Non-small cell lung cancer

Page editor		Section editor
	Eric K. Singhi, MD MD Anderson Cancer Center Houston, TX, USA LinkedIn		Amit Kulkarni, MBBS University of Minnesota Minneapolis, MN, USA LinkedIn

115 regimens on this page 229 variants on this page

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 or to one of the histology-specific, biomarker-specific, or site-specific pages that are linked below. 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!.
There are several related dedicated pages:

• Histology-specific:
  • NSCLC, Nonsquamous
  • NSCLC, Squamous
• Biomarker-specific:
  • NSCLC, ALK-positive
  • NSCLC, BRAF-mutated
  • NSCLC, EGFR-mutated
  • NSCLC, HER2-mutated
  • NSCLC, KRAS-mutated
  • NSCLC, MET-mutated
  • NSCLC, RET-positive
  • NSCLC, ROS1-positive
• Site-specific:
  • NSCLC, CNS metastases

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

• 2023: Jaiyesimi et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.3 PubMed
  • 2022: Singh et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline PubMed
• 2023: Singh et al. Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update PubMed
  • 2022: Daly et al. Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline PubMed
• 2020: Schneider et al. Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline PubMed

• 2017: Hanna et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update PubMed
  • 2015: Masters et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update PubMed
  • 2009: Azzoli et al. American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer PubMed

ASCO/CCO

Current

• 2021: Hanna et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update PubMed
• 2020: Hanna et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update PubMed
• 2017: Kris et al. Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non–small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update PubMed

• 2007: Pisters et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline PubMed

ESMO

• 2023: Hendriks et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
• 2018: Planchard et al. Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2016: Novello et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2014: Reck et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2012: Peters et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: D'Addario et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
• 2017: Postmus et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2013: Vansteenkiste et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: Crinò et al. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
• 2015: Eberhardt et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer PubMed

• 2014: Vansteenkiste et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up PubMed
• 2014: Besse et al. 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease PubMed
• 2014: Kerr et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer PubMed
• 2009: D'Addario & Felip. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: D'Addario & Felip. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2005: Felip et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC) PubMed
  • 2001: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC) PubMed

KSMO/ESMO

• 2020: Park et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS PubMed
• 2019: Wu et al. Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO-ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS PubMed

ISRS

• 2023: Mayinger et al. Stereotactic Body Radiotherapy for Lung Oligo-metastases: Systematic Review and International Stereotactic Radiosurgery Society Practice Guidelines PubMed
• 2023: Yan et al. Stereotactic body radiotherapy for Ultra-Central lung Tumors: A systematic review and Meta-Analysis and International Stereotactic Radiosurgery Society practice guidelines PubMed

NCCN

• NCCN Guidelines - Non-Small Cell Lung Cancer
  • 2017: Ettinger et al. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. PubMed
  • 2015: Ettinger et al. Non-Small Cell Lung Cancer, Version 6.2015. PubMed
  • 2014: Ettinger et al. Non–Small Cell Lung Cancer, Version 1.2015 PubMed
  • 2013: Ettinger et al. Non-small cell lung cancer, version 2.2013. PubMed
  • 2012: Ettinger et al. Non-small cell lung cancer. PubMed
  • 2008: Ettinger et al. Non-small cell lung cancer. PubMed
  • 2006: Ettinger et al. Non-small cell lung cancer clinical practice guidelines in oncology. PubMed
  • 2004: Authors not listed. Non-small cell lung cancer. Clinical practice guidelines in oncology. PubMed

SITC

• 2022: Govindan et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma PubMed
  • 2018: Brahmer et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC) PubMed

Definitive therapy for early/localized disease

Nivolumab & RT

Nivolumab & RT: Nivolumab & Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chang et al. 2023 (MDACC 2016-0737)	2017-06-30 to 2022-03-22	Randomized Phase 2 (E-esc)	RT	Superior EFS48 (primary endpoint) EFS48: 77% vs 53% (HR 0.42, 95% CI 0.22-0.80)

Immunotherapy

• Nivolumab (Opdivo) as follows:
  • Cycle 1: 480 mg IV once on day 1, started on the same day or within 36 hours of the first SABR fraction
  • Cycles 2 to 4: 480 mg IV once on day 1

Radiotherapy

• Concurrent stereotactic ablative radiotherapy (SABR)

28-day cycle for 4 cycles

References

1. MDACC 2016-0737: Chang JY, Lin SH, Dong W, Liao Z, Gandhi SJ, Gay CM, Zhang J, Chun SG, Elamin YY, Fossella FV, Blumenschein G, Cascone T, Le X, Pozadzides JV, Tsao A, Verma V, Welsh JW, Chen AB, Altan M, Mehran RJ, Vaporciyan AA, Swisher SG, Balter PA, Fujimoto J, Wistuba II, Feng L, Lee JJ, Heymach JV. Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial. Lancet. 2023 Sep 9;402(10405):871-881. Epub 2023 Jul 18. link to original article contains dosing details in abstract PubMed NCT03110978

Neoadjuvant therapy

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel

Regimen variant #1, 5/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. 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.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #2, 5/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS
Provencio et al. 2023 (NADIM II)	2019-06 to 2021-02	Randomized Phase 2 (C)	CP & Nivolumab	Seems to have inferior OS (secondary endpoint)

Note: CheckMate 816 had additional comparator options depending on histology; see the respective histology-specific pages for more details. 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.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #3, 6/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. 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.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #4, 6/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. 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.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528
2. NADIM II: Provencio M, Nadal E, González-Larriba JL, Martínez-Martí A, Bernabé R, Bosch-Barrera J, Casal-Rubio J, Calvo V, Insa A, Ponce S, Reguart N, de Castro J, Mosquera J, Cobo M, Aguilar A, López Vivanco G, Camps C, López-Castro R, Morán T, Barneto I, Rodríguez-Abreu D, Serna-Blasco R, Benítez R, Aguado de la Rosa C, Palmero R, Hernando-Trancho F, Martín-López J, Cruz-Bermúdez A, Massuti B, Romero A. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):504-513. Epub 2023 Jun 28. link to original article contains dosing details in manuscript PubMed NCT03838159

Carboplatin & Paclitaxel (CP) & Nivolumab

CP & Nivolumab: Carboplatin, Paclitaxel, Nivolumab

Regimen variant #1, 5/175/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 3 cycles

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

Subsequent treatment

• Complete resection

Regimen variant #2, 5/200/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)
Provencio et al. 2023 (NADIM II)	2019-06 to 2021-02	Randomized Phase 2 (E-esc)	CP	Seems to have superior OS (secondary endpoint) OS24: 85% vs 63.6% (HR 0.43, 95% CI 0.19-0.98) Seems to have superior pCR rate (primary endpoint)

Note: CheckMate 816 had additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

Subsequent treatment

• CheckMate 816: Complete resection
• NADIM II: Complete resection, then adjuvant nivolumab if R0 resection

Regimen variant #3, 6/175/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 3 cycles

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

Subsequent treatment

• Complete resection

Regimen variant #4, 6/200/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528
2. NADIM II: Provencio M, Nadal E, González-Larriba JL, Martínez-Martí A, Bernabé R, Bosch-Barrera J, Casal-Rubio J, Calvo V, Insa A, Ponce S, Reguart N, de Castro J, Mosquera J, Cobo M, Aguilar A, López Vivanco G, Camps C, López-Castro R, Morán T, Barneto I, Rodríguez-Abreu D, Serna-Blasco R, Benítez R, Aguado de la Rosa C, Palmero R, Hernando-Trancho F, Martín-López J, Cruz-Bermúdez A, Massuti B, Romero A. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):504-513. Epub 2023 Jun 28. link to original article contains dosing details in manuscript PubMed NCT03838159

Cisplatin & Docetaxel (DC)

DC: Docetaxel & Cisplatin

Regimen variant #1, 60/75 x 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Cisplatin (Platinol) 75 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #2, 75/75 x 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

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

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #3, 85/100 x 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pless et al. 2015 (SAKK 16/00)	2001-2012	Phase 3 (C)	Cisplatin & Docetaxel, then RT	Did not meet primary endpoint of EFS

Eligibility criteria

• Stage IIIA or N2 NSCLC

Chemotherapy

• Docetaxel (Taxotere) 85 mg/m² IV once on day 1
• Cisplatin (Platinol) 100 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. SAKK 16/00: Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Früh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015 Sep 12;386(9998):1049-56. Epub 2015 Aug 11. Erratum in: Lancet. 2015 Sep 12;386(9998):1040. link to original article contains dosing details in abstract PubMed NCT00030771
2. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528

Cisplatin & Docetaxel (DC) & Durvalumab

DC & Durvalumab: Docetaxel, Cisplatin, Durvalumab

Regimen

Study	Dates of enrollment	Evidence
Rothschild et al. 2021 (SAKK 16/14)	2016-2019	Phase 2

Eligibility criteria

• Stage IIIA(N2) NSCLC

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 3: 100 mg/m² IV once on day 1
• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 3: 85 mg/m² IV once on day 1

Immunotherapy

• Durvalumab (Imfinzi) as follows:
  • Cycles 4 & 5: 750 mg IV once on day 1

21-day cycle for 3 cycles, then 14-day cycle for 2 cycles

Subsequent treatment

• Complete resection, then adjuvant durvalumab

References

1. SAKK 16/14: Rothschild SI, Zippelius A, Eboulet EI, Savic Prince S, Betticher D, Bettini A, Früh M, Joerger M, Lardinois D, Gelpke H, Mauti LA, Britschgi C, Weder W, Peters S, Mark M, Cathomas R, Ochsenbein AF, Janthur WD, Waibel C, Mach N, Froesch P, Buess M, Bohanes P, Godar G, Rusterholz C, Gonzalez M, Pless M; Swiss Group for Clinical Cancer Research (SAKK). SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial. J Clin Oncol. 2021 Sep 10;39(26):2872-2880. Epub 2021 Jul 12. link to original article contains dosing details in manuscript PubMed NCT02572843

Cisplatin & Docetaxel (DC) & Nivolumab

DC & Nivolumab: Docetaxel, Cisplatin, Nivolumab

Regimen variant #1, 60/75/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Cisplatin (Platinol) 75 mg/m² IV once on day 1

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #2, 75/75/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

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

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528

Cisplatin & Etoposide (EP)

Regimen

Study	Dates of enrollment	Evidence
Thomas et al. 2008 (GLCCG 01/95)	1995-2003	Non-randomized part of phase 3 RCT

Chemotherapy

• Cisplatin (Platinol) 55 mg/m² IV once per day on days 1 & 4
• Etoposide (Vepesid) 100 mg/m² (route not specified) once per day on days 1 to 4

21-day cycle for 3 cycles

Subsequent treatment

• Complete surgical resection followed by adjuvant RT versus neoadjuvant Carboplatin, Vindesine, RT followed by surgical resection

References

1. GLCCG 01/95: Thomas M, Rübe C, Hoffknecht P, Macha HN, Freitag L, Linder A, Willich N, Hamm M, Sybrecht GW, Ukena D, Deppermann KM, Dröge C, Riesenbeck D, Heinecke A, Sauerland C, Junker K, Berdel WE, Semik M; German Lung Cancer Cooperative Group. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. 2008 Jul;9(7):636-48. Epub 2008 Jun 24. link to original article contains dosing details in manuscript PubMed NCT00176137

Cisplatin & Gemcitabine (GC)

Regimen variant #1, 75/2500 x 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Scagliotti et al. 2011 (CHEST)	2000-2004	Phase 3 (E-esc)	Surgery alone	Seems to have superior PFS (primary endpoint) Median PFS: 4 vs 2.2 y (aHR 0.70, 95% CI 0.50-0.97) Superior OS (secondary endpoint) Median OS: 7.8 vs 4.8 y (aHR 0.63, 95% CI 0.43-0.92)

Eligibility criteria

• Stage IB to IIIA NSCLC

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given at least 4 hours after gemcitabine
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection, 2 to 6 weeks after last dose of chemotherapy

Regimen variant #2, 75/2500 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (IMpower030)	2018-ongoing	Phase 3 (C)	1a. Carboplatin, nab-Paclitaxel, Atezolizumab 1b. Carboplatin, Pemetrexed, Atezolizumab 1c. GC & Atezolizumab 1d. Pem-Cis & Atezolizumab	TBD if different primary endpoint of EFS

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 4 cycles

Subsequent treatment

• Complete resection

References

1. CHEST: Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. link to original article contains dosing details in manuscript PubMed NCT00191126
2. IMpower030: NCT03456063

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen variant #1, 75/25

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. The timing of vinorelbine was not specified in the supplementary materials; this timing is typical.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #2, 75/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. The timing of vinorelbine was not specified in the supplementary materials; this timing is typical.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528

Cisplatin & Vinorelbine (CVb) & Nivolumab

CVb & Nivolumab: Cisplatin, Vinorelbine, Nivolumab

Regimen variant #1, 75/25/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. The timing of vinorelbine was not specified in the supplementary materials; this timing is typical.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

Regimen variant #2, 75/30/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (E-RT-esc)	1a. CP 1b. CVb 1c. DC	Superior EFS (co-primary endpoint) Median EFS: 31.6 vs 20.8 mo (HR 0.63, 97.38% CI 0.43-0.91) Superior pCR rate (co-primary endpoint) pCR rate: 24% vs 2.2% (OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. The timing of vinorelbine was not specified in the supplementary materials; this timing is typical.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Immunotherapy

• Nivolumab (Opdivo) 360 mg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528

Adjuvant therapy

Atezolizumab monotherapy

Regimen variant #1, q2wk

FDA-recommended dose

Note: This is not the dose/schedule used in the registration trial.

Preceding treatment

• Resection, then adjuvant platinum-based chemotherapy

Immunotherapy

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

14-day cycle for 26 cycles (1 year)

Regimen variant #2, q3wk

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Felip et al. 2021 (IMpower010)	2015-2018	Phase 3 (E-RT-esc)	Best supportive care	Seems to have superior DFS (primary endpoint) Median DFS: NYR vs 37.2 mo (HR 0.81, 95% CI 0.67-0.99) Did not meet secondary endpoint of OS Median OS: NYR vs NYR (sHR 0.995, 95% CI 0.78-1.28)

Preceding treatment

• IMpower010, nonsquamous: Resection, then adjuvant Cisplatin & Vinorelbine x 4 or DC x 4 or GC x 4 or Cisplatin & Pemetrexed x 4
• IMpower010, squamous: Resection, then adjuvant Cisplatin & Vinorelbine x 4 or DC x 4 or GC x 4

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycle for up to 16 cycles (1 year)

Regimen variant #3, q4wk

FDA-recommended dose

Note: This is not the dose/schedule used in the registration trial.

