Breast cancer, triple negative

Section editor transclusions Note: this page has regimens which are specific to breast cancer that is triple negative. Please see the breast cancer page for other chemotherapy regimens.

46 regimens on this page 66 variants on this page

Guidelines

ASCO

• 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline
• 2016: 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
• 2015: Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical practice guideline

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

Older

• 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017
• 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

Neoadjuvant chemotherapy

Cyclophosphamide & Doxorubicin (AC)

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AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2016 (I-SPY 2)	2010-2012	Non-randomized portion of RCT
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (C)	AC & Pembrolizumab	Inferior 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

• I-SPY 2: T x 12 wk versus Paclitaxel & VC x 12 wk
• KEYNOTE-522: Carboplatin & Paclitaxel x 4

Chemotherapy

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

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. I-SPY 2: Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol link to PMC article PubMed NCT01042379
2. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article PubMed NCT03036488

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

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ddAC: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Sikov et al. 2014 (CALGB 40603)	2009-2012	Non-randomized portion of RCT
Rugo et al. 2016 (I-SPY 2)	2010-2012	Non-randomized portion of 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

• CALGB 40603: Carboplatin & Bevacizumab x 4 versus Carboplatin & Paclitaxel x 4 versus Carboplatin, Paclitaxel, Bevacizumab versus T x 12 wk
• I-SPY2: T x 12 wk versus Paclitaxel & VC x 12 wk

Chemotherapy

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

Supportive medications

• G-CSF

14-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. CALGB 40603: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. Epub 2014 Aug 4. link to original article link to PMC article contains verified protocol PubMed NCT00861705
2. I-SPY 2: Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol link to PMC article PubMed NCT01042379
3. IMpassion031: Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020 Sep 18:S0140-6736(20)31953-X. Epub ahead of print. link to original article PubMed NCT03197935

ddAC & Atezolizumab

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ddAC & Atezolizumab: dose-dense Adriamycin (Doxorubicin), Cyclophosphamide, Atezolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mittendorf et al. 2020 (IMpassion031)	2017-2019	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.

Preceding treatment

• nab-Paclitaxel & Atezolizumab

Chemotherapy

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

Immunotherapy

• Atezolizumab (Tecentriq) 840 mg IV once on day 1

Supportive medications

• G-CSF

14-day cycle for 4 cycles

Subsequent treatment

• Surgery, then Atezolizumab x 11

References

1. IMpassion031: Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020 Sep 18:S0140-6736(20)31953-X. Epub ahead of print. link to original article contains verified protocol PubMed NCT03197935

AC & Pembrolizumab

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AC & Pembrolizumab: Adriamycin (Doxorubicin), Cyclophosphamide, Pembrolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (E-RT-esc)	AC	Superior 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

• Carboplatin, Paclitaxel, Pembrolizumab x 4

Chemotherapy

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

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery, then Pembrolizumab x 9

References

1. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article contains verified protocol PubMed NCT03036488

Carboplatin & Docetaxel

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CbD: Carboplatin & Docetaxel

Regimen

Study	Years of enrollment	Evidence	Efficacy
Sharma et al. 2016 (GOMHGUGM022011)	2010-2015	Phase II	56-59% pCR rate
Sharma et al. 2016 (PROGECT)	2011-2015	Phase II	56-59% pCR rate

Note: Sharma et al. 2016 was a combined analysis of two separate clinical trials.

Chemotherapy

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

21-day cycle for 6 cycles

Subsequent treatment

• Surgery

References

1. PROGECT: Sharma P, López-Tarruella S, García-Saenz JA, Ward C, Connor CS, Gómez HL, Prat A, Moreno F, Jerez-Gilarranz Y, Barnadas A, Picornell AC, Del Monte-Millán M, Gonzalez-Rivera M, Massarrah T, Pelaez-Lorenzo B, Palomero MI, González Del Val R, Cortes J, Fuentes Rivera H, Bretel Morales D, Márquez-Rodas I, Perou CM, Wagner JL, Mammen JM, McGinness MK, Klemp JR, Amin AL, Fabian CJ, Heldstab J, Godwin AK, Jensen RA, Kimler BF, Khan QJ, Martin M. Efficacy of neoadjuvant carboplatin plus docetaxel in triple-negative breast cancer: Combined analysis of two cohorts. Clin Cancer Res. 2017 Feb 1;23(3):649-657. Epub 2016 Jun 14. link to original article contains protocol link to PMC article PubMed NCT02302742
2. GOMHGUGM022011: Sharma P, López-Tarruella S, García-Saenz JA, Ward C, Connor CS, Gómez HL, Prat A, Moreno F, Jerez-Gilarranz Y, Barnadas A, Picornell AC, Del Monte-Millán M, Gonzalez-Rivera M, Massarrah T, Pelaez-Lorenzo B, Palomero MI, González Del Val R, Cortes J, Fuentes Rivera H, Bretel Morales D, Márquez-Rodas I, Perou CM, Wagner JL, Mammen JM, McGinness MK, Klemp JR, Amin AL, Fabian CJ, Heldstab J, Godwin AK, Jensen RA, Kimler BF, Khan QJ, Martin M. Efficacy of neoadjuvant carboplatin plus docetaxel in triple-negative breast cancer: Combined analysis of two cohorts. Clin Cancer Res. 2017 Feb 1;23(3):649-657. Epub 2016 Jun 14. link to original article contains protocol link to PMC article PubMed NCT01560663
3. CH-BC-007: NCT01150513

Carboplatin & Paclitaxel (CP)

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Regimen variant #1, 5/80

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
(PARTNER)	2016-ongoing	Phase 3 (C)	CP & Olaparib	In progress

Note: Dosing information is from CT.gov.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #2, 6/80

