is no progressive disease.

Regimen variant #2, weekly trastuzumab

Study	Dates of enrollment	Evidence
Baselga et al. 2010 (NCI-P6660)	2005-NR	Phase 2

Targeted therapy

• Pertuzumab (Perjeta) given second as follows:
  • Cycle 1: 840 mg IV once on day 2
  • Cycles 2 to 8: 420 mg IV once on day 1
• Trastuzumab (Herceptin) given first as follows:
  • Cycle 0: 4 mg/kg IV once on day -28 (that is, 28 days before the start of cycle 1)
  • Cycles 1 to 8: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 8 cycles; treatment can be continued if there is no progressive disease

References

1. NCI-P6660: Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P, Gianni L. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010 Mar 1;28(7):1138-44. Epub 2010 Feb 1. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00301899

THP (Docetaxel)

THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

THP (Paclitaxel)

THP: Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Trastuzumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Cobleigh et al. 1999	1995-04 to 1996-09	Phase 2 (RT)

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 2 mg/kg IV over 30 minutes once on day 1

7-day cycles

References

1. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999 Sep;17(9):2639-48. link to original article contains dosing details in manuscript PubMed

Trastuzumab deruxtecan monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Modi et al. 2019 (DESTINY-Breast01)	2017-2018	Phase 2 (RT)
Cortés et al. 2022 (DESTINY-Breast03)	2018-2020	Phase 3 (E-RT-switch-ic)	T-DM1	Superior PFS (primary endpoint) PFS12: 75.8% vs 34.1% (HR 0.28, 95% CI 0.22-0.37) Superior OS1 (secondary endpoint) Median OS: NYR vs NYR (HR 0.64, 95% CI 0.47-0.87)
André et al. 2023 (DESTINY-Breast02)	2018-09-06 to 2020-12-31	Phase 3 (E-switch-ooc)	Investigator's choice of: 1a. Capecitabine & Lapatinib 1b. XH	Superior PFS (primary endpoint) Median PFS: 17.8 vs 6.9 mo (HR 0.36, 95% CI 0.28-0.45)

¹Reported efficacy is based on the 2022 update.

Prior treatment criteria

• DESTINY-Breast01 & DESTINY-Breast02: Refractory to trastuzumab emtansine
• DESTINY-Breast03: Trastuzumab and taxane

Antibody-drug conjugate therapy

• Trastuzumab deruxtecan (Enhertu) 5.4 mg/kg IV once on day 1

21-day cycles

References

1. DESTINY-Breast01: Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. Epub 2019 Dec 11. link to original article contains dosing details in abstract link to PMC article PubMed NCT03248492
   1. Update: Saura C, Modi S, Krop I, Park YH, Kim SB, Tamura K, Iwata H, Tsurutani J, Sohn J, Mathias E, Liu Y, Cathcart J, Singh J, Yamashita T. Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01). Ann Oncol. 2024 Mar;35(3):302-307. Epub 2023 Dec 11. link to original article PubMed
2. DESTINY-Breast03: Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Huang CS, Kim JH, Chiu JWY, Pedrini JL, Lee C, Liu Y, Cathcart J, Bako E, Verma S, Hurvitz SA; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. link to original article contains dosing details in manuscript PubMed NCT03529110
   1. Update: Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, Chiu JWY, Xu B, Hamilton E, Madhusudan S, Iwata H, Altintas S, Henning JW, Curigliano G, Perez-Garcia JM, Kim SB, Petry V, Huang CS, Li W, Frenel JS, Antolin S, Yeo W, Bianchini G, Loi S, Tsurutani J, Egorov A, Liu Y, Cathcart J, Ashfaque S, Cortés J. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023 Jan 14;401(10371):105-117. Epub 2022 Dec 7. link to original article PubMed
   2. PRO analysis: Curigliano G, Dunton K, Rosenlund M, Janek M, Cathcart J, Liu Y, Fasching PA, Iwata H. Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Ann Oncol. 2023 Jul;34(7):569-577. Epub 2023 May 12. link to original article PubMed
   3. Subgroup analysis: Hurvitz SA, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Egorov A, Liu Y, Cathcart J, Bako E, Tecson K, Verma S, Cortés J. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open. 2024 May;9(5):102924. Epub 2024 Apr 24. link to original article PubMed
3. DESTINY-Breast02: André F, Hee Park Y, Kim SB, Takano T, Im SA, Borges G, Lima JP, Aksoy S, Gavila Gregori J, De Laurentiis M, Bianchini G, Roylance R, Miyoshi Y, Armstrong A, Sinha R, Ruiz Borrego M, Lim E, Ettl J, Yerushalmi R, Zagouri F, Duhoux FP, Fehm T, Gambhire D, Cathcart J, Wu C, Chu C, Egorov A, Krop I. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773-1785. Epub 2023 Apr 20. link to original article contains dosing details in abstract PubMed NCT03523585
   1. PRO analysis: Fehm T, Cottone F, Dunton K, André F, Krop I, Park YH, De Laurentiis M, Miyoshi Y, Armstrong A, Borrego MR, Yerushalmi R, Duhoux FP, Takano T, Lu W, Egorov A, Kim SB. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024 May;25(5):614-625. link to original article PubMed