Preceding treatment

• Resection, then adjuvant platinum-based chemotherapy

Immunotherapy

• Atezolizumab (Tecentriq) 1680 mg IV once on day 1

28-day cycle for 13 cycles (1 year)

References

1. IMpower010: Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, Wakelee H; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357. Epub 2021 Sep 20. Erratum in: Lancet. 2021 Sep 23. link to original article contains dosing details in manuscript PubMed NCT02486718
   1. Update: Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, Chella A, Reck M, Goloborodko O, Huang M, Belleli R, McNally V, Srivastava MK, Bennett E, Gitlitz BJ, Wakelee HA. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023 Oct;34(10):907-919. Epub 2023 Jul 17. link to original article PubMed

Carboplatin & Paclitaxel (CP)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Strauss et al. 2008 (CALGB 9633)	1996-2003	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS

Preceding treatment

• Lobectomy or pneumonectomy, within 4 to 8 weeks

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 45 to 60 minutes once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for 4 cycles

References

1. CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00002852
2. IFCT 0002: Westeel V, Quoix E, Puyraveau M, Lavolé A, Braun D, Laporte S, Bigay-Game L, Pujol JL, Ozenne G, Rivière A, Douillard JY, Lebeau B, Debieuvre D, Poudenx M, David P, Molinier O, Zalcman G, Lemarié E, Morin F, Depierre A, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. A randomised trial comparing preoperative to perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial). Eur J Cancer. 2013 Aug;49(12):2654-64. Epub 2013 Jun 1. link to original article PubMed NCT00198354

Cisplatin & Docetaxel (DC)

DC: Docetaxel & Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Barlesi et al. 2015	2004-2007	Phase 3 (E-switch-ic)	Cisplatin & Gemcitabine		Did not meet primary endpoint of QoL
Wakelee et al. 2017 (ECOG-ACRIN E1505)	2007-2013	Phase 3 (C)	1a. DC & Bevacizumab 1b. GC & Bevacizumab 1c. Cisplatin, Pemetrexed, Bevacizumab 1d. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS

Preceding treatment

• Barlesi et al. 2015: Complete R0 resection, within 8 weeks
• ECOG-ACRIN E1505: Complete surgical resection, within 6 to 12 weeks

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 3 cycles (Barlesi et al. 2015) or 4 cycles (ECOG-ACRIN E1505)

References

1. Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. link to original article contains dosing details in manuscript PubMed
2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains dosing details in abstract link to PMC article PubMed NCT00324805
3. IMpower010: Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, Wakelee H; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357. Epub 2021 Sep 20. Erratum in: Lancet. 2021 Sep 23. link to original article contains dosing details in manuscript PubMed NCT02486718
   1. Update: Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, Chella A, Reck M, Goloborodko O, Huang M, Belleli R, McNally V, Srivastava MK, Bennett E, Gitlitz BJ, Wakelee HA. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023 Oct;34(10):907-919. Epub 2023 Jul 17. link to original article PubMed

Cisplatin & Etoposide (EP)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	1995-2000	Phase 3 (E-esc)	Observation	Seems to have superior OS (primary endpoint) OS60: 44.5% vs 40.4% (HR 0.86, 95% CI 0.76-0.98)

Preceding treatment

• Complete surgical resection, within 60 days

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

28-day cycle for 4 cycles

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed NCT00002823
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen variant #1, 75/1200 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505)	2007-2013	Phase 3 (C)	1a. DC & Bevacizumab 1b. GC & Bevacizumab 1c. Cisplatin, Pemetrexed, Bevacizumab 1d. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS

Preceding treatment

• Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #2, 75/1250 x 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Barlesi et al. 2015	2004-2007	Phase 3 (E-switch-ic)	Cisplatin & Docetaxel		Did not meet primary endpoint of QoL

Eligibility criteria

• Stage IB–III NSCLC

Preceding treatment

• Complete R0 resection, within 8 weeks

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 3 cycles

Regimen variant #3, 75/1250 x 4

Study	Dates of enrollment	Evidence
Felip et al. 2021 (IMpower010)	2015-2018	Non-randomized part of phase 3 RCT

Preceding treatment

• Complete resection, within 4 to 12 weeks

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 4 cycles

Subsequent treatment

• Atezolizumab maintenance versus best supportive care

References

1. Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. link to original article contains dosing details in manuscript PubMed
2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains dosing details in abstract link to PMC article PubMed NCT00324805
3. IMpower010: Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, Wakelee H; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357. Epub 2021 Sep 20. Erratum in: Lancet. 2021 Sep 23. link to original article contains dosing details in manuscript PubMed NCT02486718
   1. Update: Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, Chella A, Reck M, Goloborodko O, Huang M, Belleli R, McNally V, Srivastava MK, Bennett E, Gitlitz BJ, Wakelee HA. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023 Oct;34(10):907-919. Epub 2023 Jul 17. link to original article PubMed
4. ACCIO: NCT04267848

Cisplatin & Pemetrexed

CPx: Cisplatin & Pemetrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Kreuter et al. 2013 (TREAT)	2006-2009	Randomized Phase 2 (E-switch-ic)	Cisplatin & Vinorelbine	Did not meet secondary endpoint of OS1	Superior clinical feasibility rate
Wakelee et al. 2017 (ECOG-ACRIN E1505)	2007-2013	Phase 3 (C)	1a. DC & Bevacizumab 1b. GC & Bevacizumab 1c. Cisplatin, Pemetrexed, Bevacizumab 1d. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS
Groen et al. 2019 (NVALT-8)	2007-2013	Phase 3 (C)	CPx & Nadroparin	Did not meet primary endpoint of RFS

¹Reported efficacy for TREAT is based on the 2016 update.
Note: In TREAT, this treatment was intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1.

Preceding treatment

• TREAT & NVALT-8: Complete surgical resection, within 4 to 6 weeks
• ECOG-ACRIN E1505: Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycle for 4 cycles

References

1. TREAT: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG Leuven Lung Cancer Group. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. link to original article contains dosing details in manuscript PubMed NCT00349089
   1. Update: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. link to original article PubMed
2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains dosing details in abstract link to PMC article PubMed NCT00324805
3. NVALT-8: Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Aug;121(5):372-377. Epub 2019 Jul 24. link to original article contains dosing details in manuscript link to PMC article PubMed NTR1250/1217
4. IMpower010: Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, Wakelee H; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357. Epub 2021 Sep 20. Erratum in: Lancet. 2021 Sep 23. link to original article contains dosing details in manuscript PubMed NCT02486718
   1. Update: Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, Chella A, Reck M, Goloborodko O, Huang M, Belleli R, McNally V, Srivastava MK, Bennett E, Gitlitz BJ, Wakelee HA. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023 Oct;34(10):907-919. Epub 2023 Jul 17. link to original article PubMed

Cisplatin & Vinblastine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	1995-2000	Phase 3 (E-esc)	Observation	Seems to have superior OS (primary endpoint) OS60: 44.5% vs 40.4% (HR 0.86, 95% CI 0.76-0.98)

Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vinblastine schedule is extrapolated from regimen information in Table 1 in which vinblastine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.

Preceding treatment

• Complete surgical resection, within 60 days

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once per day on days 1, 22, 43, 64
• Vinblastine (Velban) 4 mg/m² IV once per day on days 1, 8, 15, 22, 29, 43, 57

12-week course

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed NCT00002823
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed

Cisplatin & Vindesine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Arriagada et al. 2004 (IALT)	1995-2000	Phase 3 (E-esc)	Observation	Seems to have superior OS (primary endpoint) OS60: 44.5% vs 40.4% (HR 0.86, 95% CI 0.76-0.98)

Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vindesine schedule is extrapolated from regimen information in Table 1 in which vindesine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.

Preceding treatment

• Complete surgical resection, within 60 days

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once per day on days 1, 22, 43, 64
• Vindesine (Eldisine) 3 mg/m² IV once per day on days 1, 8, 15, 22, 29, 43, 57

12-week course

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed NCT00002823
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen variant #1, cisplatin 50 mg/m², 2 weeks out of 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Winton et al. 2005 (JBR.10)	1994-2001	Phase 3 (E-esc)	Observation	Superior OS (primary endpoint) Median OS: 94 vs 73 mo (HR 0.69, 95% CI 0.52-0.91)
Kreuter et al. 2013 (TREAT)	2006-2009	Randomized Phase 2 (C)	Cisplatin & Pemetrexed	Did not meet secondary endpoint of OS1	Superior clinical feasibility rate

¹Reported efficacy for TREAT is based on the 2016 update.

Preceding treatment

• JBR.10: Complete surgical resection, within 6 weeks
• TREAT: Complete surgical resection, within 4 to 6 weeks

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

Regimen variant #2, cisplatin 75 mg/m², q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505)	2007-2013	Phase 3 (C)	1a. DC & Bevacizumab 1b. GC & Bevacizumab 1c. Cisplatin, Pemetrexed, Bevacizumab 1d. Cisplatin, Vinorelbine, Bevacizumab	Did not meet primary endpoint of OS

Preceding treatment

• Complete surgical resection, within 6 to 12 weeks

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #3, cisplatin 100 mg/m², q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Douillard et al. 2006 (ANITA)	1994-2000	Phase 3 (E-esc)	Observation	Seems to have superior OS (primary endpoint) Median OS: 65.7 vs 43.7 mo (aHR 0.80, 95% CI 0.66-0.96)
Arriagada et al. 2004 (IALT)	1995-2000	Phase 3 (E-esc)	Observation	Seems to have superior OS (primary endpoint) OS60: 44.5% vs 40.4% (HR 0.86, 95% CI 0.76-0.98)

Preceding treatment

• IALT: Complete surgical resection, within 60 days
• ANITA: Complete surgical resection

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

References

1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed NCT00002823
   1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
2. JBR.10: Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed NCT00002583
   1. Update: Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. link to original article link to PMC article PubMed
3. ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed NCT00576914
4. TREAT: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators; AIO Lung Cancer Study Group; LLCG. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. link to original article contains dosing details in manuscript PubMed NCT00349089
   1. Update: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. link to original article PubMed
5. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains dosing details in abstract link to PMC article PubMed NCT00324805
6. IMpower010: Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, Wakelee H; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357. Epub 2021 Sep 20. Erratum in: Lancet. 2021 Sep 23. link to original article contains dosing details in manuscript PubMed NCT02486718
   1. Update: Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, Chella A, Reck M, Goloborodko O, Huang M, Belleli R, McNally V, Srivastava MK, Bennett E, Gitlitz BJ, Wakelee HA. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023 Oct;34(10):907-919. Epub 2023 Jul 17. link to original article PubMed

Nivolumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Provencio et al. 2023 (NADIM II)	2019-06 to 2021-02	Non-randomized part of randomized phase 2 RCT

Preceding treatment

• Neoadjuvant CP & Nivolumab x 3, then R0 surgical resection

Immunotherapy

• Nivolumab (Opdivo) 480 mg IV once on day 1

28-day cycle for 6 cycles (6 months)

References

1. NADIM II: Provencio M, Nadal E, González-Larriba JL, Martínez-Martí A, Bernabé R, Bosch-Barrera J, Casal-Rubio J, Calvo V, Insa A, Ponce S, Reguart N, de Castro J, Mosquera J, Cobo M, Aguilar A, López Vivanco G, Camps C, López-Castro R, Morán T, Barneto I, Rodríguez-Abreu D, Serna-Blasco R, Benítez R, Aguado de la Rosa C, Palmero R, Hernando-Trancho F, Martín-López J, Cruz-Bermúdez A, Massuti B, Romero A. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):504-513. Epub 2023 Jun 28. link to original article contains dosing details in manuscript PubMed NCT03838159

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2022 (PEARLS)	2016-2020	Phase 3 (E-RT-esc)	Placebo	Superior DFS (primary endpoint) Median DFS: 53.6 vs 42 mo (HR 0.76, 95% CI 0.63-0.91)

Preceding treatment

• Complete surgical resection

Immunotherapy

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

21-day cycle for up to 18 cycles

References

1. PEARLS: O'Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, Esteban E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee JS, Nakagawa K, Yang J, Samkari A, Keller SM, Mauer M, Jha N, Stahel R, Besse B, Peters S; EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022 Oct;23(10):1274-1286. Epub 2022 Sep 9. link to original article contains dosing details in abstract PubMed NCT02504372

UFT monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamaguchi et al. 2021 (WJTOG0101)	2001-2005	Phase 3 (C)	Gemcitabine	Did not meet primary endpoint of OS OS60: 68.8% vs 70% (HR 1.05, 95% CI 0.81-1.37)

Eligibility criteria

• Stage IB-IIIA NSCLC, with complete resection

Preceding treatment

• Surgery

Chemotherapy

• Tegafur and uracil (UFT) 250 mg/m²/day PO (rounded up or down to the nearest 100 mg)

1-year course

References

1. WJTOG0101: Yamaguchi M, Tada H, Mitsudomi T, Seto T, Yokoi K, Katakami N, Nakagawa K, Oda M, Ohta M, Sawa T, Yamashita M, Ikeda N, Saka H, Higashiyama M, Nomori H, Semba H, Negoro S, Chiba Y, Shimokawa M, Fukuoka M, Nakanishi Y; West Japan Thoracic Oncology Group (WJTOG). Phase III study of adjuvant gemcitabine compared with adjuvant uracil-tegafur in patients with completely resected pathological stage IB-IIIA non-small cell lung cancer (WJTOG0101). Int J Clin Oncol. 2021 Dec;26(12):2216-2223. Epub 2021 Aug 31. link to original article contains dosing details in manuscript PubMed NCT00139971

Induction chemotherapy for locally advanced disease

Carboplatin & Paclitaxel (CP)

PC: Paclitaxel & Carboplatin

Regimen variant #1, 6/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Huber et al. 2006 (CTRT99/97)	1997-2002	Non-randomized part of phase 3 RCT
Belani et al. 2005 (LAMP)	1998-2001	Phase 2
Vokes et al. 2007 (CALGB 39801)	1998-2002	Phase 3 (E-esc)	No induction	Did not meet primary endpoint of OS50%

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 over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 2 cycles

Subsequent treatment

• LAMP: Definitive RT x 6300 cGy
• CTRT99/97: Definitive Paclitaxel & RT versus RT
• CALGB 39801: Definitive CP & RT

Regimen variant #2, 6/225

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hoang et al. 2012 (ECOG 3598)	2000-2006	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.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 225 mg/m² IV once on day 1

21-day cycle for 2 cycles

Subsequent treatment

• Definitive CP & RT

References

1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. Epub 2005 Aug 8. link to original article contains dosing details in abstract PubMed
2. CTRT99/97: Huber RM, Flentje M, Schmidt M, Pöllinger B, Gosse H, Willner J, Ulm K; Bronchial Carcinoma Therapy Group. Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol. 2006 Sep 20;24(27):4397-404. link to original article contains dosing details in abstract PubMed
3. CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; CALGB. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article contains dosing details in abstract PubMed NCT00003387
4. ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00004859

Cisplatin & Vinblastine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dillman et al. 1990 (CALGB 8433)	1984-1987	Phase 3 (E-esc)	No induction	Seems to have superior OS1 (primary endpoint)
Sause et al. 1995 (RTOG 88-08)	1989-1992	Phase 3 (E-esc)	No induction	Seems to have superior OS (primary endpoint)
Curran et al. 2011 (RTOG 9410)	1994-1998	Phase 3 (C)	See link	See link

¹Reported efficacy for CALGB 8433 is based on the 1996 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.

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once per day on days 1 & 29
• Vinblastine (Velban) 5 mg/m² IV once per day on days 1, 8, 15, 22, 29

5-week course

Subsequent treatment

• Definitive RT x 6000 to 6300 cGy

References

1. CALGB 8433: Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, Carey RW, Frei EF 3rd, Green MR. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4;323(14):940-5. link to original article contains dosing details in abstract PubMed
   1. Update: Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5. link to original article PubMed
2. RTOG 88-08: Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, Dar AR, Cox JD. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995 Feb 1;87(3):198-205. link to original article contains dosing details in abstract PubMed
   1. Update: Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, Emami B, Curran W Jr, Byhardt R, Dar AR, Turrisi A 3rd. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000 Feb;117(2):358-64. link to original article PubMed
3. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed NCT01134861

Definitive therapy for early disease

Radiation therapy

RT: Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (KEYNOTE-867)	2019-ongoing	Phase 3 (C)	Pembrolizumab & RT	TBD if different co-primary endpoints of EFS/OS
Awaiting publication (PACIFIC-4)	2019-ongoing	Phase 3 (C)	Durvalumab & RT	TBD if different primary endpoint of PFS
Awaiting publication (SWOG S1914)	2020-ongoing	Phase 3 (C)	Atezolizumab & RT	TBD if different primary endpoint of OS

Radiotherapy

• External beam radiotherapy

References

1. KEYNOTE-867: NCT03924869
2. PACIFIC-4: NCT03833154
3. SWOG S1914: NCT04214262

Definitive therapy for locally advanced disease

Carboplatin & Paclitaxel (CP) & RT

CP & RT: Carboplatin, Paclitaxel, Radiation Therapy
PC & RT: Paclitaxel, Carboplatin, Radiation Therapy

Regimen variant #1, 2/40/60

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2010 (WJTOG0105)	2001-2005	Phase 3 (E-switch-ic)	1. MVP & RT	Inconclusive whether non-inferior OS (primary endpoint)
			2. Carboplatin, Irinotecan, RT	Not compared

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, 22, 29, 36
• Paclitaxel (Taxol) 40 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• Concurrent radiation therapy, 6000 cGy

6-week course

Subsequent treatment

• CP consolidation x 2

Regimen variant #2, 2/45/60

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lu et al. 2010 (ID99-303)	2000-2006	Phase 3 (C)	PC, AE-941, RT	Did not meet primary endpoint of OS
Hoang et al. 2012 (ECOG 3598)	2000-2006	Phase 3 (C)	See link	See link
Bradley et al. 2015 (RTOG 0617)	2007-2011	Phase 3 (C)	1. CP, Cetuximab, concurrent RT	Did not meet primary endpoint of OS
			2. CP & RT; high-dose RT 3. CP, Cetuximab, RT; high-dose RT	Superior OS (primary endpoint)
Liang et al. 2017	2007-2011	Phase 3 (E-switch-ic)	EP & RT	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.