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sikov et al. 2014 (CALGB 40603)	2009-2012	Phase 3 (E-esc)	Paclitaxel	Superior pCR rate
Loibl et al. 2018 (BrighTNess)	2014-2016	Phase 3 (E-esc)	1. CP & Veliparib	Did not meet primary endpoint of pCR rate
			2. Paclitaxel	Not reported in abstract

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

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• CALGB 40603: ddAC x 4, then surgery
• BrighTNess: AC x 4 or ddAC x 4, then surgery

References

1. CALGB 40603: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. Epub 2014 Aug 4. link to original article link to PMC article contains verified protocol PubMed NCT00861705
2. BrighTNess: Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):497-509. Epub 2018 Feb 28. link to original article contain protocol PubMed NCT02032277
3. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article PubMed NCT03036488
4. PARTNER: NCT03150576

Carboplatin & Paclitaxel (CP) & Pembrolizumab

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Regimen variant #1, q3wk carboplatin

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (E-RT-esc)	Carboplatin & Paclitaxel	Superior 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.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• AC & Pembrolizumab x 4 or EC & Pembrolizumab x 4, then surgery, then Pembrolizumab x 9

Regimen variant #2, weekly carboplatin

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (E-RT-esc)	Carboplatin & Paclitaxel	Superior 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.

Chemotherapy

• Carboplatin (Paraplatin) AUC 1.5 IV once per day on days 1, 8, 15
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• AC & Pembrolizumab x 4 or EC & Pembrolizumab x 4, then surgery, then Pembrolizumab x 9

References

1. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article contains verified protocol PubMed NCT03036488

Carboplatin & nab-Paclitaxel

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gluz et al. 2018 (WSG-ADAPT-TN)	2013-2015	Phase III (E-switch-ic)	Gemcitabine & nab-Paclitaxel	Superior pCR rate

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1 & 8
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. WSG-ADAPT-TN: Gluz O, Nitz U, Liedtke C, Christgen M, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, von Schumann R, Kates R, Kates R, Schumacher J, Wuerstlein R, Kreipe HH, Harbeck N; West German Study Group. Comparison of neoadjuvant nab-paclitaxel+carboplatin vs nab-paclitaxel+gemcitabine in triple-negative breast cancer: randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst. 2018 Jun 1;110(6):628-637. link to original article contains verified protocol PubMed NCT01815242

Cisplatin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Silver et al. 2010 (DFCI 04-183)	2004-NR	Phase II	50% good pathologic response

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. DFCI 04-183: Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, Garber JE. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1145-53. Epub 2010 Jan 25. link to original article contains verified protocol link to PMC article PubMed NCT00148694

Cisplatin & Bevacizumab

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Regimen

Study	Evidence	Efficacy
Ryan et al. 2009	Phase II	26% clinical CR

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) as follows:
  • Cycles 1 to 3: 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. Abstract: P. D. Ryan, N. M. Tung, S. J. Isakoff, M. Golshan, A. Richardson, A. D. Corben, B. L. Smith, R. Gelman, E. P. Winer, and J. E. Garber. Neoadjuvant cisplatin and bevacizumab in triple negative breast cancer (TNBC): Safety and efficacy. Journal of Clinical Oncology 2009 27:15_suppl, 551-551. link to abstract

Docetaxel & Bevacizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2012 (GeparQuinto)	2007-2010	Phase III (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.

Preceding treatment

• EC & Bevacizumab x 4

Chemotherapy

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

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. GeparQuinto: von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Group. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article contains verified protocol PubMed NCT00567554

Cyclophosphamide & Epirubicin (EC)

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EC: Epirubicin & Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (C)	EC & Pembrolizumab	Inferior 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

• Carboplatin & Paclitaxel x 4

Chemotherapy

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

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article PubMed NCT03036488

Cyclophosphamide & Epirubicin (EC) & Bevacizumab

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EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2012 (GeparQuinto)	2007-2010	Phase III (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.

Chemotherapy

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

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Docetaxel & Bevacizumab, then surgery

References

1. GeparQuinto: von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Group. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article contains verified protocol PubMed NCT00567554

Cyclophosphamide & Epirubicin (EC) & Pembrolizumab

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EC & Pembrolizumab: Epirubicin, Cyclophosphamide, Pembrolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (E-RT-esc)	EC	Superior 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

• Carboplatin, Paclitaxel, Pembrolizumab x 4

Chemotherapy

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

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery, then Pembrolizumab x 9

References

1. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article contains verified protocol PubMed NCT03036488

nab-Paclitaxel & Atezolizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mittendorf et al. 2020 (IMpassion031)	2017-2019	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.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1 & 8

Immunotherapy

• Atezolizumab (Tecentriq) 840 mg IV once on day 1

14-day cycle for 6 cycles

Subsequent treatment

• ddAC & Atezolizumab x 4, then Surgery

References

1. IMpassion031: Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020 Sep 18:S0140-6736(20)31953-X. Epub ahead of print. link to original article contains verified protocol PubMed NCT03197935

Paclitaxel monotherapy

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T: Taxol (Paclitaxel)
wP: weekly Paclitaxel

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sikov et al. 2014 (CALGB 40603)	2009-2012	Phase 3 (C)	Carboplatin & Paclitaxel Carboplatin, Paclitaxel, Bevacizumab Paclitaxel & Bevacizumab	Inferior pCR rate
Rugo et al. 2016 (I-SPY 2)	2010-2012	Adaptively Randomized Phase II (C)	Paclitaxel & VC	Seems to have inferior pCR rate
Loibl et al. 2018 (BrighTNess)	2014-2016	Phase 3 (C)	1. Carboplatin & Paclitaxel	Not reported in abstract
			2. CP & Veliparib	Inferior 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.