Trastuzumab emtansine monotherapy

T-DM1: Trastuzumab-DM1 (Trastuzumab emtansine)

Example orders

• Example orders for trastuzumab emtansine (Kadcyla) in breast cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Verma et al. 2012 (EMILIA)	2009-2011	Phase 3 (E-RT-switch-ooc)	Capecitabine & Lapatinib	Superior OS1 (co-primary endpoint) Median OS: 29.9 vs 25.9 mo (HR 0.75, 95% CI 0.64-0.88)
Krop et al. 2014 (TH3RESA)	2011-09-14 to 2012-11-19	Phase 3 (E-switch-ooc)	Physician's choice	Superior OS2 (co-primary endpoint) Median OS: 22.7 vs 15.8 mo (HR 0.68, 95% CI 0.54-0.85)
Cortés et al. 2022 (DESTINY-Breast03)	2018-2020	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS

¹Reported efficacy for EMILIA is based on the 2017 update.
²Reported efficacy for TH3RESA is based on the 2017 update.

Antibody-drug conjugate therapy

• Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

References

1. EMILIA: Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00829166
   1. PRO analysis: Welslau M, Diéras V, Sohn JH, Hurvitz SA, Lalla D, Fang L, Althaus B, Guardino E, Miles D. Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer. 2014 Mar 1;120(5):642-51. Epub 2013 Nov 12. link to original article PubMed
   2. Update: Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):732-742. Epub 2017 May 16. link to original article link to PMC article PubMed
2. TH3RESA: Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H; TH3RESA study collaborators. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):689-99. Epub 2014 May 2. link to original article contains dosing details in abstract PubMed NCT01419197
   1. Update: Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017 Jun;18(6):743-754. Epub 2017 May 16. link to original article PubMed
3. DESTINY-Breast03: Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Huang CS, Kim JH, Chiu JWY, Pedrini JL, Lee C, Liu Y, Cathcart J, Bako E, Verma S, Hurvitz SA; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. link to original article contains dosing details in manuscript PubMed NCT03529110
   1. Update: Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, Chiu JWY, Xu B, Hamilton E, Madhusudan S, Iwata H, Altintas S, Henning JW, Curigliano G, Perez-Garcia JM, Kim SB, Petry V, Huang CS, Li W, Frenel JS, Antolin S, Yeo W, Bianchini G, Loi S, Tsurutani J, Egorov A, Liu Y, Cathcart J, Ashfaque S, Cortés J. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023 Jan 14;401(10371):105-117. Epub 2022 Dec 7. link to original article PubMed
   2. PRO analysis: Curigliano G, Dunton K, Rosenlund M, Janek M, Cathcart J, Liu Y, Fasching PA, Iwata H. Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Ann Oncol. 2023 Jul;34(7):569-577. Epub 2023 May 12. link to original article PubMed
   3. Subgroup analysis: Hurvitz SA, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Egorov A, Liu Y, Cathcart J, Bako E, Tecson K, Verma S, Cortés J. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open. 2024 May;9(5):102924. Epub 2024 Apr 24. link to original article PubMed

Vinorelbine & Margetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (E-RT-switch-ic)	1a. Eribulin & Trastuzumab 1b. Gemcitabine & Trastuzumab 1c. VH 1d. XH	Seems to have superior PFS (primary endpoint) Median PFS: 6 vs 5 mo (HR 0.76, 95% CI 0.59-0.98) Did not meet secondary endpoint of OS1 Median OS: 21.6 vs 21.9 mo (HR 0.95, 95% CI 0.77-1.17)

¹Reported efficacy is based on the 2022 update.