Preceding treatment

• ECOG 3598: PC induction x 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36 given second
• Paclitaxel (Taxol) 45 mg/m² IV over 1 to 3 hours once per day on days 1, 8, 15, 22, 29, 36 given first

Radiotherapy

• Concurrent radiation therapy: 200 cGy fractions x 30 fractions (total of 6000 cGy)

6-week course

Subsequent treatment

• RTOG 0617: PC consolidation x 2

Regimen variant #3, 2/45/63

Study	Dates of enrollment	Evidence
Belani et al. 2005 (LAMP)	1998-02 to 2001-06	Phase 2

Preceding treatment

• PC induction

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, given second
• Paclitaxel (Taxol) 45 mg/m² IV over 1 to 3 hours once per day on days 1, 8, 15, 22, 29, 36, given first

Radiotherapy

• Concurrent radiation therapy: 180 cGy fractions x 25 fractions, then 200 cGy fractions x 9 fractions

7-week course

Subsequent treatment

• PC consolidation x 2

Regimen variant #4, 2/50/66

Study	Dates of enrollment	Evidence
Vokes et al. 2007 (CALGB 39801)	1998-2002	Non-randomized part of phase 3 RCT

Preceding treatment

• PC induction x 2 versus no induction

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, given second
• Paclitaxel (Taxol) 50 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, given first

Radiotherapy

• Concurrent radiation therapy, 6600 cGy

7-week course

References

1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. Epub 2005 Aug 8. link to original article contains dosing details in abstract PubMed
2. CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; CALGB. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article contains dosing details in manuscript PubMed NCT00003387
3. ID99-303: Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, Choy H, Desjardins P, Esparaz BT, Truong MT, Saxman S, Kelaghan J, Bleyer A, Fisch MJ. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst. 2010 Jun 16;102(12):859-65. Epub 2010 May 26. link to original article link to PMC article contains dosing details in abstract PubMed NCT00005838
4. WJTOG0105: Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010 Aug 10;28(23):3739-45. Epub 2010 Jul 12. link to original article contains dosing details in manuscript PubMed NCT00144053
   1. Update: Zenke Y, Tsuboi M, Chiba Y, Tsujino K, Satouchi M, Sawa K, Shimizu J, Daga H, Fujimoto D, Mori M, Aoki T, Sawa T, Omori S, Saka H, Iwamoto Y, Okuno M, Hirashima T, Kashiwabara K, Tachihara M, Yamamoto N, Nakagawa K. Effect of Second-generation vs Third-generation Chemotherapy Regimens With Thoracic Radiotherapy on Unresectable Stage III Non-Small-Cell Lung Cancer: 10-Year Follow-up of a WJTOG0105 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):904-909. link to original article link to PMC article PubMed
5. ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00004859
6. RTOG 0617: Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00533949
   1. Update: Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. link to original article link to PMC article PubMed
   2. Dataset: Project Data Sphere
7. Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains dosing details in manuscript PubMed NCT01494558
8. ECOG-ACRIN EA5181: NCT04092283
9. MS200647_0005: NCT03840902
10. PACIFIC 2: NCT03519971

Carboplatin, Vinorelbine, RT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Strøm et al. 2013 (Conrad)	2006-2011	Phase 3 (E-esc)	Carboplatin & Vinorelbine	Superior OS (primary endpoint) Median OS: 12.6 vs 9.7 mo

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1
• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1 & 8

Radiotherapy

• Concurrent radiation therapy as follows:
  • Cycle 2: 280 cGy per day on days 1 to 5, 8 to 12, 15 to 19 (4200 cGy in 15 fractions)

21-day cycle for 4 cycles

References

1. Conrad: Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U; Norwegian Lung Cancer Study Group. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013 Sep 17;109(6):1467-75. Epub 2013 Aug 20. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN63778716

Carboplatin & RT

Carboplatin & RT: Carboplatin & Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Atagi et al. 2012 (JCOG0301)	2003-2010	Phase 3 (E-esc)	RT	Seems to have superior OS (primary endpoint) Median OS: 22.4 vs 16.9 mo (HR 0.68, 95.4% CI 0.47-0.98)

Chemotherapy

• Carboplatin (Paraplatin) 30 mg/m² IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26

Radiotherapy

• Concurrent radiation therapy: 6000 cGy, details not available in abstract

One course

References

1. JCOG0301: Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; JCOG Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. link to original article contains dosing details in abstract PubMed NCT00132665

Cisplatin & RT

Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schaake-Koning et al. 1992	1984-1989	Phase 3 (E-esc)	1. Cisplatin & RT; weekly cisplatin	Did not meet primary endpoint of OS
			2. RT	Superior OS (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 6 mg/m² IV once per day on days 1 to 5, 8 to 12, 36 to 40, 43 to 47

Radiotherapy

• Concurrent radiation therapy 300 cGy per day on days 1 to 5, 8 to 12, then 250 cGy per day on days 36 to 40, 43 to 47

7-week course

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Blanke et al. 1995	1986-1992	Phase 3 (E-esc)	RT	Might have superior PFS (co-primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once per day on days 1, 22, 43

Radiotherapy

• Concurrent radiation therapy 6000 to 6500 cGy total tumor dose in daily fractions of 180 to 200 cGy

6.5-week course

References

1. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier JP, van Zandwijk N, Bartelink H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30. link to original article contains dosing details in abstract PubMed
2. Blanke C, Ansari R, Mantravadi R, Gonin R, Tokars R, Fisher W, Pennington K, O'Connor T, Rynard S, Miller M, Einhorn L. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol. J Clin Oncol. 1995 Jun;13(6):1425-9. link to original article contains dosing details in abstract PubMed

Cisplatin, Docetaxel, RT

DC & RT: Docetaxel, Cisplatin, Radiation Therapy
DP & RT: Docetaxel, Platinol (Cisplatin), Radiation Therapy

Regimen variant #1, 20/20

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Oh et al. 2013 (KASLC 0401)	2005-2007	Phase 3 (C)	1. TP & RT 2. GC & RT	Did not meet primary endpoint of ORR
Ahn et al. 2015 (KCSG-LU05-04)	2005-2011	Non-randomized part of phase 3 RCT

Note: In KCSG-LU05-04, no benefit was observed to giving post-definitive consolidation.

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36
• Docetaxel (Taxotere) 20 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• Concurrent radiation therapy, 200 cGy fractions x 33 fractions (total dose: 6600 cGy)

6-week course

Subsequent treatment

• KCSG-LU05-04: Cisplatin & Docetaxel consolidation versus no further treatment

Regimen variant #2, 40/40

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Segawa et al. 2010 (OLCSG 0007)	2000-2005	Phase 3 (E-switch-ic)	MVP & RT	Might have superior OS24 (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 40 mg/m² IV once per day on days 1, 8, 29, 36
• Docetaxel (Taxotere) 40 mg/m² IV once per day on days 1, 8, 29, 36

Radiotherapy

• Concurrent radiation therapy, 200 cGy fractions x 30 fractions (total dose: 6000 cGy)

6-week course

References

1. OLCSG 0007: Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, Watanabe Y, Sugimoto K, Shibayama T, Yonei T, Ueoka H, Takemoto M, Kanazawa S, Takata I, Nogami N, Hotta K, Hiraki A, Tabata M, Matsuo K, Tanimoto M. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol. 2010 Jul 10;28(20):3299-306. Epub 2010 Jun 7. link to original article contains dosing details in abstract PubMed UMIN000000085
2. KASLC 0401: Oh IJ, Kim KS, Kim YC, Ban HJ, Kwon YS, Kim YI, Lim SC, Chung WK, Nam TK, Song JY, Yoon MS, Ahn SJ. A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401. Cancer Chemother Pharmacol. 2013 Dec;72(6):1247-54. Epub 2013 Oct 5. link to original article contains dosing details in abstract PubMed
3. KCSG-LU05-04: Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. Epub 2015 Jul 6. link to original article contains dosing details in manuscript PubMed NCT00326378

Cisplatin, Etoposide, RT

EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy

Regimen variant #1, 4500 cGy with response-adapted treatment

Study	Dates of enrollment	Evidence
Albain et al. 2002 (SWOG 9019)	1992-1995	Phase 2
Albain et al. 2009 (RTOG 93-09)	1994-2001	Non-randomized part of phase 3 RCT

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1, 8, 29, 36
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5, 29 to 33

Radiotherapy

• Concurrent radiation therapy, 180 cGy fractions x 25 fractions (total dose: 4500 cGy), to start within 24 hours of cycle 1 day 1

8-week course

Subsequent treatment

• SWOG 9019: Patients were re-imaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 200 cGy per day x 8 fractions for a total of 6100 cGy administered overall
• RTOG 93-09: Additional radiation to 6100 cGy followed by EP consolidation versus surgery followed by EP consolidation

Regimen variant #2, 60 to 6600 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2008 (SWOG S0023)	2001-2005	Non-randomized part of phase 3 RCT
Hanna et al. 2008 (HOG Lun 01-24)	2002-2006	Non-randomized part of phase 3 RCT
Liang et al. 2017	2007-2011	Phase 3 (C)	PC & RT	Might have superior OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1, 8, 29, 33
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5, 29 to 33

Radiotherapy

• Concurrent radiation therapy, 180 to 200 cGy fractions x 30 to 33 fractions (total dose: 6000 to 6600 cGy)

6- to 6.5-week course

Subsequent treatment

• SWOG S0023: Docetaxel consolidation x 3, then gefitinib maintenance versus placebo
• HOG Lun 01-24: Docetaxel consolidation versus observation
• Liang et al. 2017: Optional consolidation chemotherapy
• MS200647_0005: Durvalumab consolidation

Regimen variant #3, 6600 cGy, split cisplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fournel et al. 2005 (NPC 95-01)	1996-2000	Phase 3 (E-switch-ic)	Cisplatin & Vinorelbine, then RT	Did not meet primary endpoint of OS

Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 5, 29 to 33
• Etoposide (Vepesid) 50 mg/m² IV once per day on days 1 to 5, 29 to 33

Radiotherapy

• Concurrent radiation therapy, 200 cGy fractions x 33 fractions (total dose: 6600 cGy)

6.5-week course

Subsequent treatment

• Cisplatin & Vinorelbine consolidation

Regimen variant #4, 6960 cGy (hyperfractionated)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Curran et al. 2011 (RTOG 9410)	1994-1998	Phase 3 (E-switch-ic)	1. Cisplatin, Vinblastine, RT	Did not meet primary endpoint of OS
			2. Cisplatin & Vinblastine, then RT	Might have superior OS (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 1, 8, 29, 36
• Etoposide (Vepesid) 50 mg PO twice per day on days 1 to 5, 8 to 12, 29 to 33, 36 to 40

Radiotherapy

• Concurrent radiation therapy, 120 cGy fractions (total dose: 6960 cGy), given twice per day for 5 days per week, starting on cycle 1 day 1

6-week course

References

1. SWOG 9019: Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002 Aug 15;20(16):3454-60. link to original article contains dosing details in abstract PubMed
2. Schild SE, Stella PJ, Geyer SM, Bonner JA, Marks RS, McGinnis WL, Goetz SP, Kuross SA, Mailliard JA, Kugler JW, Schaefer PL, Jett JR. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):370-8. link to original article PubMed
3. NPC 95-01: Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, Delhoume JY, Le Treut J, Silvani JA, Dansin E, Bozonnat MC, Daurés JP, Mornex F, Pérol M; Groupe Lyon-Saint-Etienne d'Oncologie Thoracique; Groupe Français de Pneumo-Cancérologie. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005 Sep 1;23(25):5910-7. Epub 2005 Aug 8. link to original article contains dosing details in abstract PubMed
4. SWOG S0023: Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. link to original article contains dosing details in manuscript PubMed NCT00020709
5. HOG Lun 01-24: Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L; Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and US Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. link to original article contains dosing details in abstract PubMed NCT00216125
6. RTOG 93-09: Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009 Aug 1;374(9687):379-86. Epub 2009 Jul 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00002550
7. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed NCT01134861
8. Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains dosing details in manuscript PubMed NCT01494558
9. MS200647_0005: NCT03840902
10. PACIFIC 2: NCT03519971

Cisplatin, Pemetrexed, RT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (MS200647_0005)	2019-ongoing	Phase 3 (C)	1a. CP, Bintrafusp alfa, RT 1b. Cisplatin, Pemetrexed, Bintrafusp alfa, RT 1c. EP, Bintrafusp alfa, RT	TBD if different primary endpoint of PFS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once per day on days 1, 22, 43
• Pemetrexed (Alimta) 500 mg/m² IV once per day on days 1, 22, 43

Radiotherapy

• Concurrent IMRT, 200 cGy fractions x 30 (total dose: 6000 cGy)

9-week course

Subsequent treatment

• Durvalumab consolidation

References

1. MS200647_0005: contains dosing details on CT.gov NCT03840902

Cisplatin, Vinblastine, RT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Curran et al. 2011 (RTOG 9410)	1994-1998	Phase 3 (E-switch-ic)	1. Cisplatin, Etoposide, RT	Did not meet primary endpoint of OS
			2. Cisplatin & Vinblastine, then RT	Seems to have superior OS (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once per day on days 1 & 29
• Vinblastine (Velban) 5 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

• Concurrent radiation therapy

5-week course

References

1. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed NCT01134861

Cisplatin, Vinorelbine, RT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Eberhardt et al. 2015 (ESPATUE)	2004-2013	Phase 3 (E-switch-ooc)	Surgery	Did not meet primary endpoint of OS

Preceding treatment

• Cisplatin & Paclitaxel induction

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once per day on days 2 & 9
• Vinorelbine (Navelbine) 20 mg/m² IV once per day on days 2 & 9

Radiotherapy

• Concurrent radiation therapy 150 cGy twice per day for 30 fractions (4500 cGy total)

21-day course

References

1. ESPATUE: Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V, Welter S, Budach W, Spengler W, Kimmich M, Fischer B, Schmidberger H, De Ruysscher D, Belka C, Cordes S, Hepp R, Lütke-Brintrup D, Lehmann N, Schuler M, Jöckel KH, Stamatis G, Stuschke M. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol. 2015 Dec 10;33(35):4194-201. Epub 2015 Nov 2. link to original article contains dosing details in abstract PubMed

Radiation therapy

RT: Radiation Therapy

Regimen variant #1, 2000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ball et al. 1997	1988-1993	Phase 3 (C)	5-FU & RT	Seems to have inferior OS

Radiotherapy

• External beam radiotherapy 400 cGy in 5 fractions (2000 cGy total)

5-day course

Regimen variant #2, 4500 cGy + 1800 cGy boost (6300 cGy total)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Curran et al. 2011 (RTOG 9410)	1994-1998	Phase 3 (C)	See link	See link
Belani et al. 2005 (LAMP)	1998-2001	Phase 2

Preceding treatment

• LAMP: Induction Carboplatin & Paclitaxel x 2
• RTOG 9410: Induction Cisplatin & Vinblastine x 5 wk

Radiotherapy

• External beam radiotherapy 4500 cGy in 180 cGy fractions x 25 fractions, then 1800 cGy boost in 200 cGy fractions x 9 fractions

7-week course

Regimen variant #3, 6000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Perez et al. 1988	NR	Phase 3 (C)	Levamisole & RT	Did not meet endpoint of OS
Morton et al. 1991	1983-1987	Phase 3 (C)	MACC & RT	Did not meet primary endpoint of OS
Clamon et al. 1999 (CALGB 9130)	1991-NR	Phase 3 (C)	Carboplatin & RT	Did not meet primary endpoint of OS
Bradley et al. 2002 (RTOG 93-04)	1994-1998	Phase 3 (C)	Beta-interferon & RT	Did not meet primary endpoint of OS
Groen et al. 2004	1995-1998	Phase 3 (C)	Carboplatin & RT	Did not meet primary endpoint of OS24
Atagi et al. 2012 (JCOG0301)	2003-2010	Phase 3 (C)	Carboplatin & RT	Seems to have inferior OS