Chemotherapy

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

28-day cycle for 3 cycles

Subsequent treatment

• CALGB 40603: ddAC x 4, then surgery
• I-SPY2 & BrighTNess: AC x 4 or ddAC x 4, then surgery

References

1. CALGB 40603: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. Epub 2014 Aug 4. link to original article link to PMC article contains verified protocol PubMed NCT00861705
2. I-SPY 2: Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol link to PMC article PubMed NCT01042379
3. BrighTNess: Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):497-509. Epub 2018 Feb 28. link to original article contain protocol PubMed NCT02032277

Neoadjuvant response criteria

Clinical response rate (cRR)

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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

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• 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)

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• 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)

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• 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

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• 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

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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

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

Adjuvant chemotherapy

Cyclophosphamide & Doxorubicin (AC)

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AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1990 (NSABP B-15)	1984-1988	Phase 3 (E-RT-de-esc)	1. AC, then CMF	Did not meet primary endpoints of DFS/OS
			2. CMF	Did not meet primary endpoints of DFS/OS
Yardley et al. 2017 (TITAN - breast)	2008-2011	Non-randomized portion of RCT

Note: NSABP B-15 was conducted prior to routine testing of HER2, so it technically included "double-negative" patients. TITAN is labeled "TITAN - breast" so as not to confuse it with the trial by the same name in NSCLC.

Preceding treatment

• Surgery

Chemotherapy

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

21-day cycle for 4 cycles

Subsequent treatment

• TITAN: Ixabepilone versus Paclitaxel

References

1. NSABP B-15: Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG, Shibata H, Paterson AHG, Sutherland CM, Robert NJ, Ager PJ, Levy L, Wolter J, Wozniak T, Fisher ER, Deutsch M. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. link to original article contains verified protocol PubMed
   1. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
2. TITAN: Yardley DA, Arrowsmith ER, Daniel BR, Eakle J, Brufsky A, Drosick DR, Kudrik F, Bosserman LD, Keaton MR, Goble SA, Bubis JA, Priego VM, Pendergrass K, Manalo Y, Bury M, Gravenor DS, Rodriguez GI, Inhorn RC, Young RR, Harwin WN, Silver C, Hainsworth JD, Burris HA 3rd. TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):649-658. Epub 2017 May 15. link to original article contains verified protocol PubMed NCT00789581

Bevacizumab-containing therapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cameron et al. 2013 (BEATRICE)	2007-2010	Phase 3 (E-esc)	Standard adjuvant therapy	Did not meet primary endpoint of IDFS

This is the negative experimental arm of an important negative trial, so is included here for historical reference purposes, only.

Preceding treatment

• Surgery

Chemotherapy

• Standard chemotherapy (not specified)

Targeted therapy

• Bevacizumab (Avastin)

References

1. BEATRICE: Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger GG, Suter TM, Toi M, Parmar M, Laeufle R, Im YH, Romieu G, Harvey V, Lipatov O, Pienkowski T, Cottu P, Chan A, Im SA, Hall PS, Bubuteishvili-Pacaud L, Henschel V, Deurloo RJ, Pallaud C, Bell R. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013 Sep;14(10):933-42. Epub 2013 Aug 7. link to original article PubMed NCT00528567
   1. Update: Bell R, Brown J, Parmar M, Toi M, Suter T, Steger GG, Pivot X, Mackey J, Jackisch C, Dent R, Hall P, Xu N, Morales L, Provencher L, Hegg R, Vanlemmens L, Kirsch A, Schneeweiss A, Masuda N, Overkamp F, Cameron D. Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. Ann Oncol. 2017 Apr 1;28(4):754-760. link to original article PubMed

Capecitabine monotherapy

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Regimen variant #1, 1300 mg/m²/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2021 (SYSUCC-001)	2010-2016	Phase 3 (E-esc)	Observation	Seems to have superior DFS

Note: this is a continuous (uninterrupted) dosing schema.

Preceding treatment

• "Standard adjuvant therapy"

Chemotherapy

• Capecitabine (Xeloda) 650 mg/m² PO twice per day

28-day cycle for 13 cycles (1 year)

Regimen variant #2, 2000 mg/m²/day x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mayer et al. 2021 (ECOG-ACRIN EA1131)	2015-2021	Phase 3 (C)	1. Carboplatin 2. Cisplatin	Inconclusive whether non-inferior iDFS

Preceding treatment

• At least one cycle of taxane with or without anthracycline, then surgery

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day

21-day cycle for 6 cycles

Regimen variant #3, 2000 mg/m²/day x 8

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lluch et al. 2019 (GEICAM/2003-11; CIBOMA/2004-01)	2006-2011	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of DFS

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day

21-day cycle for 8 cycles

Regimen variant #4, 2500 mg/m²/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Masuda et al. 2017 (CREATE-X)	2007-2012	Phase 3 (E-esc)	Standard therapy	Superior OS

Note: All patients in CREATE-X had residual disease at time of surgical resection. Although this trial was not specifically for TNBC, a large number (N=286) of enrolled patients had TNBC, and the survival benefit appeared limited to this group in the subgroup analysis.

Preceding treatment

• Neoadjuvant chemotherapy containing anthracycline, taxane, or both, then surgery