Chemotherapy

• Vinorelbine (Navelbine) 25 to 30 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article PubMed

Vinorelbine & Trastuzumab (VH)

VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen variant #1, 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (C)	1a. Capecitabine & Margetuximab 1b. Eribulin & Margetuximab 1c. Gemcitabine & Margetuximab 1d. Vinorelbine & Margetuximab	Seems to have inferior PFS
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (C)	1a. THP (Docetaxel) 1b. THP (Paclitaxel) 1c. nab-Paclitaxel, Pertuzumab, Trastuzumab 1d. VHP 1e. EHP 1f. XHP 1g. GHP	Might have inferior OS

Note: this is the lower bound of vinorelbine dosing specified in SOPHIA.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase 3 (C)	1a. Capecitabine & Margetuximab 1b. Eribulin & Margetuximab 1c. Gemcitabine & Margetuximab 1d. Vinorelbine & Margetuximab	Seems to have inferior PFS

Note: this is the upper bound of vinorelbine dosing specified in SOPHIA.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
André et al. 2014 (BOLERO-3)	2009-2012	Phase 3 (C)	VH & Everolimus	Inferior PFS
Harbeck et al. 2016 (LUX-Breast 1)	2010-2013	Phase 3 (C)	Afatinib & Vinorelbine	Did not meet primary endpoint of PFS Median PFS: 5.6 vs 5.5 mo (HR 0.91, 95% CI 0.71-1.16)

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1
  • Cycle 2 onwards: 2 mg/kg IV once on day 1

7-day cycles

References

1. BOLERO-3: André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. link to original article PubMed NCT01007942
2. LUX-Breast 1: Harbeck N, Huang CS, Hurvitz S, Yeh DC, Shao Z, Im SA, Jung KH, Shen K, Ro J, Jassem J, Zhang Q, Im YH, Wojtukiewicz M, Sun Q, Chen SC, Goeldner RG, Uttenreuther-Fischer M, Xu B, Piccart-Gebhart M; LUX-Breast 1 study group. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):357-66. Epub 2016 Jan 26. link to original article contains dosing details in manuscript PubMed NCT01125566
3. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02492711
   1. Update: Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Bachelot T, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Schwartz GN, Pluard TJ, Ricci F, Gwin WR 3rd, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Gal-Yam EN, Yerushalmi R, Fasching PA, Kaufman PA, Ashley EJ, Perez-Olle R, Hong S, Rosales MK, Gradishar WJ; SOPHIA Study Group. Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial. J Clin Oncol. 2023 Jan 10;41(2):198-205. Epub 2022 Nov 4. link to original article link to PMC article PubMed
4. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202
5. SWOG-S0347: NCT00103233

Vinorelbine & Trastuzumab (VH) & Everolimus

VH & Everolimus: Vinorelbine, Herceptin (Trastuzumab), Everolimus

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
André et al. 2014 (BOLERO-3)	2009-2012	Phase 3 (E-esc)	VH	Superior PFS (primary endpoint) Median PFS: 7 vs 5.8 mo (HR 0.78, 95% CI 0.65-0.95)

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1
  • Cycle 2 onwards: 2 mg/kg IV once on day 1
• Everolimus (Afinitor) 5 mg PO once per day on days 1 to 7

7-day cycles

References

1. BOLERO-3: André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. link to original article PubMed NCT01007942

VHP

VHP: Vinorelbine, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

XHP

XHP: Xeloda (Capecitabine), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Urruticoechea et al. 2017 (PHEREXA)	2010-2013	Phase 3 (E-esc)	Capecitabine & Trastuzumab	Might have superior PFS (primary endpoint) Median PFS: 11.1 vs 9 mo (HR 0.82, 95% CI 0.65-1.02)
Yamamoto et al. 2022 (PRECIOUS)	2015-2018	Phase 3 (E-esc)	1a. TH (Docetaxel) 1b. TH (Paclitaxel) 1c. nab-Paclitaxel & Trastuzumab 1d. VH 1e. EH 1f. XH 1g. GH	Might have superior OS1 (secondary endpoint) Median OS: 28.8 vs 23.4 mo (HR 0.71, 95% CI NA-1.03) Seems to have superior PFS (primary endpoint) Median PFS: 5.3 vs 4.2 mo (sHR 0.76, 95% CI NA-0.97)

¹Results are based on a one-sided statistical analysis.