Preceding treatment

• CALGB 9130: Induction Cisplatin & Vinblastine x 5 wk

Radiotherapy

• External beam radiotherapy 6000 cGy

One course

References

1. Perez CA, Bauer M, Emami BN, Byhardt R, Brady LW, Doggett RL, Gardner P, Zinninger M. Thoracic irradiation with or without levamisole (NSC #177023) in unresectable non-small cell carcinoma of the lung: a phase III randomized trial of the RTOG. Int J Radiat Oncol Biol Phys. 1988 Dec;15(6):1337-46. link to original article PubMed
2. Morton RF, Jett JR, McGinnis WL, Earle JD, Therneau TM, Krook JE, Elliott TE, Mailliard JA, Nelimark RA, Maksymiuk AW, Drummond RG, Laurie JA, Kugler JW, Anderson RT. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer: a randomized, phase III trial. Ann Intern Med. 1991 Nov 1;115(9):681-6. link to original article PubMed
3. Ball D, Smith J, Bishop J, Olver I, Davis S, O'Brien P, Bernshaw D, Ryan G, Millward M. A phase III study of radiotherapy with and without continuous-infusion fluorouracil as palliation for non-small-cell lung cancer. Br J Cancer. 1997;75(5):690-7. link to original article link to PMC article PubMed
4. CALGB 9130: Clamon G, Herndon J, Cooper R, Chang AY, Rosenman J, Green MR; CALGB; ECOG. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999 Jan;17(1):4-11. link to original article PubMed
5. RTOG 93-04: Bradley JD, Scott CB, Paris KJ, Demas WF, Machtay M, Komaki R, Movsas B, Rubin P, Sause WT. A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1173-9. link to original article contains dosing details in abstract PubMed
6. Groen HJ, van der Leest AH, Fokkema E, Timmer PR, Nossent GD, Smit WJ, Nabers J, Hoekstra HJ, Hermans J, Otter R, van Putten JW, de Vries EG, Mulder NH. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol. 2004 Mar;15(3):427-32. link to original article PubMed
7. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. Epub 2005 Aug 8. link to original article contains dosing details in abstract PubMed
8. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed NCT01134861
9. JCOG0301: Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; JCOG Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. link to original article contains dosing details in abstract PubMed NCT00132665
10. SWOG S1914: NCT04214262

Consolidation after definitive therapy for inoperable disease

Carboplatin & Paclitaxel (CP)

Regimen variant #1, 5/200 x 2

Study	Dates of enrollment	Evidence
Yamamoto et al. 2010 (WJTOG0105)	2001-2005	Non-randomized part of phase 3 RCT

Preceding treatment

• Definitive CP & RT

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 2 cycles

Regimen variant #2, 6/200 x 2

Study	Dates of enrollment	Evidence
Belani et al. 2005 (LAMP)	1998-2001	Phase 2
Bradley et al. 2015 (RTOG 0617)	2007-2011	Non-randomized part of phase 3 RCT

Preceding treatment

• Definitive CP & RT

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 2 cycles

References

1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. Epub 2005 Aug 8. link to original article contains dosing details in abstract PubMed
2. WJTOG0105: Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010 Aug 10;28(23):3739-45. Epub 2010 Jul 12. link to original article contains dosing details in manuscript PubMed NCT00144053
   1. Update: Zenke Y, Tsuboi M, Chiba Y, Tsujino K, Satouchi M, Sawa K, Shimizu J, Daga H, Fujimoto D, Mori M, Aoki T, Sawa T, Omori S, Saka H, Iwamoto Y, Okuno M, Hirashima T, Kashiwabara K, Tachihara M, Yamamoto N, Nakagawa K. Effect of Second-generation vs Third-generation Chemotherapy Regimens With Thoracic Radiotherapy on Unresectable Stage III Non-Small-Cell Lung Cancer: 10-Year Follow-up of a WJTOG0105 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):904-909. link to original article link to PMC article PubMed
3. RTOG 0617: Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00533949
   1. Update: Bradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Paulus R, Curran WJ Jr, Choy H. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Mar 1;38(7):706-714. Epub 2019 Dec 16. link to original article link to PMC article PubMed
   2. Dataset: Project Data Sphere

Maintenance after definitive therapy for inoperable disease

Durvalumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Antonia et al. 2017 (PACIFIC)	2014-2016	Phase 3 (E-RT-esc)	Placebo	Superior OS1 (co-primary endpoint) Median OS: 47.5 vs 29.1 mo (HR 0.72, 95% CI 0.59-0.89)
Awaiting publication (CheckMate 73L)	2019-2025	Phase 3 (C)	1. Ipilimumab & Nivolumab 2. Nivolumab	TBD if different primary endpoint of PFS
Awaiting publication (SKYSCRAPER-03)	2020-2024	Phase 3 (C)	Atezolizumab & Tiragolumab	TBD if different primary endpoint of PFS
Awaiting publication (KEYLYNK-012)	2020-2026	Phase 3 (C)	1. Olaparib & Pembrolizumab 2. Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (BGB-A317-A1217-301)	2021-2025	Phase 3 (C)	1. Ociperlimab & Tislelizumab 2. Tislelizumab	TBD if different primary endpoint of PFS
Awaiting publication (PACIFIC-9)	2022-2026	Phase 3 (C)	1. Durvalumab & Monalizumab 2. Durvalumab & Oleclumab	TBD if different primary endpoint of PFS
Awaiting publication (PACIFIC-8)	2022-2027	Phase 3 (C)	Domvanalimab & Durvalumab	TBD if different primary endpoint of PFS

¹Reported efficacy is based on the 2022 update.

Preceding treatment

• PACIFIC: "Two or more cycles (defined according to local practice) of platinum-based chemoradiotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 6600 cGy), in which the mean dose to the lung was less than 2000 cGy, the V20 (the volume of lung parenchyma that received 2000 cGy or more) was less than 35%, or both."

Immunotherapy

• Durvalumab (Imfinzi) 10 mg/kg IV once on day 1

14-day cycle for up to 26 cycles (1 year)

References

1. PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains dosing details in manuscript PubMed NCT02125461
   1. Update: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. link to original article PubMed
   2. PRO analysis: Hui R, Özgüroğlu M, Villegas A, Daniel D, Vicente D, Murakami S, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Gray JE, Rydén A, Viviers L, Poole L, Zhang Y, Dennis PA, Antonia SJ. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol. 2019 Dec;20(12):1670-1680. Epub 2019 Oct 7. link to original article PubMed
   3. Update: Gray JE, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, Cho BC, Planchard D, Paz-Ares L, Faivre-Finn C, Vansteenkiste JF, Spigel DR, Wadsworth C, Taboada M, Dennis PA, Özgüroğlu M, Antonia SJ. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC. J Thorac Oncol. 2020 Feb;15(2):288-293. Epub 2019 Oct 14. link to original article link to PMC article PubMed
   4. Update: Faivre-Finn C, Vicente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste JF, Spigel DR, Garassino MC, Reck M, Senan S, Naidoo J, Rimner A, Wu YL, Gray JE, Özgüroğlu M, Lee KH, Cho BC, Kato T, de Wit M, Newton M, Wang L, Thiyagarajah P, Antonia SJ. Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial. J Thorac Oncol. 2021 May;16(5):860-867. Epub 2021 Jan 19. link to original article PubMed
   5. Update: Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, Vansteenkiste JF, Garassino MC, Hui R, Quantin X, Rimner A, Wu YL, Özgüroğlu M, Lee KH, Kato T, de Wit M, Kurata T, Reck M, Cho BC, Senan S, Naidoo J, Mann H, Newton M, Thiyagarajah P, Antonia SJ. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022 Apr 20;40(12):1301-1311. Epub 2022 Feb 2. link to original article link to PMC article PubMed
2. BGB-A317-A1217-301: NCT04866017
3. CheckMate 73L: NCT04026412
4. KEYLYNK-012: NCT04380636
5. PACIFIC-8: NCT05211895
6. PACIFIC-9: NCT05221840
7. SKYSCRAPER-03: NCT04513925

Sugemalimab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhou et al. 2022 (GEMSTONE-301)	2018-2020	Phase 3 (E-esc)	Placebo	Superior PFS (primary endpoint) Median PFS: 9 vs 5.8 mo (HR 0.64, 95% CI 0.48-0.85)

Preceding treatment

• Concurrent or sequential definitive chemoradiotherapy

Immunotherapy

• Sugemalimab (Cejemly) 1200 mg IV once on day 1

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

References

1. GEMSTONE-301: Zhou Q, Chen M, Jiang O, Pan Y, Hu D, Lin Q, Wu G, Cui J, Chang J, Cheng Y, Huang C, Liu A, Yang N, Gong Y, Zhu C, Ma Z, Fang J, Chen G, Zhao J, Shi A, Lin Y, Li G, Liu Y, Wang D, Wu R, Xu X, Shi J, Liu Z, Cui N, Wang J, Wang Q, Zhang R, Yang J, Wu YL. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):209-219. Epub 2022 Jan 14. link to original article contains dosing details in abstract PubMed NCT03728556

Advanced or metastatic disease, first-line

Atezolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (SKYSCRAPER-01)	2020-ongoing	Phase 3 (C)	Atezolizumab & Tiragolumab	TBD if different co-primary endpoints of PFS/OS

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

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. SKYSCRAPER-01: NCT04294810

Carboplatin & Docetaxel

DCb: Docetaxel & Carboplatin

Regimen variant #1, 4 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Booton et al. 2006 (BTOG1)	2001-06 to 2002-11	Phase 3 (E-switch-ic)	1a. MIC 1b. MVP	Did not meet primary endpoint of OS

Chemotherapy

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

21-day cycle for 4 cycles

Regimen variant #2, 5 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Groen et al. 2011 (NVALT-4)	2003-2007	Phase 3 (C)	DCb & Celecoxib	Did not meet primary endpoint of OS

Chemotherapy

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

21-day cycle for 5 cycles

Regimen variant #3, 6 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lynch et al. 2010 (BMS099)	2005-01 to 2006-11	Phase 3 (C)	1a. CP & Cetuximab 1b. DCb & Cetuximab	Did not meet primary endpoint of PFS

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

Regimen variant #4, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fossella et al. 2003 (TAX 326)	1998-2000	Phase 3 (E-RT-switch-ic)	1. Cisplatin & Docetaxel	Not reported
			2. Cisplatin & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

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

21-day cycles

References

1. TAX 326: Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains dosing details in abstract PubMed
2. BTOG1: Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. link to original article contains dosing details in manuscript PubMed
3. BMS099: Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. link to original article contains dosing details in abstract PubMed NCT00112294
4. NVALT-4: Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, Dalesio O, Biesma B, Smit HJ, Termeer A, Hiltermann TJ, van den Borne BE, Schramel FM. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol. 2011 Nov 10;29(32):4320-6. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NTR1703

Carboplatin & Etoposide (CE)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Klastersky et al. 1990 (EORTC 07861)	1987-1989	Phase 3 (E-switch-ic)	Cisplatin & Etoposide	Might have inferior ORR

Chemotherapy

• Carboplatin (Paraplatin) 325 mg/m² IV over 60 minutes once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

3- to 4-week cycles

References

1. EORTC 07861: Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. link to original article contains dosing details in manuscript PubMed

Carboplatin & Gemcitabine (GCb)

GC: Gemcitabine & Carboplatin
GCa: Gemcitabine & Carboplatin
GCb: Gemcitabine & Carboplatin

Regimen variant #1, 4/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Helbekkmo et al. 2007	2003-10 to 2004-12	Phase 3 (E-switch-ic)	VCb	Did not meet primary endpoint of OS

Note: AUC was calculated using the Chatelut formula.

Chemotherapy

• Carboplatin (Paraplatin) AUC 4 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycle for 3 cycles

Regimen variant #2, 5/1000 q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Grønberg et al. 2009	2005-04 to 2006-07	Phase 3 (C)	Carboplatin & Pemetrexed		Did not meet primary endpoint of HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 4 cycles

Regimen variant #3, 5/1000 q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Danson et al. 2003	1997-2001	Phase 3 (E-switch-ic)	1a. MIC 1b. MVP	Did not meet primary endpoint of OS

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycle for 4 cycles

Regimen variant #4, 5/1200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Zatloukal et al. 2003	1999-2001	Phase 3 (E-switch-ic)	Cisplatin & Gemcitabine		Did not meet primary endpoint of grade 3/4 toxicity
Rudd et al. 2005	1999-2001	Phase 3 (E-switch-ic)	MIC	Superior OS (primary endpoint)

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #5, 5/1250 q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Sederholm et al. 2005	1998-2001	Phase 3 (C)	Gemcitabine	Seems to have superior OS
Bepler et al. 2013 (MCC-15005)	2007-2010	Phase 3 (C)	ERCC1 and RRM1 expression-based chemotherapy	Did not meet primary endpoint of PFS6
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 to 6 cycles

Regimen variant #6, 6/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kosmidis et al. 2007	2000-2004	Phase 3 (C)	Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #7, 6/1250 ("GCb6")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Ferry et al. 2017 (BTOG2)	2005-2009	Phase 3 (E-switch-ic)	1. GC; GC50	Seems to have superior OS (primary endpoint)
			2. GC; GC80	Non-inferior OS (primary endpoint)
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 to 6 cycles

Regimen variant #8, 300/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Grigorescu et al. 2002	1997-2000	Phase 3 (E-switch-ic)	Cisplatin & Vinblastine	Superior OS

Chemotherapy

• Carboplatin (Paraplatin) 300 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Grigorescu AC, Draghici IN, Nitipir C, Gutulescu N, Corlan E. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer. 2002 Jul;37(1):9-14. link to original article contains dosing details in abstract PubMed
2. Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. link to original article contains dosing details in abstract PubMed
3. Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. link to original article contains dosing details in abstract PubMed
4. Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG, Littler JA, Hatton M, Johnson PW, Martin WM, Rankin EM, James LE, Gregory WM, Qian W, Lee SM; London Lung Cancer Group. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol. 2005 Jan 1;23(1):142-53. link to original article contains dosing details in abstract PubMed
5. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR; Swedish Lung Cancer Study Group. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. link to original article contains dosing details in manuscript PubMed
6. Helbekkmo N, Sundstrøm SH, Aasebø U, Brunsvig PF, von Plessen C, Hjelde HH, Garpestad OK, Bailey A, Bremnes RM; Norwegian Lung Cancer Study Group. Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer. 2007 Aug 6;97(3):283-9. Epub 2007 Jun 26. link to original article link to PMC article contains dosing details in manuscript PubMed
7. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains dosing details in abstract PubMed
8. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains dosing details in manuscript PubMed
9. ALPHA A1-99002L: Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. link to original article contains dosing details in abstract PubMed NCT00054392
10. MCC-15005: Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, Gadgeel S, Zhao X, Schreiber F, Brahmer J, Chiappori A, Tanvetyanon T, Pinder-Schenck M, Gray J, Haura E, Antonia S, Fischer JR. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013 Jul 1;31(19):2404-12. Epub 2013 May 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00499109
11. NITRO: Davidson A, Veillard AS, Tognela A, Chan MM, Hughes BG, Boyer M, Briscoe K, Begbie S, Abdi E, Crombie C, Long J, Boyce A, Lewis CR, Varma S, Broad A, Muljadi N, Chinchen S, Espinoza D, Coskinas X, Pavlakis N, Millward M, Stockler MR; Australasian Lung cancer Trials Group (ALTG); Australasian Lung cancer Trials Group ALTG. A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial. Ann Oncol. 2015 Nov;26(11):2280-6. Epub 2015 Sep 7. link to original article PubMed ACTRN12608000588392
12. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
    3. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. Epub 2021 Apr 19. link to original article link to PMC article PubMed
13. BTOG2: Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K; British Thoracic Oncology Group. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00112710

Carboplatin & Gemcitabine (GCb) & Paclitaxel

PCG: Paclitaxel, Carboplatin, Gemcitabine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Paccagnella et al. 2006	1998-2004	Phase 2/3 (E-esc)	CP	Seems to have superior OS (co-primary endpoint) Median OS: 10.8 vs 8.3 mo (HR 0.76, 95% CI 0.60-0.97)

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first
• Carboplatin (Paraplatin) AUC 6 IV once on day 1, given second
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 to 60 minutes once per day on days 1 & 8, given third

Supportive therapy

• Dexamethasone (Decadron) 16 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
• Ranitidine (Zantac) (or equivalent) 50 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel

21-day cycle for at least 6 cycles

References

1. Paccagnella A, Oniga F, Bearz A, Favaretto A, Clerici M, Barbieri F, Riccardi A, Chella A, Tirelli U, Ceresoli G, Tumolo S, Ridolfi R, Biason R, Nicoletto MO, Belloni P, Veglia F, Ghi MG. Adding gemcitabine to paclitaxel/carboplatin combination increases survival in advanced non-small-cell lung cancer: results of a phase II-III study. J Clin Oncol. 2006 Feb 1;24(4):681-7. Erratum in: J Clin Oncol. 2006 May 10;24(14):2220. link to original article contains dosing details in manuscript PubMed

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
TC: Taxol (Paclitaxel) & Carboplatin

Regimen variant #1, 5/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase 3 (C)	Pembrolizumab	Inferior OS
Rizvi et al. 2020 (MYSTIC)	2015-07-21 to 2016-06-08	Phase 3 (C)	1. Durvalumab	Might have inferior OS
			2. Durvalumab & Tremelimumab	Did not meet co-primary endpoints of PFS/OS
Wu et al. 2020 (KEYNOTE-042 China Extension)	2016-08-26 to 2018-01-04	Phase 3 (C)	Pembrolizumab	Inferior OS
Sezer et al. 2021 (EMPOWER-Lung 1)	2017-06-27 to 2020-02-27	Phase 3 (C)	Cemiplimab	Inferior OS
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2)	2019-06-17 to 2020-09-30	Phase 3 (C)	Investigator's choice of: 1a. CP & Cemiplimab 1b. Cisplatin, Paclitaxel, Cemiplimab	Inferior OS

Note: In EMPOWER-Lung 3 part 2, patients with nonsquamous histology had additional treatment options; see the histology-specific page for more information.