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for 6 to 8 cycles

References

1. CREATE-X: Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M. Adjuvant capecitabine for breast cancer after preoperative chemotherapy; Japan Breast Cancer Research Group; Korean Breast Cancer Study Group; Korean Cancer Study Group. N Engl J Med. 2017 Jun 1;376(22):2147-2159. link to original article contains verified protocol PubMed UMIN000000843
2. GEICAM/2003-11; CIBOMA/2004-01: Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, Guerrero-Zotano Á, García-Sáenz JA, Torres R, de la Haba J, García-Martínez E, Gómez HL, Llombart A, Bofill JS, Baena-Cañada JM, Barnadas A, Calvo L, Pérez-Michel L, Ramos M, Fernández I, Rodríguez-Lescure Á, Cárdenas J, Vinholes J, Martínez de Dueñas E, Godes MJ, Seguí MA, Antón A, López-Álvarez P, Moncayo J, Amorim G, Villar E, Reyes S, Sampaio C, Cardemil B, Escudero MJ, Bezares S, Carrasco E, Martín M; GEICAM Spanish Breast Cancer Group; CIBOMA (Iberoamerican Coalition for Research in Breast Oncology); LACOG (Latin American Cooperative Oncology Group). Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01). J Clin Oncol. 2020 Jan 20;38(3):203-213. Epub 2019 Dec 5. Erratum in: J Clin Oncol. 2020 Mar 10;38(8):847. link to original article link to PMC article PubMed NCT00130533
3. SYSUCC-001: Wang X, Wang SS, Huang H, Cai L, Zhao L, Peng RJ, Lin Y, Tang J, Zeng J, Zhang LH, Ke YL, Wang XM, Liu XM, Chen QJ, Zhang AQ, Xu F, Bi XW, Huang JJ, Li JB, Pang DM, Xue C, Shi YX, He ZY, Lin HX, An X, Xia W, Cao Y, Guo Y, Su YH, Hua X, Wang XY, Hong RX, Jiang KK, Song CG, Huang ZZ, Shi W, Zhong YY, Yuan ZY; South China Breast Cancer Group (SCBCG). Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial. JAMA. 2021 Jan 5;325(1):50-58. link to original article contains protocol link to PMC article PubMed NCT01112826
4. ECOG-ACRIN EA1131: Mayer IA, Zhao F, Arteaga CL, Symmans WF, Park BH, Burnette BL, Tevaarwerk AJ, Garcia SF, Smith KL, Makower DF, Block M, Morley KA, Jani CR, Mescher C, Dewani SJ, Tawfik B, Flaum LE, Mayer EL, Sikov WM, Rodler ET, Wagner LI, DeMichele AM, Sparano JA, Wolff AC, Miller KD. Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131. J Clin Oncol. 2021 Aug 10;39(23):2539-2551. Epub 2021 Jun 6. link to original article contains verified protocol PubMed NCT02445391
5. SASCIA: NCT04595565

Capecitabine & Docetaxel (TX)

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TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)
XT: Xeloda (Capecitabine) & Taxotere (Docetaxel)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2020 (CBCSG010)	2012-2013	Phase 3 (E-esc)	Docetaxel	Seems to have superior 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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• XEC x 3

References

1. CBCSG010: Li J, Yu K, Pang D, Wang C, Jiang J, Yang S, Liu Y, Fu P, Sheng Y, Zhang G, Cao Y, He Q, Cui S, Wang X, Ren G, Li X, Yu S, Liu P, Qu X, Tang J, Wang O, Fan Z, Jiang G, Zhang J, Wang J, Zhang H, Wang S, Zhang J, Jin F, Rao N, Ma B, He P, Xu B, Zhuang Z, Wang J, Sun Q, Guo X, Mo M, Shao Z; CBCSG010 Study Group. Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial. J Clin Oncol. 2020 Jun 1;38(16):1774-1784. Epub 2020 Apr 10. link to original article contains verified protocol link to PMC article PubMed NCT01642771

Carboplatin & Paclitaxel (CP)

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PCb: Paclitaxel & Carboplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yu et al. 2020 (PATTERN)	2011-2016	Phase 3 (E-esc)	FEC-D	Seems to have superior DFS

Preceding treatment

• Surgery

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

28-day cycle for 6 cycles

References

1. PATTERN: Yu KD, Ye FG, He M, Fan L, Ma D, Mo M, Wu J, Liu GY, Di GH, Zeng XH, He PQ, Wu KJ, Hou YF, Wang J, Wang C, Zhuang ZG, Song CG, Lin XY, Toss A, Ricci F, Shen ZZ, Shao ZM. Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Women With Triple-Negative Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Sep 1;6(9):1390-1396. link to original article link to PMC article contains protocol PubMed NCT01216111

CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 1000/50/2000

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ploner et al. 2003 (ABCSG 3)	1984-NR	Phase 3 (C)	AV-CMF	Did not meet endpoints of DFS/OS

Note: this trial was conducted prior to routine testing of HER2, so it technically included "double-negative" patients.

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) 25 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 1000 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

Regimen variant #2, 1400/80/1200

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1990 (NSABP B-15)	1984-1988	Phase 3 (C)	1. AC	Did not meet primary endpoints of DFS/OS
			2. AC, then CMF	Did not meet primary endpoints of DFS/OS

Note: this trial was conducted prior to routine testing of HER2, so it technically included "double-negative" patients.

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 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) 600 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

References

1. NSABP B-15: Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG, Shibata H, Paterson AHG, Sutherland CM, Robert NJ, Ager PJ, Levy L, Wolter J, Wozniak T, Fisher ER, Deutsch M. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. link to original article contains verified protocol PubMed
2. ABCSG 3: Ploner F, Jakesz R, Hausmaninger H, Kolb R, Stierer M, Fridrik M, Steindorfer P, Gnant M, Haider K, Mlineritsch B, Tschurtschenthaler G, Steger G, Seifert M, Kubista E, Samonigg H; ABCSG. Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie. 2003 Apr;26(2):115-9. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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T: Taxotere (Docetaxel)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2020 (CBCSG010)	2012-2013	Phase 3 (C)	XT	Seems to have inferior 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

Chemotherapy

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

21-day cycle for 3 cycles

Subsequent treatment

• FEC x 3

References

1. CBCSG010: Li J, Yu K, Pang D, Wang C, Jiang J, Yang S, Liu Y, Fu P, Sheng Y, Zhang G, Cao Y, He Q, Cui S, Wang X, Ren G, Li X, Yu S, Liu P, Qu X, Tang J, Wang O, Fan Z, Jiang G, Zhang J, Wang J, Zhang H, Wang S, Zhang J, Jin F, Rao N, Ma B, He P, Xu B, Zhuang Z, Wang J, Sun Q, Guo X, Mo M, Shao Z; CBCSG010 Study Group. Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial. J Clin Oncol. 2020 Jun 1;38(16):1774-1784. Epub 2020 Apr 10. link to original article contains verified protocol link to PMC article PubMed