Prior treatment criteria

• PRECIOUS: History of pertuzumab and trastuzumab‐containing chemotherapy; pertuzumab not permitted in the regimen immediately prior to this.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PHEREXA: Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol. 2017 Sep 10;35(26):3030-3038. Epub 2017 Apr 24. link to original article contains dosing details in manuscript PubMed NCT01026142
2. PRECIOUS: Yamamoto Y, Iwata H, Taira N, Masuda N, Takahashi M, Yoshinami T, Ueno T, Toyama T, Yamanaka T, Takano T, Kashiwaba M, Tsugawa K, Hasegawa Y, Tamura K, Tada H, Hara F, Fujisawa T, Niikura N, Saji S, Morita S, Toi M, Ohno S. Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS). Cancer Sci. 2022 Sep;113(9):3169-3179. Epub 2022 Jul 23. link to original article link to PMC article contains dosing details in supplement PubMed UMIN000018202

Maintenance for metastatic or unresectable disease

Pertuzumab & Trastuzumab

Regimen

Study	Dates of enrollment	Evidence
Baselga et al. 2011 (CLEOPATRA)	2008-2010	Non-randomized part of phase 3 RCT

Preceding treatment

• First-line THP (Docetaxel) for at least 6 cycles

Targeted therapy

• Pertuzumab (Perjeta) 420 mg IV once on day 1
• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycles

References

1. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. HRQoL analysis: Cortés J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. Epub 2013 Jul 17. link to original article PubMed
   3. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article link to PMC article PubMed
   4. Update: Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. link to original article PubMed

Trastuzumab monotherapy

Regimen variant #1, q3wk dosing

Study	Dates of enrollment	Evidence
Perez et al. 2005 (NCCTG 983252)	1999-04 to 2003-07	Phase 2
Valero et al. 2010 (BCIRG 007)	2001-2004	Non-randomized part of phase 3 RCT
Baselga et al. 2011 (CLEOPATRA)	2008-2010	Non-randomized part of phase 3 RCT
Gelmon et al. 2015 (NCIC-CTG MA.31)	2008-2011	Non-randomized part of phase 3 RCT

Preceding treatment

• NCCTG 983252: First-line TPC (q3wk) x 8
• BCIRG 007: First-line TH (Docetaxel) x 8 versus TCH (Taxotere) x 8
• CLEOPATRA: First-line TH (Docetaxel)
• NCIC-CTG MA.31: First-line TH (Paclitaxel) x 6 or TH (Docetaxel) x 8

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, weekly dosing

Study	Dates of enrollment	Evidence
Robert et al. 2006	1998-2002	Non-randomized part of phase 3 RCT
Perez et al. 2005 (NCCTG 983252)	1999-04 to 2003-07	Phase 2
Marty et al. 2005 (M77001)	2000-2002	Non-randomized part of phase 2 RCT

Preceding treatment

• M77001: First-line TH (Docetaxel) for at least 6 cycles
• NCCTG 983252: First-line TPC (weekly) x 6
• Robert et al. 2006: First-line TP x 6 versus TPC x 6

Targeted therapy

• Trastuzumab (Herceptin) 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. M77001: Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains dosing details in manuscript PubMed
2. NCCTG 983252: Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. link to original article PubMed
3. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article PubMed
4. BCIRG 007: Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains dosing details in manuscript PubMed NCT00047255
5. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. HRQoL analysis: Cortés J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. Epub 2013 Jul 17. link to original article PubMed
   3. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article link to PMC article PubMed
   4. Update: Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. link to original article PubMed
6. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article contains dosing details in manuscript PubMed NCT00667251

Additional resources

• Gail model Breast Cancer Risk Assessment Tool
  • Gail model breast cancer risk factors
• Breast cancer BRCA1 & BRCA2 genetic testing
• My Cancer Genome