Biomarker eligibility criteria

• EMPOWER-Lung 1: PD-L1 expressed in at least 50% of tumor cells
• KEYNOTE-042 & KEYNOTE-042 China Extension: PD-L1 tumor proportion score (TPS) of at least 1%

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for 4 to 6 cycles

Subsequent treatment

• KEYNOTE-024: Patients with nonsquamous histology could optionally proceed to pemetrexed switch maintenance

Regimen variant #2, 6/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stathopoulos et al. 2004	2000-2003	Phase 3 (C)	Paclitaxel & Vinorelbine	Did not meet co-primary endpoints of ORR/OS
Lynch et al. 2012 (CA184-041NSCLC)	2008-2009	Randomized Phase 2 (C)	1. CP & Ipilimumab; phased ipilimumab	Seems to have inferior irPFS
			2. CP & Ipilimumab; concurrent ipilimumab	Did not meet primary endpoint of irPFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Supportive therapy

• Corticosteroids could be used as premedication for paclitaxel infusion.

21-day cycle for up to 6 cycles

Regimen variant #3, 6/200 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Socinski et al. 2002	1998-2000	Phase 3 (E-de-esc)	CP; indefinite	Did not meet primary endpoint of OS	Did not meet primary endpoint of QoL
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2)	2019-06-17 to 2020-09-30	Phase 3 (C)	Investigator's choice of: 1a. CP & Cemiplimab 1b. Cisplatin, Paclitaxel, Cemiplimab	Inferior OS

Note: In EMPOWER-Lung 3 part 2, patients with nonsquamous histology had additional treatment options; see the histology-specific page for more information.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV once on day 1, given 30 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg (route not specified) once on day 1, given 30 minutes prior to paclitaxel
• One of the following H2 blockers:
  • Ranitidine (Zantac) 50 mg IV once on day 1, given 30 minutes prior to paclitaxel
  • Cimetidine (Tagamet) 300 mg IV once on day 1, given 30 minutes prior to paclitaxel

21-day cycle for 4 cycles

Subsequent treatment

• Socinski et al. 2002, upon progression: Second-line Paclitaxel

Regimen variant #4, 6/200 x 4 to 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Laurie et al. 2013 (NCIC-CTG BR.29)	2008-2011	Phase 3 (C)	CP & Cediranib	Did not meet primary endpoint of OS	Less toxic
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase 3 (C)	Pembrolizumab	Inferior OS
Rizvi et al. 2020 (MYSTIC)	2015-07-21 to 2016-06-08	Phase 3 (C)	1. Durvalumab	Might have inferior OS
			2. Durvalumab & Tremelimumab	Did not meet co-primary endpoints of PFS/OS
Wu et al. 2020 (KEYNOTE-042 China Extension)	2016-08-26 to 2018-01-04	Phase 3 (C)	Pembrolizumab	Inferior OS

Biomarker eligibility criteria

• KEYNOTE-042 & KEYNOTE-042 China Extension: PD-L1 tumor proportion score (TPS) of at least 1%

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for 4 to 6 cycles

Subsequent treatment

• KEYNOTE-024, patients with nonsquamous histology: optional pemetrexed switch maintenance

Regimen variant #5, 6/200 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Johnson et al. 2004	NR	Randomized Phase 2 (C)	PacCBev	Seems to have inferior TTP
Herbst et al. 2005 (TRIBUTE)	2001-07-18 to 2002-08-19	Phase 3 (C)	CP & Erlotinib	Did not meet primary endpoint of OS
Schuette et al. 2006	NR	Phase 3 (C)	CP; weekly	Seems to have non-inferior ORR (primary endpoint)	Mixed toxicity
Hirsh et al. 2011 (A8501001)	2005-2007	Phase 3 (C)	CP & Agatolimod	Did not meet primary endpoint of OS
Scagliotti et al. 2010 (ESCAPE)	2006-02 to 2007-05	Phase 3 (C)	CP & Sorafenib	Did not meet primary endpoint of OS
Okamoto et al. 2010 (LETS)	2006-2008	Phase 3 (C)	Carboplatin & S-1	Non-inferior OS
Langer et al. 2014 (A4021016)	2008-04 to 2009-09	Phase 3 (C)	CP & Figitumumab	Might have superior OS (primary endpoint) Median OS: 9.8 vs 8.6 mo (HR 0.85, 95% CI 0.71-1.01)
Lara et al. 2011 (ATTRACT-1)	2008-04 to 2009-10	Phase 3 (C)	CP & Vadimezan	Did not meet primary endpoint of OS
Herbst et al. 2017 (SWOG S0819)	2009-2014	Phase 3 (C)	1a. CP & Cetuximab 1b. CP, Bevacizumab, Cetuximab	Did not meet co-primary endpoints of PFS/OS
Ramalingam et al. 2016 (M10-898)	2012-2013	Randomized Phase 2 (C)	CP & Veliparib	Did not meet primary endpoint of PFS

Biomarker eligibility criteria

• SWOG S0819: EGFR FISH positive

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, 60 minutes after completion of paclitaxel
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 6 cycles

Regimen variant #6, 6/200 x 8

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Leighl et al. 2005 (NCIC-CTG BR.18)	2000-2002	Phase 3 (C)	CP & Rebimastat	Did not meet primary endpoint of OS	Less toxic

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for 8 cycles

Regimen variant #7, 6/200 indefinitely

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosell et al. 2002	1996-04 to 1997-07	Phase 3 (E-switch-ic)	Cisplatin & Paclitaxel	Seems to have inferior OS
Kosmidis et al. 2002	1998-2000	Phase 3 (E-switch-ic)	Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS
Paccagnella et al. 2006	1998-2004	Phase 2/3 (C)	PCG	Seems to have inferior OS
Ohe et al. 2006 (FACS)	2000-2002	Phase 3 (E-switch-ic)	1. Cisplatin & Gemcitabine	Inconclusive whether non-inferior OS (primary endpoint)
			2. Cisplatin & Irinotecan	Inconclusive whether non-inferior OS (primary endpoint)
			3. Cisplatin & Vinorelbine	Inconclusive whether non-inferior OS (primary endpoint)
Blumenschein et al. 2008 (SPIRIT II)	2002-NR	Phase 3 (C)	CP & Bexarotene	Did not meet primary endpoint of OS
Socinski et al. 2012 (CA031)	2007-2009	Phase 3 (C)	Carboplatin & nab-Paclitaxel	Inferior ORR

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO once on day -1, given 12 hours prior to paclitaxel, then 20 mg IV once on day 1, given 30 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1, given 30 minutes prior to paclitaxel
• Cimetidine (Tagamet) (dose/route not specified) once on day 1, given 30 minutes prior to paclitaxel
• Ondansetron (Zofran) 16 mg IV once on day 1, given 15 minutes prior to chemotherapy, then 8 mg PO twice per day on days 1 to 3

21-day cycles

Regimen variant #8, 6/225

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2001 (SWOG 9509)	1996-1998	Phase 3 (E-switch-ic)	Cisplatin & Vinorelbine	Did not meet primary endpoint of OS
Schiller et al. 2002 (ECOG E1594)	1996-1999	Phase 3 (E-switch-ic)	1. Cisplatin & Docetaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
			3. Cisplatin & Paclitaxel	Did not meet primary endpoint of OS
Lilenbaum et al. 2005 (CALGB 9730)	1997-2000	Phase 3 (E-esc)	Paclitaxel	Did not meet primary endpoint of OS Median OS: 8.8 vs 6.7 mo (HR 0.91, 95% CI 0.77-1.17)
Herbst et al. 2004 (INTACT 2)	2000-05 to 2001-04	Phase 3 (C)	CP & Gefitinib	Did not meet primary endpoint of OS
Williamson et al. 2005 (SWOG S0003)	2000-2002	Phase 3 (C)	CP & Tirapazamine	Did not meet primary endpoint of OS
Belani et al. 2008 (BMS TAX/MEN.12)	2000-2004	Phase 3 (C)	CP; weekly paclitaxel	Did not meet primary endpoint of OS
Treat et al. 2009 (ALPHA A1-99002L)	2000-2005	Phase 3 (C)	1. Carboplatin & Gemcitabine 2. Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS
Kubota et al. 2008 (JMTO LC00-03)	2001-2005	Phase 3 (C)	Gemcitabine & Vinorelbine, then Docetaxel	Did not meet primary endpoint of OS Median OS: 14.1 vs 13.6 mo
Weissman et al. 2011 (SR96669)	2004-03-04 to 2005-04-15	Phase 3 (C)	GemOx	Did not meet primary endpoint of PFS Median PFS: 4.7 vs 4.4 mo
Lynch et al. 2010 (BMS099)	2005-01 to 2006-11	Phase 3 (C)	1a. CP & Cetuximab 1b. DCb & Cetuximab	Did not meet primary endpoint of PFS Median PFS: 4.2 vs 4.4 mo (HR 1.11, 95% CI 0.94-1.31)

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 225 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 4 cycles (BMS TAX/MEN.12), 6 cycles (ALPHA A1-99002L, BMS099, CALGB 9730, INTACT 2, JMTO LC00-03, SR96669, SWOG S0003), 10 cycles (SWOG 9509), or indefinitely (ECOG E1594)

Subsequent treatment

• BMS TAX/MEN.12: Paclitaxel maintenance

References

1. SWOG 9509: Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. link to original article contains dosing details in manuscript PubMed
2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains dosing details in abstract PubMed
3. Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, Unger P, Lee J, Lee JH, Tynan M, Moore M, Kies MS. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002 Mar 1;20(5):1335-43. link to original article contains dosing details in manuscript PubMed
4. Kosmidis P, Mylonakis N, Nicolaides C, Kalophonos C, Samantas E, Boukovinas J, Fountzilas G, Skarlos D, Economopoulos T, Tsavdaridis D, Papakostas P, Bacoyiannis C, Dimopoulos M. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2002 Sep 1;20(17):3578-85. link to original article contains dosing details in abstract PubMed
5. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. link to original article contains dosing details in abstract PubMed
6. INTACT 2: Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004 Mar 1;22(5):785-94. link to original article contains dosing details in abstract PubMed
7. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article contains dosing details in manuscript PubMed
8. Stathopoulos GP, Veslemes M, Georgatou N, Antoniou D, Giamboudakis P, Katis K, Tsavdaridis D, Rigatos SK, Dimitroulis I, Bastani S, Loukides S, Vergos K, Marossis K, Grigoratou T, Kalatzi E, Charalambatou M, Paspalli A, Michalopoulou P, Stoka M, Gerogianni A. Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial. Ann Oncol. 2004 Jul;15(7):1048-55. link to original article contains dosing details in abstract PubMed
9. CALGB 9730: Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, Graziano SL, Perry MC, Saville W, Chahinian P, Weeks JC, Holland JC, Green MR. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer and Leukemia Group B (study 9730). J Clin Oncol. 2005 Jan 1;23(1):190-6. link to original articlecontains dosing details in manuscript PubMed NCT00003117
10. NCIC-CTG BR.18: Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Depierre A, Santoro A, Betticher DC, Gatzemeier U, Jassem J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR18. J Clin Oncol. 2005 Apr 20;23(12):2831-9. link to original article contains dosing details in manuscript PubMed NCT00006229
11. TRIBUTE: Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25. link to original article contains dosing details in manuscript PubMed NCT00047736
12. SWOG S0003: Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR; SWOG. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005 Dec 20;23(36):9097-104. link to original article contains dosing details in abstract PubMed NCT00006484
13. Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N, Appel T, Ukena D. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer. 2006 Mar;7(5):338-43. link to original article contains dosing details in abstract PubMed
14. Paccagnella A, Oniga F, Bearz A, Favaretto A, Clerici M, Barbieri F, Riccardi A, Chella A, Tirelli U, Ceresoli G, Tumolo S, Ridolfi R, Biason R, Nicoletto MO, Belloni P, Veglia F, Ghi MG. Adding gemcitabine to paclitaxel/carboplatin combination increases survival in advanced non-small-cell lung cancer: results of a phase II-III study. J Clin Oncol. 2006 Feb 1;24(4):681-7. Erratum in: J Clin Oncol. 2006 May 10;24(14):2220. link to original article contains dosing details in manuscript PubMed
15. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains dosing details in manuscript PubMed
16. BMS TAX/MEN.12: Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol. 2008 Jan 20;26(3):468-73. link to original article contains dosing details in abstract PubMed NCT00035152
17. SPIRIT II: Blumenschein GR Jr, Khuri FR, von Pawel J, Gatzemeier U, Miller WH Jr, Jotte RM, Le Treut J, Sun SL, Zhang JK, Dziewanowska ZE, Negro-Vilar A. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008 Apr 10;26(11):1879-85. link to original article contains dosing details in manuscript PubMed NCT00050960
18. JMTO LC00-03: Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, Fujita Y, Teramukai S, Fukushima M, Furuse K; Japan Multi-National Trial Organisation. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol. 2008 Dec;9(12):1135-42. Epub 2008 Nov 13. link to original article contains dosing details in abstract PubMed NCT00079287
19. ALPHA A1-99002L: Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. link to original article contains dosing details in abstract PubMed NCT00054392
20. BMS099: Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. link to original article contains dosing details in abstract PubMed NCT00112294
21. ESCAPE: Scagliotti G, Novello S, von Pawel J, Reck M, Rodrigues Pereira J, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010 Apr 10;28(11):1835-42. Epub 2010 Mar 8. link to original article contains dosing details in abstract PubMed NCT00300885
    1. Dataset: Project Data Sphere
22. LETS: Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata T, Fukuoka M, Nakagawa K; West Japan Oncology Group. Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study. J Clin Oncol. 2010 Dec 20;28(36):5240-6. Epub 2010 Nov 15. link to original article contains dosing details in manuscript PubMed UMIN000000503
23. SR96669: Weissman CH, Reynolds CH, Neubauer MA, Pritchard S, Kobina S, Asmar L. A phase III randomized trial of gemcitabine-oxaliplatin versus carboplatin-paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011 Feb;6(2):358-64. link to original article contains dosing details in abstract PubMed NCT00087802
24. A8501001: Hirsh V, Paz-Ares L, Boyer M, Rosell R, Middleton G, Eberhardt WE, Szczesna A, Reiterer P, Saleh M, Arrieta O, Bajetta E, Webb RT, Raats J, Benner RJ, Fowst C, Meech SJ, Readett D, Schiller JH. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Jul 1;29(19):2667-74. Epub 2011 May 31. link to original article contains dosing details in manuscript PubMed NCT00254891
25. ATTRACT-1: Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A, Scagliotti G. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 1;29(22):2965-71. Epub 2011 Jun 27. link to original article contains dosing details in manuscript PubMed NCT00662597
26. CA184-041_NSCLC: Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains dosing details in manuscript PubMed NCT00527735
27. CA031: Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains dosing details in manuscript PubMed NCT00540514
    1. Dataset: Project Data Sphere
28. NCIC-CTG BR.29: Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, Boyer MJ, Arnold AM, Clingan P, Laberge F, Fenton D, Hirsh V, Zukin M, Stockler MR, Lee CW, Chen EX, Montenegro A, Ding K, Bradbury PA. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer. 2014 Mar;50(4):706-12. Epub 2013 Dec 17. link to original article contains dosing details in manuscript PubMed NCT00795340
29. A4021016: Langer CJ, Novello S, Park K, Krzakowski M, Karp DD, Mok T, Benner RJ, Scranton JR, Olszanski AJ, Jassem J. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2014 Jul 1;32(19):2059-66. Epub 2014 Jun 2. link to original article link to PMC article PubMed NCT00596830
30. NITRO: Davidson A, Veillard AS, Tognela A, Chan MM, Hughes BG, Boyer M, Briscoe K, Begbie S, Abdi E, Crombie C, Long J, Boyce A, Lewis CR, Varma S, Broad A, Muljadi N, Chinchen S, Espinoza D, Coskinas X, Pavlakis N, Millward M, Stockler MR; Australasian Lung cancer Trials Group (ALTG); Australasian Lung cancer Trials Group ALTG. A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial. Ann Oncol. 2015 Nov;26(11):2280-6. Epub 2015 Sep 7. link to original article PubMed ACTRN12608000588392
31. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
    3. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. Epub 2021 Apr 19. link to original article link to PMC article PubMed
32. M10-898: Ramalingam SS, Blais N, Mazieres J, Reck M, Jones CM, Juhasz E, Urban L, Orlov S, Barlesi F, Kio E, Keiholz U, Qin Q, Qian J, Nickner C, Dziubinski J, Xiong H, Ansell P, McKee M, Giranda V, Gorbunova V. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin Cancer Res. 2017 Apr 15;23(8):1937-1944. Epub 2016 Oct 10. link to original article contains dosing details in abstract PubMed NCT01560104
33. SWOG S0819: Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. link to original article contains dosing details in abstract link to PMC article PubMed NCT00946712
34. MYSTIC: Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. link to original article contains dosing details in supplement link to PMC article PubMed NCT02453282
35. KEYNOTE-042 China Extension: Wu YL, Zhang L, Fan Y, Zhou J, Zhang L, Zhou Q, Li W, Hu C, Chen G, Zhang X, Zhou C, Dang T, Sadowski S, Kush DA, Zhou Y, Li B, Mok T. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study. Int J Cancer. 2021 May 1;148(9):2313-2320. Epub 2020 Dec 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03850444
36. EMPOWER-Lung 1: Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, Clingan P, Sriuranpong V, Rizvi N, Gao B, Li S, Lee S, McGuire K, Chen CI, Makharadze T, Paydas S, Nechaeva M, Seebach F, Weinreich DM, Yancopoulos GD, Gullo G, Lowy I, Rietschel P. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021 Feb 13;397(10274):592-604. link to original article contains dosing details in manuscript PubMed NCT03088540
    1. Update: Özgüroğlu M, Kilickap S, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, Nechaeva M, Schenker M, Cicin I, Ho GF, Kulyaba Y, Zyuhal K, Scheusan RI, Garassino MC, He X, Kaul M, Okoye E, Li Y, Li S, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Sep;24(9):989-1001. Epub 2023 Aug 14. link to original article PubMed
37. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
    1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed
38. ARC-10: NCT04736173