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fetting et al. 1998 (INT-0108)	1989-1993	Phase 3 (C)	FAC x 16 weeks	Did not meet primary endpoints of RFS60/OS60

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU)
• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)

21-day cycle for 6 cycles

References

1. INT-0108: Fetting JH, Gray R, Fairclough DL, Smith TJ, Margolin KA, Citron ML, Grove-Conrad M, Cella D, Pandya K, Robert N, Henderson IC, Osborne CK, Abeloff MD; ECOG; CALGB. Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study. J Clin Oncol. 1998 Jul;16(7):2382-91. link to original article PubMed

FEC

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FEC: Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2020 (CBCSG010)	2012-2013	Phase 3 (C)	XEC	Seems to have inferior 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 T x 3

Chemotherapy

• 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

21-day cycle for 3 cycles

References

1. CBCSG010: Li J, Yu K, Pang D, Wang C, Jiang J, Yang S, Liu Y, Fu P, Sheng Y, Zhang G, Cao Y, He Q, Cui S, Wang X, Ren G, Li X, Yu S, Liu P, Qu X, Tang J, Wang O, Fan Z, Jiang G, Zhang J, Wang J, Zhang H, Wang S, Zhang J, Jin F, Rao N, Ma B, He P, Xu B, Zhuang Z, Wang J, Sun Q, Guo X, Mo M, Shao Z; CBCSG010 Study Group. Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial. J Clin Oncol. 2020 Jun 1;38(16):1774-1784. Epub 2020 Apr 10. link to original article contains verified protocol link to PMC article PubMed

Pembrolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2020 (KEYNOTE-522)	2017-2018	Phase 3 (E-RT-esc)	Placebo	Superior 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

• Surgery

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 9 cycles

References

1. KEYNOTE-522: Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article contains verified protocol PubMed NCT03036488

T-AC (Paclitaxel)

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T-AC: Taxol (Paclitaxel) followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
In progress (ALEXANDRA)	2018-ongoing	Phase 3 (C)	1. T-AC & Atezolizumab 2. T-EC & Atezolizumab	In progress

Note: Dosing information is from ASCO 2021 Abstract TPS597.

Preceding treatment

• Surgery

Chemotherapy, part 1

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

7-day cycle for 12 cycles

Chemotherapy, part 2

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

14-day cycle for 4 cycles

References

1. ALEXANDRA: NCT03498716

T-EC (Paclitaxel)

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T-EC: Taxol (Paclitaxel) followed by Epirubicin & Cyclophosphamide

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
In progress (ALEXANDRA)	2018-ongoing	Phase 3 (C)	1. T-AC & Atezolizumab 2. T-EC & Atezolizumab	In progress

Note: Dosing information is from ASCO 2021 Abstract TPS597.

Preceding treatment

• Surgery

Chemotherapy, part 1

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

7-day cycle for 12 cycles

Chemotherapy, part 2

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

14-day cycle for 4 cycles

References

1. ALEXANDRA: NCT03498716

XEC

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XEC: Xeloda (Capecitabine), Epirubicin, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2020 (CBCSG010)	2012-2013	Phase 3 (E-switch-ic)	FEC	Seems to have superior 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 XT x 3

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 3 cycles

References

1. CBCSG010: Li J, Yu K, Pang D, Wang C, Jiang J, Yang S, Liu Y, Fu P, Sheng Y, Zhang G, Cao Y, He Q, Cui S, Wang X, Ren G, Li X, Yu S, Liu P, Qu X, Tang J, Wang O, Fan Z, Jiang G, Zhang J, Wang J, Zhang H, Wang S, Zhang J, Jin F, Rao N, Ma B, He P, Xu B, Zhuang Z, Wang J, Sun Q, Guo X, Mo M, Shao Z; CBCSG010 Study Group. Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial. J Clin Oncol. 2020 Jun 1;38(16):1774-1784. Epub 2020 Apr 10. link to original article contains verified protocol link to PMC article PubMed

Metastatic disease, first-line therapy

Carboplatin & Gemcitabine (GCb)

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GCb: Gemcitabine & Carboplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Shaughnessy et al. 2011 (TCD11485)	2007-2009	Randomized Phase II (C)	GCb & Iniparib	Inferior OS
O'Shaughnessy et al. 2014 (EFC11486)	2009-2010	Phase 3 (C)	GCb & Iniparib	Might have inferior PFS
Cortes et al. 2020 (KEYNOTE-355)	2017-2018	Phase III (C)	Investigator's choice of: 1. GCb & Pembrolizumab 2. Paclitaxel & Pembrolizumab 3. nab-Paclitaxel & Pembrolizumab	Inferior PFS1

¹Reported efficacy for KEYNOTE-355 is for patients with CPS of 10 or more.

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1 & 8
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. TCD11485: O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011 Jan 20;364(3):205-14. Epub 2011 Jan 5. link to original article contains protocol PubMed NCT00540358
2. EFC11486: O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. Epub 2014 Oct 27. link to original article contains protocol PubMed NCT00938652
3. KEYNOTE-355: Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. link to original article contains verified protocol PubMed NCT02819518
4. PRESERVE 2: EudraCT 2020-004930-39

Carboplatin & Gemcitabine (GCb) & Pembrolizumab

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GCb & Pembrolizumab: Gemcitabine, Carboplatin, Pembrolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2020 (KEYNOTE-355)	2017-2018	Phase III (E-RT-esc)	Investigator's choice of: 1. GCb 2. Paclitaxel 3. nab-Paclitaxel	Superior PFS1 (HR 0.6, 95% CI 0.49-0.86)

¹Reported efficacy is in the group with CPS of 10 or more.

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1 & 8
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

1. KEYNOTE-355: Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. link to original article contains verified protocol PubMed NCT02819518

Cisplatin & Docetaxel (DC)

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TP: Taxotere (Docetaxel) & Platinol (Cisplatin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fan et al. 2012	NR	Phase III (E-switch-ic)	TX (Taxotere)	Seems to have superior OS

Chemotherapy

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

21-day cycle for up to 6 cycles

References

1. Fan Y, Xu BH, Yuan P, Ma F, Wang JY, Ding XY, Zhang P, Li Q, Cai RG. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol. 2013 May;24(5):1219-25. Epub 2012 Dec 5. link to original article contains protocol PubMed

Cisplatin & Gemcitabine (GC)

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hu et al. 2015 (CBCSG006)	2011-2013	Phase III (E-switch-ic)	Gemcitabine & Paclitaxel	Superior PFS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 8 cycles

References

1. CBCSG006: Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, Wang BY, Teng YE, Tong ZS, Pan YY, Yin YM, Wu CP, Jiang ZF, Wang XJ, Lou GY, Liu DG, Feng JF, Luo JF, Sun K, Gu YJ, Wu J, Shao ZM. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):436-46. Epub 2015 Mar 18. link to original article contains protocol PubMed NCT01287624

Docetaxel monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tutt et al. 2018 (TNT)	2008-2014	Phase III (C)	Carboplatin	Did not meet primary endpoint of ORR

Chemotherapy

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

21-day cycle for 6 cycles

References

1. TNT: Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, Owen J, Abraham J, Barrett S, Barrett-Lee P, Brown R, Chan S, Dowsett M, Flanagan JM, Fox L, Grigoriadis A, Gutin A, Harper-Wynne C, Hatton MQ, Hoadley KA, Parikh J, Parker P, Perou CM, Roylance R, Shah V, Shaw A, Smith IE, Timms KM, Wardley AM, Wilson G, Gillett C, Lanchbury JS, Ashworth A, Rahman N, Harries M, Ellis P, Pinder SE, Bliss JM. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med. 2018 May;24(5):628-637. Epub 2018 Apr 30. link to original article link to PMC article PubMed NCT00532727

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pandya et al. 2007 (ECOG E3185)	1987-1991	Phase 3 (C)	CAF/TsAVbH	Did not meet primary endpoint of TTF

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1 & 8
• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14

28-day cycle for up to 6 cycles

References

1. ECOG E3185: Pandya KJ, Hu P, Osborne CK, Falkson G, Tormey DC; ECOG. Phase III study of standard combination versus rotating regimen of induction chemotherapy in patients with hormone insensitive metastatic breast cancer: an Eastern Cooperative Oncology Group Intergroup Study (E3185). Am J Clin Oncol. 2007 Apr;30(2):113-25. link to original article contains verified protocol PubMed

Paclitaxel monotherapy

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Regimen variant #1, 80 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kim et al. 2017 (LOTUS)	2014-2016	Randomized Phase II (C)	Ipatasertib & Paclitaxel	Seems to have inferior PFS

Chemotherapy

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

28-day cycles

Regimen variant #2, 90 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2020 (KEYNOTE-355)	2017-2018	Phase III (C)	Investigator's choice of: 1. GCb & Pembrolizumab 2. Paclitaxel & Pembrolizumab 3. nab-Paclitaxel & Pembrolizumab	Inferior PFS1
Miles et al. 2021 (IMpassion131)	2017-2019	Phase III (C)	Paclitaxel & Atezolizumab	Did not meet primary endpoint of PFS

¹Reported efficacy for KEYNOTE-355 is for patients with CPS of 10 or more.

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. LOTUS: Kim SB, Dent R, Im SA, Espié M, Blau S, Tan AR, Isakoff SJ, Oliveira M, Saura C, Wongchenko MJ, Kapp AV, Chan WY, Singel SM, Maslyar DJ, Baselga J; LOTUS investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1360-1372. Epub 2017 Aug 8. link to original article PubMed NCT02162719
2. KEYNOTE-355: Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. link to original article contains verified protocol PubMed NCT02819518
3. IMpassion131: Miles D, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios C, Xu B, Wardley A, Kaen D, Andrade L, Semiglazov V, Reinisch M, Patel S, Patre M, Morales L, Patel SL, Kaul M, Barata T, O'Shaughnessy J; IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021 Aug;32(8):994-1004. Epub 2021 Jul 1. link to original article contains protocol PubMed NCT03125902

Paclitaxel & Pembrolizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2020 (KEYNOTE-355)	2017-2018	Phase III (E-RT-esc)	Investigator's choice of: 1. Carboplatin & Gemcitabine 2. Paclitaxel 3. nab-Paclitaxel	Superior PFS1 (HR 0.6, 95% CI 0.49-0.86)

¹Reported efficacy is in the group with CPS of 10 or more.
Note: the duration of chemotherapy and immunotherapy cycles is different.