Carboplatin & nab-Paclitaxel

Regimen variant #1, AUC 5

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2022 (POSEIDON)	2017-06-27 to 2018-09-19	Phase 3 (C)	1. CnP & Durvalumab	Might have inferior OS
			2. CnP, Durvalumab, Tremelimumab	Inferior OS

Note: POSEIDON had additional treatment options for histology-specific subgroups; please see the respective pages for more details.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 to 6 cycles

Regimen variant #2, AUC 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Socinski et al. 2012 (CA031)	2007-2009	Phase 3 (E-RT-switch-ic)	Carboplatin & Paclitaxel	Superior ORR (primary endpoint)
Johnson et al. 2022 (POSEIDON)	2017-06-27 to 2018-09-19	Phase 3 (C)	1. CnP & Durvalumab	Might have inferior OS
			2. CnP, Durvalumab, Tremelimumab	Inferior OS

Note: In CA031, treatment could continue past 6 cycles at physician's discretion if there was no progressive disease or unacceptable toxicity. POSEIDON had additional treatment options for histology-specific subgroups; please see the respective pages for more details.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 (Calvert formula) IV once on day 1, given second
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

21-day cycle for 4 to 6 cycles

References

1. CA031: Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains dosing details in manuscript PubMed NCT00540514
   1. Dataset: Project Data Sphere
2. POSEIDON: Johnson ML, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Laktionov K, Kim SW, Ursol G, Hussein M, Lim FL, Yang CT, Araujo LH, Saito H, Reinmuth N, Shi X, Poole L, Peters S, Garon EB, Mok T; POSEIDON investigators. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023 Feb 20;41(6):1213-1227. Epub 2022 Nov 3. link to original article link to PMC article PubMed NCT03164616

Carboplatin, nab-Paclitaxel, Durvalumab

Regimen variant #1, AUC 5

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2022 (POSEIDON)	2017-06-27 to 2018-09-19	Phase 3 (E-esc)	1. CnP	Might have superior OS (co-primary endpoint) Median OS: 13.3 vs 11.7 mo (HR 0.86, 95% CI 0.72-1.02) Superior PFS (co-primary endpoint) Median PFS: 5.5 vs 4.8 mo (HR 0.74, 95% CI 0.62-0.89)
			2. CnP, Durvalumab, Tremelimumab	Not reported

Note: POSEIDON had additional treatment options for histology-specific subgroups; please see the respective pages for more details.

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 5 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Durvalumab (Imfinzi) as follows:
  • Cycles 1 to 4: 1500 mg IV over 60 minutes once on day 1
  • Cycle 5 onwards: 1500 mg IV over 60 minutes once on day 1

21-day cycle for 4 cycles, then 28-day cycles

Regimen variant #2, AUC 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2022 (POSEIDON)	2017-06-27 to 2018-09-19	Phase 3 (E-esc)	1. CnP	Might have superior OS (co-primary endpoint) Median OS: 13.3 vs 11.7 mo (HR 0.86, 95% CI 0.72-1.02) Superior PFS (co-primary endpoint) Median PFS: 5.5 vs 4.8 mo (HR 0.74, 95% CI 0.62-0.89)
			2. CnP, Durvalumab, Tremelimumab	Not reported

Note: POSEIDON had additional treatment options for histology-specific subgroups; please see the respective pages for more details.

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 6 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Durvalumab (Imfinzi) as follows:
  • Cycles 1 to 4: 1500 mg IV over 60 minutes once on day 1
  • Cycle 5 onwards: 1500 mg IV over 60 minutes once on day 1

21-day cycle for 4 cycles, then 28-day cycles

References

1. POSEIDON: Johnson ML, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Laktionov K, Kim SW, Ursol G, Hussein M, Lim FL, Yang CT, Araujo LH, Saito H, Reinmuth N, Shi X, Poole L, Peters S, Garon EB, Mok T; POSEIDON investigators. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023 Feb 20;41(6):1213-1227. Epub 2022 Nov 3. link to original article link to PMC article PubMed NCT03164616

Carboplatin, nab-Paclitaxel, Durvalumab, Tremelimumab

Regimen variant #1, AUC 5

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2022 (POSEIDON)	2017-06-27 to 2018-09-19	Phase 3 (E-RT-esc)	1. CnP	Superior OS (co-primary endpoint) Median OS: 14 vs 11.7 mo (HR 0.77, 95% CI 0.65-0.92) Superior PFS (co-primary endpoint) Median PFS: 6.2 vs 4.8 mo (HR 0.72, 95% CI 0.60-0.86)
			2. CnP & Durvalumab	Not reported

Note: POSEIDON had additional treatment options for histology-specific subgroups; please see the respective pages for more details.

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 5 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Durvalumab (Imfinzi) as follows:
  • Cycles 1 to 4: 1500 mg IV over 60 minutes once on day 1
  • Cycle 5 onwards: 1500 mg IV over 60 minutes once on day 1
• Tremelimumab (Imjudo) as follows:
  • Cycles 1 to 4, 6: 75 mg IV over 60 minutes once on day 1

21-day cycle for 4 cycles, then 28-day cycles

Regimen variant #2, AUC 6

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2022 (POSEIDON)	2017-06-27 to 2018-09-19	Phase 3 (E-RT-esc)	1. CnP	Superior OS (co-primary endpoint) Median OS: 14 vs 11.7 mo (HR 0.77, 95% CI 0.65-0.92) Superior PFS (co-primary endpoint) Median PFS: 6.2 vs 4.8 mo (HR 0.72, 95% CI 0.60-0.86)
			2. CnP & Durvalumab	Not reported

Note: POSEIDON had additional treatment options for histology-specific subgroups; please see the respective pages for more details.

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 6 IV once on day 1
• Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once per day on days 1, 8, 15

Immunotherapy

• Durvalumab (Imfinzi) as follows:
  • Cycles 1 to 4: 1500 mg IV over 60 minutes once on day 1
  • Cycle 5 onwards: 1500 mg IV over 60 minutes once on day 1
• Tremelimumab (Imjudo) as follows:
  • Cycles 1 to 4, 6: 75 mg IV over 60 minutes once on day 1

21-day cycle for 4 cycles, then 28-day cycles

References

1. POSEIDON: Johnson ML, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Laktionov K, Kim SW, Ursol G, Hussein M, Lim FL, Yang CT, Araujo LH, Saito H, Reinmuth N, Shi X, Poole L, Peters S, Garon EB, Mok T; POSEIDON investigators. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023 Feb 20;41(6):1213-1227. Epub 2022 Nov 3. link to original article link to PMC article PubMed NCT03164616

Carboplatin & Paclitaxel (CP) & Bevacizumab

PacCBev: Paclitaxel, Carboplatin, Bevacizumab
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 2004	NR	Randomized Phase 2 (E-esc)	Carboplatin & Paclitaxel	Seems to have superior TTP (co-primary endpoint)
Herbst et al. 2017 (SWOG S0819)	2009-2014	Phase 3 (C)	1a. CP & Cetuximab 1b. CP, Bevacizumab, Cetuximab	Did not meet co-primary endpoints of PFS/OS

Biomarker eligibility criteria

• SWOG S0819: EGFR FISH positive

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1, given third, starting 60 minutes after the completion of carboplatin
  • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles

References

1. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
2. SWOG S0819: Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. link to original article contains dosing details in abstract link to PMC article PubMed NCT00946712

Carboplatin & Paclitaxel (CP) & Cemiplimab

Regimen variant #1, 5/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2)	2019-06-17 to 2020-09-30	Phase 3 (E-RT-esc)	Investigator's choice of: 1a. CP 1b. Cisplatin & Paclitaxel	Superior OS (primary endpoint) Median OS: 21.9 vs 13 mo (HR 0.71, 95% CI 0.53-0.93)

Note: In EMPOWER-Lung 3 part 2, patients with nonsquamous histology had additional treatment options; see the histology-specific page for more information.

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 5 IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 200 mg/m² IV once on day 1

Immunotherapy

• Cemiplimab (Libtayo) 350 mg IV once on day 1

21-day cycle for up to 36 cycles (2 years)

Regimen variant #2, 6/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2)	2019-06-17 to 2020-09-30	Phase 3 (E-RT-esc)	Investigator's choice of: 1a. CP 1b. Cisplatin & Paclitaxel	Superior OS (primary endpoint) Median OS: 21.9 vs 13 mo (HR 0.71, 95% CI 0.53-0.93)

Note: In EMPOWER-Lung 3 part 2, patients with nonsquamous histology had additional treatment options; see the histology-specific page for more information.

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 6 IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 200 mg/m² IV once on day 1

Immunotherapy

• Cemiplimab (Libtayo) 350 mg IV once on day 1

21-day cycle for up to 36 cycles (2 years)

References

1. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
   1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed

Carboplatin & Paclitaxel (CP) & Ipilimumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lynch et al. 2012 (CA184-041NSCLC)	2008-2009	Randomized Phase 2 (E-esc)	1. Carboplatin & Paclitaxel	Seems to have superior irPFS (primary endpoint)
			2. CP & Ipilimumab; concurrent Ipilimumab	Not reported

Note: this is the "phased" approach to this regimen.

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 3 to 6: 10 mg/kg IV once on day 1

Supportive therapy

• Corticosteroids could be used as premedication for paclitaxel infusion or for toxicity management.

21-day cycle for up to 6 cycles

Subsequent treatment

• Maintenance ipilimumab

References

1. CA184-041_NSCLC: Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains dosing details in manuscript PubMed NCT00527735

Carboplatin & Pemetrexed

CP: Carboplatin & Pemetrexed
Carbo-Pem: Carboplatin & Pemetrexed

Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen variant #1, 5/500 x 4 to 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Wu et al. 2020 (KEYNOTE-042 China Extension)	2016-08-26 to 2018-01-04	Phase 3 (C)	Pembrolizumab	Inferior OS

Biomarker eligibility criteria

• KEYNOTE-042 China Extension: PD-L1 TPS of at least 1%

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

• KEYNOTE-024: Optional pemetrexed maintenance
• KEYNOTE-042 China Extension, patients with nonsquamous histology: Optional pemetrexed maintenance

Regimen variant #2, 6/500 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Grønberg et al. 2009	2005-04 to 2006-07	Phase 3 (E-switch-ic)	Carboplatin & Gemcitabine		Did not meet primary endpoint of HRQoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

Regimen variant #3, 6/500 x 4 to 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL
Wu et al. 2020 (KEYNOTE-042 China Extension)	2016-08-26 to 2018-01-04	Phase 3 (C)	Pembrolizumab	Inferior OS

Biomarker eligibility criteria

• KEYNOTE-042 China Extension: PD-L1 TPS of at least 1%

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Supportive therapy

• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose prior to pemetrexed
• Folic acid (Folate) 1 mg PO once per day

21-day cycle for 4 to 6 cycles

Subsequent treatment

• KEYNOTE-024: Optional pemetrexed maintenance
• KEYNOTE-042 China Extension, patients with nonsquamous histology: Optional pemetrexed maintenance

References

1. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S; Norwegian Lung Cancer Study Group. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains dosing details in abstract PubMed
2. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
   3. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. Epub 2021 Apr 19. link to original article link to PMC article PubMed
3. KEYNOTE-042 China Extension: Wu YL, Zhang L, Fan Y, Zhou J, Zhang L, Zhou Q, Li W, Hu C, Chen G, Zhang X, Zhou C, Dang T, Sadowski S, Kush DA, Zhou Y, Li B, Mok T. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study. Int J Cancer. 2021 May 1;148(9):2313-2320. Epub 2020 Dec 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03850444

Carboplatin & Vinorelbine

VC: Vinorelbine & Carboplatin

Regimen variant #1, IV vinorelbine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tan et al. 2005 (GLOB 2)	2000-2002	Phase 3 (C)	Gemcitabine & Vinorelbine	Did not meet primary endpoint of ORR

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

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, PO vinorelbine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fløtten et al. 2012	2007-2009	Phase 3 (C)	Gemcitabine & Vinorelbine	Did not meet primary endpoint of 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.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1 & 8

21-day cycle for 3 cycles

References

1. GLOB 2: Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. link to original article contains dosing details in abstract PubMed
2. Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. link to original article link to PMC article contains dosing details in abstract PubMed NCT00737867

Cemiplimab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sezer et al. 2021 (EMPOWER-Lung 1)	2017-06-27 to 2020-02-27	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Gemcitabine 1b. Carboplatin & Paclitaxel 1c. Carboplatin & Pemetrexed 1d. Cisplatin & Gemcitabine 1e. Cisplatin & Paclitaxel 1f. Cisplatin & Pemetrexed	Superior OS1 (co-primary endpoint) Median OS: 26.1 vs 13.3 mo (HR 0.57, 95% CI 0.46-0.71)

¹Reported efficacy is based on the 2023 update.
Note: some of the comparator platinum doublets appear to be histology-specific, but this is not specified in the manuscript or protocol. We have reached out to the authors for clarification. Per Sanofi, "it was strongly recommended that patients with squamous NSCLC do not receive pemetrexed-containing regimens"; otherwise, no histology-specific guidance was provided to the investigator.