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

1. KEYNOTE-355: Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. link to original article contains verified protocol PubMed NCT02819518

nab-Paclitaxel monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2018 (IMpassion130)	2015-2017	Phase III (C)	nab-Paclitaxel & Atezolizumab	Might have inferior OS
Cortes et al. 2020 (KEYNOTE-355)	2017-2018	Phase III (C)	Investigator's choice of: 1. GCb & Pembrolizumab 2. Paclitaxel & Pembrolizumab 3. nab-Paclitaxel & Pembrolizumab	Inferior PFS1

¹Reported efficacy for KEYNOTE-355 is for patients with CPS of 10 or more.
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. IMpassion130: Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379(22):2108-2121. Epub 2018 Oct 20. link to original article contains verified protocol PubMed NCT02425891
   1. Update: Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Henschel V, Molinero L, Chui SY, Maiya V, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Investigators. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):44-59. Epub 2019 Nov 27. link to original article PubMed
   2. Update: Emens LA, Adams S, Barrios CH, Diéras V, Iwata H, Loi S, Rugo HS, Schneeweiss A, Winer EP, Patel S, Henschel V, Swat A, Kaul M, Molinero L, Patel S, Chui SY, Schmid P. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021 Aug;32(8):983-993. Epub 2021 Jul 1. Erratum in: Ann Oncol. 2021 Aug 2;: Erratum in: Ann Oncol. 2021 Dec;32(12):1650. link to original article PubMed
2. KEYNOTE-355: Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. link to original article contains verified protocol PubMed NCT02819518

nab-Paclitaxel & Atezolizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2018 (IMpassion130)	2015-2017	Phase III (E-RT-esc)	nab-Paclitaxel	Might have superior OS1 Median OS: 21 vs 18.7 mo (HR 0.87, 95% CI 0.75-1.02)

¹Reported efficacy is based on the 2021 update.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Atezolizumab (Tecentriq) 840 mg IV once per day on days 1 & 15

28-day cycles

References

1. IMpassion130: Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379(22):2108-2121. Epub 2018 Oct 20. link to original article contains verified protocol PubMed NCT02425891
   1. Update: Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Henschel V, Molinero L, Chui SY, Maiya V, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Investigators. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):44-59. Epub 2019 Nov 27. link to original article PubMed
   2. Update: Emens LA, Adams S, Barrios CH, Diéras V, Iwata H, Loi S, Rugo HS, Schneeweiss A, Winer EP, Patel S, Henschel V, Swat A, Kaul M, Molinero L, Patel S, Chui SY, Schmid P. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021 Aug;32(8):983-993. Epub 2021 Jul 1. Erratum in: Ann Oncol. 2021 Aug 2;: Erratum in: Ann Oncol. 2021 Dec;32(12):1650. link to original article PubMed

nab-Paclitaxel & Pembrolizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2020 (KEYNOTE-355)	2017-2018	Phase III (E-RT-esc)	Investigator's choice of: 1. Carboplatin & Gemcitabine 2. Paclitaxel 3. nab-Paclitaxel	Superior PFS1 (HR 0.6, 95% CI 0.49-0.86)

¹Reported efficacy is for patients with CPS of 10 or more.
Note: the duration of chemotherapy and immunotherapy cycles is different.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

1. KEYNOTE-355: Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. link to original article contains verified protocol PubMed NCT02819518

Metastatic disease, subsequent lines of therapy

Capecitabine monotherapy

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Regimen variant #1, 2000 mg/m²/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2007 (CA163-046)	2003-2006	Phase 3 (C)	Capecitabine & Ixabepilone	Inferior PFS
Sparano et al. 2010 (CA163-048)	2003-2006	Phase 3 (C)	Capecitabine & Ixabepilone	Inferior PFS
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Note: 25% of the patients in CA163-046 had TNBC. KEYNOTE-119 did not specify capecitabine dosing, which was left to the local standard of care. This is the lower bound of dosing specified in ASCENT.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

Regimen variant #2, 2500 mg/m²/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Note: This is the upper bound of dosing specified in ASCENT.

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

1. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed NCT00080301
   1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
   2. Pooled subgroup analysis: Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, Patel A, Vahdat L. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III, randomized clinical trials. Clin Breast Cancer. 2018 Dec;18(6):489-497. Epub 2018 Aug 4. link to original article PubMed
2. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. link to original article contains verified protocol link to PMC article PubMed NCT00082433
   1. Pooled subgroup analysis: Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, Patel A, Vahdat L. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III, randomized clinical trials. Clin Breast Cancer. 2018 Dec;18(6):489-497. Epub 2018 Aug 4. link to original article PubMed
3. KEYNOTE-119: Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, Schmid P, Tamura K, Testa L, Witzel I, Ohtani S, Turner N, Zambelli S, Harbeck N, Andre F, Dent R, Zhou X, Karantza V, Mejia J, Cortes J; KEYNOTE-119 investigators. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):499-511. Epub 2021 Mar 4. link to original article does not contain protocol PubMed NCT02555657
4. ASCENT: Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. link to original article contains verified protocol PubMed NCT02574455

Capecitabine & Ixabepilone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2007 (CA163-046)	2003-2006	Phase 3 (E-esc)	Capecitabine	Superior PFS
Sparano et al. 2010 (CA163-048)	2003-2006	Phase 3 (E-esc)	Capecitabine	Superior PFS

Note: 25% of the patients in CA163-046 had TNBC.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Ixabepilone (Ixempra) 40 mg/m² IV once on day 1

21-day cycles

References

1. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed NCT00080301
   1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
   2. Pooled subgroup analysis: Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, Patel A, Vahdat L. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III, randomized clinical trials. Clin Breast Cancer. 2018 Dec;18(6):489-497. Epub 2018 Aug 4. link to original article PubMed
2. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. link to original article contains verified protocol link to PMC article PubMed NCT00082433
   1. Pooled subgroup analysis: Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, Patel A, Vahdat L. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III, randomized clinical trials. Clin Breast Cancer. 2018 Dec;18(6):489-497. Epub 2018 Aug 4. link to original article PubMed

Carboplatin & Gemcitabine (GCb)

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GCb: Gemcitabine & Carboplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Shaughnessy et al. 2014 (EFC11486)	2009-2010	Phase 3 (C)	GCb & Iniparib	Might have inferior PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1 & 8
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. EFC11486: O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. Epub 2014 Oct 27. link to original article contains protocol PubMed NCT00938652

Enzalutamide monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Traina et al. 2018 (MDV3100-11)	2013-2014	Phase II	CBR @ 16 wks: 25% (95% CI 17-33)

Patients had AR-positive TNBC.