Biomarker eligibility criteria

• PD-L1 expressed in at least 50% of tumor cells

Immunotherapy

• Cemiplimab (Libtayo) 350 mg IV over 30 minutes once on day 1

21-day cycle for up to 36 cycles (2 years)

References

1. EMPOWER-Lung 1: Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, Clingan P, Sriuranpong V, Rizvi N, Gao B, Li S, Lee S, McGuire K, Chen CI, Makharadze T, Paydas S, Nechaeva M, Seebach F, Weinreich DM, Yancopoulos GD, Gullo G, Lowy I, Rietschel P. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021 Feb 13;397(10274):592-604. link to original article contains dosing details in manuscript PubMed NCT03088540
   1. Update: Özgüroğlu M, Kilickap S, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, Nechaeva M, Schenker M, Cicin I, Ho GF, Kulyaba Y, Zyuhal K, Scheusan RI, Garassino MC, He X, Kaul M, Okoye E, Li Y, Li S, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Sep;24(9):989-1001. Epub 2023 Aug 14. link to original article PubMed

Cisplatin & Docetaxel (DC)

DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin

Regimen variant #1, 50/75

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Berghmans et al. 2013 (ELCWP-01041)	2003-2009	Phase 3 (C)	1. GIP 2. IG	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 75/75

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schiller et al. 2002 (ECOG E1594)	1996-1999	Phase 3 (E-switch-ic)	1. Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
			3. Cisplatin & Paclitaxel	Did not meet primary endpoint of OS
Fossella et al. 2003 (TAX 326)	1998-2000	Phase 3 (E-RT-switch-ic)	1. Carboplatin & Docetaxel	Not reported
			2. Cisplatin & Vinorelbine	Seems to have superior OS (primary endpoint)
Cobo et al. 2007	2001-2005	Phase 3 (C)	ERCC1 mRNA-guided therapy	Seems to have inferior ORR
Tan et al. 2009 (GLOB3)	2004-2006	Phase 3 (C)	Cisplatin & Vinorelbine	Did not meet primary endpoint of TTF

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 (GLOB3) or indefinitely (ECOG E1594, TAX326, Cobo et al. 2007)

Regimen variant #3, 80/60

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kubota et al. 2004	1998-2000	Phase 3 (E-switch-ic)	Cisplatin & Vindesine	Seems to have superior OS (primary endpoint) Median OS: 11.3 vs 9.6 mo
Takeda et al. 2009 (WJTOG0203)	2003-2005	Phase 3 (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS
Kubota et al. 2015 (TCOG0701 CATS)	2007-04 to 2008-12	Phase 3 (C)	Cisplatin & S-1	Non-inferior OS (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 90 minutes once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1, given first

21-day cycle for 3 to 6 cycles

Regimen variant #4, 80/100

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Georgoulias et al. 2001	1997-1999	Phase 3 (C)	Docetaxel & Gemcitabine	Did not meet co-primary endpoints of ORR/TTP
Georgoulias et al. 2003	NR	Phase 3 (C)	Docetaxel	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 2
• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycles

References

1. Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, Palamidas P, Vlachonikolis I; Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001 May 12;357(9267):1478-84. link to original article PubMed
2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains dosing details in abstract PubMed
3. Georgoulias V, Pallis AG, Kourousis C, Alexopoulos A, Ardavanis A, Agelidou A, Agelidou M, Toumbis M, Tzannes S, Pavlakou G, Ziotopoulos P, Tzelepatiotis E, Samaras N; Hellenic Oncology Research Group. Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study. Clin Lung Cancer. 2003 Mar;4(5):288-93. link to original article PubMed
   1. Update: Georgoulias V, Ardavanis A, Agelidou A, Agelidou M, Chandrinos V, Tsaroucha E, Toumbis M, Kouroussis C, Syrigos K, Polyzos A, Samaras N, Papakotoulas P, Christofilakis C, Ziras N, Alegakis A. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol. 2004 Jul 1;22(13):2602-9. link to original article contains dosing details in abstract PubMed
4. TAX 326: Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains dosing details in abstract PubMed
5. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004 Jan 15;22(2):254-61. link to original article contains dosing details in abstract PubMed
6. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 2007 Jul 1;25(19):2747-54. link to original article contains dosing details in manuscript PubMed
7. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains dosing details in manuscript PubMed
8. GLOB3: Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R. Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and iv vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2009 Jul;20(7):1249-56. Epub 2009 Mar 10. link to original article contains dosing details in abstract PubMed
9. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains dosing details in manuscript PubMed NCT00144066
10. ELCWP-01041: Berghmans T, Lafitte JJ, Scherpereel A, Paesmans M, Lecomte J, Marco VG, Meert AP, Leclercq N, Sculier JP; European Lung Cancer Working Party. An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC. Anticancer Res. 2013 Dec;33(12):5477-82. link to original article contains dosing details in manuscript PubMed NCT00622349
11. TCOG0701 CATS: Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S; Tokyo Cooperative Oncology Group. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol. 2015 Jul;26(7):1401-8. Epub 2015 Apr 23. link to original article link to PMC article contains dosing details in abstract PubMed UMIN000000608

Cisplatin & Etoposide (EP)

PE: Platinol (Cisplatin) & Etoposide
EC: Etoposide & Cisplatin

Regimen variant #1, 60/360

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ruckdeschel et al. 1986 (ECOG E1581)	1981-1983	Phase 3 (E-switch-ic)	1. CAMP 2. Cisplatin & Vindesine 3. MVP	Did not meet primary endpoint

Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Etoposide (Vepesid) 120 mg/m² IV once per day on days 4, 6, 8

21-day cycles

Regimen variant #2, 75/300

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bonomi et al. 2000 (ECOG E5592)	1993-08 to 1994-12	Phase 3 (C)	Cisplatin & Paclitaxel	Seems to have inferior OS
Belani et al. 2005	1995-05-19 to 1996-07-17	Phase 3 (C)	Carboplatin & Paclitaxel	Might have superior OS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 60 minutes once on day 1
• Etoposide (Vepesid) 100 mg/m² IV over 45 minutes once per day on days 1 to 3

21-day cycles

Regimen variant #3, 100/300

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cardenal et al. 1999	1995-07 to 1996-06	Phase 3 (C)	Cisplatin & Gemcitabine	Inferior TTP

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

21-day cycles

Regimen variant #4, 105/600

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Font et al. 1999	1993-1995	Phase 3 (C)	PE; dose-dense	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 35 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 200 mg/m² IV once per day on days 1 to 3

28-day cycles

Regimen variant #5, 120/300

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Klastersky et al. 1990 (EORTC 07861)	1987-1989	Phase 3 (C)	Carboplatin & Etoposide	Might have superior ORR
Comella et al. 1996	1993-1995	Phase 3 (C)	Carboplatin, Cisplatin, Etoposide, Vinorelbine	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 120 mg/m² IV once on day 1
  • Comella et al. 1996 gave 40 mg/m² IV once per day on days 1 to 3
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

3- to 4-week cycles

References

1. ECOG E1581: Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. link to original article contains dosing details in manuscript PubMed
2. EORTC 07861: Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organisation for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. link to original article contains dosing details in manuscript PubMed
3. Comella P, Frasci G, De Cataldis G, Panza N, Cioffi R, Curcio C, Belli M, Bianco A, Ianniello G, Maiorino L, Della Vittoria M, Perchard J, Comella G; Gruppo Oncologico Campano. Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Br J Cancer. 1996 Dec;74(11):1805-11. link to original article link to PMC article contains dosing details in abstract PubMed
4. Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. link to original article contains dosing details in abstract PubMed
5. Font A, Moyano AJ, Puerto JM, Tres A, Garcia-Giron C, Barneto I, Anton A, Sanchez JJ, Salvador A, Rosell R; Spanish Lung Cancer Group. Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. Cancer. 1999 Feb 15;85(4):855-63. link to original article PubMed
6. ECOG E5592: Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. link to original article contains dosing details in manuscript PubMed
7. Belani CP, Lee JS, Socinski MA, Robert F, Waterhouse D, Rowland K, Ansari R, Lilenbaum R, Natale RB. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol. 2005 Jul;16(7):1069-75. Epub 2005 Apr 28. link to original article contains dosing details in abstract PubMed

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

Regimen variant #1, 70/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2007	2002-2004	Phase 3 (E-de-esc)	1a. Cisplatin & Paclitaxel x 6 1b. GC x 6	Non-inferior OS (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #2, 75/1250 q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Bissett et al. 2005 (AG-3340-017)	1999-2001	Phase 3 (C)	GC & Prinomastat	Did not meet primary endpoint of OS
Novello et al. 2007	2001-2004	Phase 3 (C)	GC x 2, then gemcitabine x 3	Inconclusive whether non-inferior OS
Manegold et al. 2011	2005-2007	Phase 3 (C)	GC & PF-3512676	Did not meet primary endpoint of OS
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (C)	Pembrolizumab	Inferior OS	Inferior HRQoL

Note: Patients in Novello et al. 2007 received 5 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 30 minutes once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV over 2 hours once per day on days 1 & 8

21-day cycle for up to 6 cycles (see note)

Regimen variant #3, 80/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ohe et al. 2006 (FACS)	2000-2002	Phase 3 (E-switch-ic)	1. Carboplatin & Paclitaxel	Inconclusive whether non-inferior OS (primary endpoint)
			2. Cisplatin & Irinotecan	Inconclusive whether non-inferior OS (primary endpoint)
			3. Cisplatin & Vinorelbine	Inconclusive whether non-inferior OS (primary endpoint)
Takeda et al. 2009 (WJTOG0203)	2003-2005	Phase 3 (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 6 cycles (WJTOG0203) or indefinitely (FACS)

Regimen variant #4, 80/1125

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wachters et al. 2003	1998-2002	Phase 3 (C)	Epirubicin & Gemcitabine	Did not meet primary endpoint of PFS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 2
• Gemcitabine (Gemzar) 1125 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 5 cycles

Regimen variant #5, 80/1200 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 2003 (NCIC-CTG BR.14)	1998-2001	Phase 3 (C)	Gemcitabine & Vinorelbine	Might have superior OS
Gridelli et al. 2007 (GECO)	2003-2005	Phase 3 (C)	1. GC & Rofecoxib 2. Cisplatin & Gemcitabine; PCI gemcitabine 3. GC & Rofecoxib; PCI gemcitabine	Did not meet primary endpoint of OS
Gridelli et al. 2012 (TORCH)	2006-2009	Phase 3 (C)	Erlotinib	Seems to have superior OS Median OS: 11.6 vs 8.7 mo (HR 0.81, 95% CI 0.68-0.96)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Subsequent treatment

• TORCH, at progression: Second-line erlotinib

Regimen variant #6, 80/1250 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ferry et al. 2017 (BTOG2)	2005-2009	Phase 3 (E-esc)	1. GC; GC50	Seems to have superior OS (primary endpoint)
			2. GCb6	Non-inferior OS (primary endpoint)
Pérol et al. 2012 (IFCT-GFPC 0502)	2006-2009	Non-randomized part of phase 3 RCT

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Subsequent treatment

• IFCT-GFPC 0502: Erlotinib versus gemcitabine switch maintenance versus observation

Regimen variant #7, 80/1250 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Giaccone et al. 2004 (INTACT 1)	2000-05 to 2001-03	Phase 3 (C)	GC & Gefitinib	Did not meet primary endpoint of OS
Gatzemeier et al. 2007 (TALENT)	2001-11 to 2002-09	Phase 3 (C)	GC & Erlotinib	Did not meet primary endpoint of OS
Boni et al. 2012 (FAST)	2001-2006	Phase 3 (C)	1. GIN 2. GN	Seems to have superior OS
			3. GIP	Did not meet primary endpoint of OS
Paz-Ares et al. 2006	2002-2004	Phase 3 (C)	GC & Aprinocarsen	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 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 6 cycles

Regimen variant #8, 100/1000 q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ridolfi et al. 2011	2000-2004	Phase 3 (C)	GC & LD IL-2	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #9, 100/1000 q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Crinò et al. 1999	1995-1997	Phase 3 (E-switch-ic)	MIC	Seems to have superior ORR
Sandler et al. 2000	1995-1997	Phase 3 (E-RT-esc)	Cisplatin	Superior OS
Schiller et al. 2002 (ECOG E1594)	1996-1999	Phase 3 (E-switch-ic)	1. Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Docetaxel	Did not meet primary endpoint of OS
			3. Cisplatin & Paclitaxel	Superior PFS
Scagliotti et al. 2008 (JMDB)	2004-07 to 2005-12	Phase 3 (C)	Cisplatin & Pemetrexed	Seems to have non-inferior OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #10, 100/1250

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cardenal et al. 1999	1995-07 to 1996-06	Phase 3 (E-RT-switch-ic)	Cisplatin & Etoposide	Superior TTP
Alberola et al. 2003	1998-2000	Phase 3 (C)	1. CGV 2. GV-VI	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for 6 cycles (Alberola et al. 2003) or indefinitely (Cardenal et al. 1999)

Regimen variant #11, 100/1400

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gebbia et al. 2003	NR	Phase 3 (E-switch-ic)	Cisplatin & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1400 mg/m² IV once per day on days 1 & 8

28-day cycles

References

1. Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. link to original article contains dosing details in abstract PubMed
2. Crinò L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999 Nov;17(11):3522-30. link to original article contains dosing details in abstract PubMed
3. Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000 Jan;18(1):122-30. link to original article contains dosing details in abstract PubMed
4. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains dosing details in abstract PubMed
5. Gebbia V, Galetta D, Caruso M, Verderame F, Pezzella G, Valdesi M, Borsellino N, Pandolfo G, Durini E, Rinaldi M, Loizzi M, Gebbia N, Valenza R, Tirrito ML, Varvara F, Colucci G; Gruppo Ocologico Italia Meridionale. Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Lung Cancer. 2003 Feb;39(2):179-89. link to original article contains dosing details in abstract PubMed
6. NCIC-CTG BR.14: Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00004100
7. Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jiménez U, González-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Peñas R, Felip E, López-Vivanco G; Spanish Lung Cancer Group. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003 Sep 1;21(17):3207-13. link to original article contains dosing details in abstract PubMed
8. Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. link to original article contains dosing details in abstract PubMed
9. Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Br J Cancer. 2003 Oct 6;89(7):1192-9. link to original article link to PMC article contains dosing details in abstract PubMed
10. INTACT 1: Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. link to original article contains dosing details in abstract PubMed
11. AG-3340-017: Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J Clin Oncol. 2005 Feb 1;23(4):842-9. link to original article contains dosing details in abstract PubMed NCT00004199
12. Paz-Ares L, Douillard JY, Koralewski P, Manegold C, Smit EF, Reyes JM, Chang GC, John WJ, Peterson PM, Obasaju CK, Lahn M, Gandara DR. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2006 Mar 20;24(9):1428-34. link to original article contains dosing details in abstract PubMed
13. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains dosing details in manuscript PubMed
14. Novello S, Bruzzi P, Barone C, Buosi R, Masotti A, Michetti G, Fioretti M, Barbera S, Spatafora M, Garetto L, Mazzanti P, Dongiovanni V, Selvaggi G, Crinò L, Scagliotti GV. Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Ann Oncol. 2007 May;18(5):903-8. Epub 2007 Mar 9. link to original article contains dosing details in abstract PubMed
15. TALENT: Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007 Apr 20;25(12):1545-52. link to original article contains dosing details in abstract PubMed
16. GECO: Gridelli C, Gallo C, Ceribelli A, Gebbia V, Gamucci T, Ciardiello F, Carozza F, Favaretto A, Daniele B, Galetta D, Barbera S, Rosetti F, Rossi A, Maione P, Cognetti F, Testa A, Di Maio M, Morabito A, Perrone F; GECO investigators. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol. 2007 Jun;8(6):500-12. link to original article contains dosing details in abstract PubMed NCT00385606
17. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains dosing details in manuscript PubMed
18. JMDB: Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains dosing details in abstract PubMed NCT00087711
19. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains dosing details in manuscript PubMed NCT00144066
20. Manegold C, van Zandwijk N, Szczesna A, Zatloukal P, Au JS, Blasinska-Morawiec M, Serwatowski P, Krzakowski M, Jassem J, Tan EH, Benner RJ, Ingrosso A, Meech SJ, Readett D, Thatcher N. A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2012 Jan;23(1):72-7. Epub 2011 Apr 4. link to original article contains dosing details in abstract PubMed
21. Ridolfi L, Bertetto O, Santo A, Naglieri E, Lopez M, Recchia F, Lissoni P, Galliano M, Testore F, Porta C, Maglie M, Dall'agata M, Fumagalli L, Ridolfi R. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Int J Oncol. 2011 Oct;39(4):1011-7. Epub 2011 Jun 24. link to original article contains dosing details in abstract PubMed
22. FAST: Boni C, Tiseo M, Boni L, Baldini E, Recchia F, Barone C, Grossi F, Germano D, Matano E, Marini G, Labianca R, Di Costanzo F, Bagnulo A, Pennucci C, Caroti C, Mencoboni M, Zanelli F, Prochilo T, Cafferata MA, Ardizzoni A; Gruppo Oncologico Italiano di Ricerca Clinica. Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). Br J Cancer. 2012 Feb 14;106(4):658-65. Epub 2012 Jan 12. link to original article link to PMC article contains dosing details in manuscript PubMed
23. TORCH: Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, Maione P, Morgillo F, Genestreti G, Favaretto A, Leighl N, Wierzbicki R, Cinieri S, Alam Y, Siena S, Tortora G, Felletti R, Riccardi F, Mancuso G, Rossi A, Cantile F, Tsao MS, Saieg M, da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A, Perrone F. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012 Aug 20;30(24):3002-11. Epub 2012 Jul 9. link to original article contains dosing details in abstract PubMed NCT00349219
    1. HRQoL analysis: Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, Maione P, Gebbia V, Morgillo F, Wierzbicki R, Favaretto A, Alam Y, Cinieri S, Siena S, Bianco R, Riccardi F, Spatafora M, Ravaioli A, Felletti R, Fregoni V, Genestreti G, Rossi A, Mancuso G, Fasano M, Morabito A, Tsao MS, Signoriello S, Perrone F, Gridelli C. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advancednon-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1830-1844. link to original article PubMed
24. IFCT-GFPC 0502: Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original articlecontains dosing details in manuscript PubMed NCT00300586
25. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
    3. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. Epub 2021 Apr 19. link to original article link to PMC article PubMed
26. BTOG2: Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00112710