Endocrine therapy

• Enzalutamide (Xtandi) 160 mg PO once per day

Continued indefinitely

References

1. MDV3100-11: Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018 Mar 20;36(9):884-890. Epub 2018 Jan 26. link to original article contains verified protocol PubMed NCT01889238

Eribulin monotherapy

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Regimen variant #1, 1.23 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Note: This is the European dosing in ASCENT.

Chemotherapy

• Eribulin (Halaven) 1.23 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #2, 1.4 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2011 (EMBRACE)	2006-2008	Phase 3 (E-RT-switch-ic)	Investigator's choice	Seems to have superior OS
Kaufman et al. 2015 (E7389-G000-301)	2006-2009	Phase 3 (E-switch-ic)	Capecitabine	Might have superior OS
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Note: in EMBRACE, 144 patients (19%) had triple-negative breast cancer. In E7389-G000-301, 150 patients (24.5%) had triple-negative breast cancer. KEYNOTE-119 did not specify capecitabine dosing, which was left to the local standard of care. This is the North American dosing in ASCENT.

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV over 2 to 5 minutes once per day on days 1 & 8

21-day cycles

References

1. EMBRACE: Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article contains protocol PubMed NCT00388726
2. E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article contains verified protocol PubMed NCT00337103
3. KEYNOTE-119: Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, Schmid P, Tamura K, Testa L, Witzel I, Ohtani S, Turner N, Zambelli S, Harbeck N, Andre F, Dent R, Zhou X, Karantza V, Mejia J, Cortes J; KEYNOTE-119 investigators. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):499-511. Epub 2021 Mar 4. link to original article does not contain protocol PubMed NCT02555657
4. ASCENT: Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. link to original article contains verified protocol PubMed NCT02574455

Gemcitabine monotherapy

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Regimen variant #1, 800 mg/m² 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Note: This is the lower bound of dosing specified by ASCENT.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 1000 mg/m² 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS

Note: KEYNOTE-119 did not specify gemcitabine dosing, which was left to the local standard of care. This is a gemcitabine dosing schema used in recent phase 3 RCTs.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 1200 mg/m² 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Note: This is the upper bound of dosing specified by ASCENT.

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #4, 1250 mg/m² 2 weeks out of 3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS

Note: KEYNOTE-119 did not specify gemcitabine dosing, which was left to the local standard of care. This is a gemcitabine dosing schema used in recent phase 3 RCTs.

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycles

References

1. KEYNOTE-119: Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, Schmid P, Tamura K, Testa L, Witzel I, Ohtani S, Turner N, Zambelli S, Harbeck N, Andre F, Dent R, Zhou X, Karantza V, Mejia J, Cortes J; KEYNOTE-119 investigators. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):499-511. Epub 2021 Mar 4. link to original article does not contain protocol PubMed NCT02555657
2. ASCENT: Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. link to original article contains verified protocol PubMed NCT02574455

Sacituzumab govitecan monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bardia et al. 2017 (IMMU-132-01)	2013-2016	Phase I/II (RT)
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (E-RT-switch-ooc)	1. Capecitabine 2. Eribulin 3. Gemcitabine 4. Vinorelbine	Superior OS Median OS: 12 mo vs 7 mo (HR 0.49, 95% CI 0.38-0.59)

Antibody-drug conjugate therapy

• Sacituzumab govitecan (Trodelvy) 10 mg/kg IV once per day on days 1 & 8

21-day cycles

References

1. IMMU-132-01: Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN, Shah NC, O'Shaughnessy J, Kalinsky K, Guarino M, Abramson V, Juric D, Tolaney SM, Berlin J, Messersmith WA, Ocean AJ, Wegener WA, Maliakal P, Sharkey RM, Govindan SV, Goldenberg DM, Vahdat LT. Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer. J Clin Oncol. 2017 Jul 1;35(19):2141-2148. Epub 2017 Mar 14. link to original article link to PMC article PubMed NCT01631552
   1. Update: Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O'Shaughnessy J, Moroose RL, Santin AD, Abramson VG, Shah NC, Rugo HS, Goldenberg DM, Sweidan AM, Iannone R, Washkowitz S, Sharkey RM, Wegener WA, Kalinsky K. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019 Feb 21;380(8):741-751. link to original article PubMed
2. ASCENT: Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. link to original article contains verified protocol PubMed NCT02574455

Vinorelbine monotherapy

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Regimen variant #1, 25 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bardia et al. 2021 (ASCENT)	2017-2019	Phase 3 (C)	Sacituzumab govitecan	Inferior OS

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #2, 30 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS

Note: KEYNOTE-119 did not specify vinorelbine dosing, which was left to the local standard of care. This is a vinorelbine dosing schema used in recent phase 3 RCTs.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #3, 30 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS

Note: KEYNOTE-119 did not specify vinorelbine dosing, which was left to the local standard of care. This is a vinorelbine dosing schema used in recent phase 3 RCTs.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once on day 1

21-day cycles

Regimen variant #4, 30 mg/m² 2 out of 3 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winer et al. 2021 (KEYNOTE-119)	2015-2017	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of OS

Note: KEYNOTE-119 did not specify vinorelbine dosing, which was left to the local standard of care. This is a vinorelbine dosing schema used in recent phase 3 RCTs.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. KEYNOTE-119: Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, Schmid P, Tamura K, Testa L, Witzel I, Ohtani S, Turner N, Zambelli S, Harbeck N, Andre F, Dent R, Zhou X, Karantza V, Mejia J, Cortes J; KEYNOTE-119 investigators. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):499-511. Epub 2021 Mar 4. link to original article does not contain protocol PubMed NCT02555657
2. ASCENT: Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. link to original article contains verified protocol PubMed NCT02574455

Investigational agents

Drugs with some degree of promising activity in clinical trials.