Cisplatin & Gemcitabine (GC) & Cetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Butts et al. 2008	NR	Randomized Phase 2 (E-esc)	1a. GCb 1b. GC	Non-comparative

Chemotherapy

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

Targeted therapy

• Cetuximab (Erbitux) as follows:
  • Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once per day on days 8 & 15
  • Cycles 2 to 6: 250 mg/m² IV once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

References

1. Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol. 2007 Dec 20;25(36):5777-84. Erratum in: J Clin Oncol. 2008 Jul 1;26(19): 3295. link to original article contains dosing details in manuscript PubMed

Cisplatin & Irinotecan (IC)

IP: Irinotecan & Platinol (Cisplatin)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Negoro et al. 2003	1995-1998	Phase 3 (E-switch-ic)	1. Cisplatin & Vindesine	Did not meet primary endpoint of OS
			2. Irinotecan	Not reported
Ohe et al. 2006 (FACS)	2000-2002	Phase 3 (C)	1. Carboplatin & Paclitaxel	Inconclusive whether non-inferior OS
			2. Cisplatin & Gemcitabine	Inconclusive whether non-inferior OS
			3. Cisplatin & Vinorelbine	Inconclusive whether non-inferior OS
Takeda et al. 2009 (WJTOG0203)	2003-2005	Phase 3 (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Irinotecan (Camptosar) 60 mg/m² IV once per day on days 1, 8, 15

28-day cycle for up to 6 cycles (WJTOG0203) or indefinitely (FACS & Negoro et al. 2003)

References

1. Negoro S, Masuda N, Takada Y, Sugiura T, Kudoh S, Katakami N, Ariyoshi Y, Ohashi Y, Niitani H, Fukuoka M; CPT-11 Lung Cancer Study Group West. Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer. Br J Cancer. 2003 Feb 10;88(3):335-41. link to original article link to PMC article contains dosing details in manuscript PubMed
2. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains dosing details in manuscript PubMed
3. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains dosing details in manuscript PubMed NCT00144066

Cisplatin & Paclitaxel

PC: Paclitaxel & Cisplatin

Regimen variant #1, 70/175 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2007	2002-2004	Phase 3 (E-de-esc)	1a. Cisplatin & Paclitaxel x 6 1b. GC x 6	Non-inferior OS (primary endpoint)

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 4 cycles

Regimen variant #2, 70/175 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2007	2002-2004	Phase 3 (C)	1a. Cisplatin & Paclitaxel x 4 1b. GC x 4	Non-inferior OS
Shi et al. 2020 (PM-03-2015)	2015-2018	Phase 3 (C)	Cisplatin & Paclitaxel micellar	Inferior PFS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen variant #3, 75/135, q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Stathopoulos et al. 2010a	2006-2008	Phase 3 (C)	Liposomal Cisplatin & Paclitaxel	Did not meet secondary endpoints	More toxic

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1, given second
• Paclitaxel (Taxol) 135 mg/m² IV over 3 hours once on day 1, given first

14-day cycle for up to 9 cycles

Regimen variant #4, 75/135, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bonomi et al. 2000 (ECOG E5592)	1993-08 to 1994-12	Phase 3 (E-RT-switch-ic)	Cisplatin & Etoposide	Seems to have superior OS
Schiller et al. 2002 (ECOG E1594)	1996-1999	Phase 3 (C)	1. Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Docetaxel	Did not meet primary endpoint of OS
			3. Cisplatin & Gemcitabine	Inferior PFS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 2, given second
• Paclitaxel (Taxol) 135 mg/m² IV continuous infusion over 24 hours, started on day 1, given first

21-day cycles

Regimen variant #5, 75/200 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2)	2019-06-17 to 2020-09-30	Phase 3 (C)	Investigator's choice of: 1a. CP & Cemiplimab 1b. Cisplatin, Paclitaxel, Cemiplimab 1c. Carboplatin, Pemetrexed, Cemiplimab 1d. Cisplatin, Pemetrexed, Cemiplimab	Inferior OS

Note: In EMPOWER-Lung 3 part 2, patients with nonsquamous histology had additional treatment options; see the histology-specific page for more information.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for 4 cycles

Regimen variant #6, 80/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gatzemeier et al. 2000	1995-01 to 1996-04	Phase 3 (E-esc)	Cisplatin	Did not meet primary endpoint of OS
Smit et al. 2003 (EORTC 08975)	1998-2000	Phase 3 (C)	1. Cisplatin & Gemcitabine 2. Gemcitabine & Paclitaxel	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycle for up to 6 cycles

Regimen variant #7, 80/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosell et al. 2002	1996-04 to 1997-07	Phase 3 (E-switch-ic)	Carboplatin & Paclitaxel	Non-inferior RR (primary endpoint) Seems to have superior OS (secondary endpoint)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycles

References

1. ECOG E5592: Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. link to original article contains dosing details in abstract PubMed
2. Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, de Marinis F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallant G. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Oct 1;18(19):3390-9. link to original article contains dosing details in abstract PubMed
3. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; ECOG. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains dosing details in manuscript PubMed
4. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. link to original article contains dosing details in abstract PubMed
5. EORTC 08975: Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C, Neymark N, Giaccone G; EORTC Lung Cancer Group. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organisation for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol. 2003 Nov 1;21(21):3909-17. link to original article contains dosing details in abstract PubMed NCT00003589
6. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains dosing details in manuscript PubMed
7. Stathopoulos GP, Antoniou D, Dimitroulis J, Michalopoulou P, Bastas A, Marosis K, Stathopoulos J, Provata A, Yiamboudakis P, Veldekis D, Lolis N, Georgatou N, Toubis M, Pappas Ch, Tsoukalas G. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010 Nov;21(11):2227-32. Epub 2010 May 3. link to original article link to PMC article contains dosing details in manuscript PubMed
8. PM-03-2015: Shi M, Gu A, Tu H, Huang C, Wang H, Yu Z, Wang X, Cao L, Shu Y, Wang H, Yang R, Li X, Chang J, Hu Y, Shen P, Hu Y, Guo Z, Tao M, Zhang Y, Liu X, Sun Q, Zhang X, Jiang Z, Zhao J, Chen F, Yu H, Zhang W, Sun J, Li D, Zhou J, Han B, Wu YL. Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, randomized, multicenter, phase III trial. Ann Oncol. 2021 Jan;32(1):85-96. Epub 2020 Oct 29. link to original article contains dosing details in abstract PubMed NCT02667743
9. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
   1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed

Cisplatin, Paclitaxel, Cemiplimab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2)	2019-06-17 to 2020-09-30	Phase 3 (E-RT-esc)	Investigator's choice of: 1a. CP 1b. Cisplatin & Paclitaxel	Superior OS (primary endpoint) Median OS: 21.9 vs 13 mo (HR 0.71, 95% CI 0.53-0.93)

Note: In EMPOWER-Lung 3 part 2, patients with nonsquamous histology had additional treatment options; see the histology-specific page for more information.

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 200 mg/m² IV once on day 1

Immunotherapy

• Cemiplimab (Libtayo) 350 mg IV once on day 1

21-day cycle for up to 36 cycles (2 years)

References

1. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
   1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine
CV: Cisplatin & Vinorelbine
NP: Navelbine (Vinorelbine) & Platinol (Cisplatin)
PV: Platinol (Cisplatin) & Vinorelbine
VC: Vinorelbine & Cisplatin

Regimen variant #1, 75/25

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Martoni et al. 2005	1998-2003	Phase 3 (E-switch-ic)	Cisplatin & Gemcitabine	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Subsequent treatment

• Vinorelbine maintenance

Regimen variant #2, 80/25

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ohe et al. 2006 (FACS)	2000-2002	Phase 3 (E-switch-ic)	1. Carboplatin & Paclitaxel	Inconclusive whether non-inferior OS (primary endpoint)
			2. Cisplatin & Gemcitabine	Inconclusive whether non-inferior OS (primary endpoint)
			3. Cisplatin & Irinotecan	Inconclusive whether non-inferior OS (primary endpoint)
Takeda et al. 2009 (WJTOG0203)	2003-2005	Phase 3 (C)	Platinum doublet x 3, then Gefitinib	Did not meet primary endpoint of OS
Pirker et al. 2009 (FLEX)	2004-2006	Phase 3 (C)	Cisplatin, Vinorelbine, Cetuximab	Seems to have inferior OS

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles (FLEX; WJTOG0203) or indefinitely (FACS)

Regimen variant #3, 80/30, 2 out of 3 weeks vinorelbine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Gridelli et al. 2003 (NCIC-CTG BR.14)	1998-2001	Phase 3 (C)	Gemcitabine & Vinorelbine	Might have superior OS
Georgoulias et al. 2005	1999-2002	Phase 3 (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS
Gebbia et al. 2008	2003-01 to 2004-12	Phase 3 (C)	Cisplatin & Vinorelbine; 3 out of 4 weeks	Did not meet primary endpoint of OS	Less toxic

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 8
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for 6 cycles (NCIC-CTG BR.14) or up to 9 cycles (Georgoulias et al. 2005) or indefinitely (Gebbia et al. 2008)

Regimen variant #4, 80/30, weekly vinorelbine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Depierre et al. 1994	1989-1991	Phase 3 (E-esc)	Vinorelbine	Superior TTP
Souquet et al. 2002 (GLOB-1)	1998-02 to 1999-06	Phase 3 (C)	NIP	Did not meet primary endpoint of OS1

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #5, 100/25 q4wk/weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wozniak et al. 1998 (SWOG S9308)	1993-1995	Phase 3 (E-RT-esc)	Cisplatin	Superior OS
Kelly et al. 2001 (SWOG 9509)	1996-1998	Phase 3 (C)	Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
Fossella et al. 2003 (TAX 326)	1998-2000	Phase 3 (C)	1. Carboplatin & Docetaxel	Did not meet primary endpoint of OS
			2. Cisplatin & Docetaxel	Seems to have inferior OS
Ramlau et al. 2008 (SPIRIT I)	2003-NR	Phase 3 (C)	CVb & Bexarotene	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for up to 10 cycles (SWOG 9509) or indefinitely (SPIRIT I, SWOG S9308, TAX 326)

Regimen variant #6, 100/25 q4wk/weekly --> bi-weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Scagliotti et al. 2002	1998-2000	Phase 3 (C)	1. Carboplatin & Paclitaxel 2. Cisplatin & Gemcitabine	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Vinorelbine (Navelbine) as follows:
  • Cycles 1 to 3: 25 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 4 onwards: 25 mg/m² IV once per day on days 1 & 15

28-day cycles

Regimen variant #7, 100/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pujol et al. 2005	1999-2001	Phase 3 (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 60 to 120 minutes once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV over 10 to 20 minutes once per day on days 1, 8, 15, 22

28-day cycle for 6 cycles

Regimen variant #8, 120/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Le Chevalier et al. 1994	1989-1991	Phase 3 (E-RT-esc)	1. Cisplatin & Vindesine	Seems to have superior OS
			2. Vinorelbine	Superior OS
Comella et al. 2000	1997-1999	Phase 3 (C)	1. Cisplatin & Gemcitabine	Not reported
			2. PGV	Inferior OS

Note: in Comella et al. 2000, vinorelbine was given for a total of 10 weeks.

Chemotherapy

• Cisplatin (Platinol) 120 mg/m² IV once on day 1
• Vinorelbine (Navelbine) as follows:
  • Cycle 1: 30 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 2 onwards: 30 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

28-day course, then 42-day cycles (see note)

References

1. Depierre A, Chastang C, Quoix E, Lebeau B, Blanchon F, Paillot N, Lemarie E, Milleron B, Moro D, Clavier J, Herman D, Tuchais E, Jacoulet P, Brechot JM, Cordier JF, Solal-Celigny P, Badri N, Besenval M. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol. 1994 Jan;5(1):37-42. link to original article contains dosing details in abstract PubMed
2. Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S, Gottfried M, Ruffle P, Panizo A, Gaspard MH, Ravaioli A, Besenval M, Besson F, Martinez A, Berthaud P, Tursz T. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994 Feb;12(2):360-7. link to original article contains dosing details in abstract PubMed
3. SWOG S9308: Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, Albain KS, Kelly K, Taylor SA, Gandara DR, Livingston RB; SWOG. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998 Jul;16(7):2459-65. link to original article contains dosing details in manuscript PubMed
4. Comella P, Frasci G, Panza N, Manzione L, De Cataldis G, Cioffi R, Maiorino L, Micillo E, Lorusso V, Di Rienzo G, Filippelli G, Lamberti A, Natale M, Bilancia D, Nicolella G, Di Nota A, Comella G; Southern Italy Cooperative Oncology Group. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 2000 Apr;18(7):1451-7. link to original article contains dosing details in manuscript PubMed
5. SWOG 9509: Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. link to original article contains dosing details in manuscript PubMed
6. Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini L, Tonato M; Italian Lung Cancer Project. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002 Nov 1;20(21):4285-91. link to original article contains dosing details in abstract PubMed
7. GLOB-1: Souquet PJ, Tan EH, Rodrigues Pereira J, Van Klaveren R, Price A, Gatzemeier U, Jaworski M, Burillon JP, Aubert D. GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients. Ann Oncol. 2002 Dec;13(12):1853-61. Erratum in: Ann Oncol. 2003 Feb;14(2):347. link to original article contains dosing details in abstract PubMed
8. TAX 326: Fossella F, Rodrigues Pereira J, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains dosing details in abstract PubMed
9. NCIC-CTG BR.14: Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00004100
10. Martoni A, Marino A, Sperandi F, Giaquinta S, Di Fabio F, Melotti B, Guaraldi M, Palomba G, Preti P, Petralia A, Artioli F, Picece V, Farris A, Mantovani L. Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer. 2005 Jan;41(1):81-92. link to original article contains dosing details in abstract PubMed
11. Georgoulias V, Ardavanis A, Tsiafaki X, Agelidou A, Mixalopoulou P, Anagnostopoulou O, Ziotopoulos P, Toubis M, Syrigos K, Samaras N, Polyzos A, Christou A, Kakolyris S, Kouroussis C, Androulakis N, Samonis G, Chatzidaki D. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2005 May 1;23(13):2937-45. Epub 2005 Feb 22. link to original article contains dosing details in manuscript PubMed
12. Pujol JL, Breton JL, Gervais R, Rebattu P, Depierre A, Morère JF, Milleron B, Debieuvre D, Castéra D, Souquet PJ, Moro-Sibilot D, Lemarié E, Kessler R, Janicot H, Braun D, Spaeth D, Quantin X, Clary C. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol. 2005 Apr;16(4):602-10. Epub 2005 Mar 1. link to original article contains dosing details in manuscript PubMed
13. FACS: Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains dosing details in manuscript PubMed
14. Gebbia V, Galetta D, Lorusso V, Caruso M, Verderame F, Pezzella G, Borsellino N, Durini E, Valenza R, Agostara B, Colucci G; Gruppo Oncologico Italia Meridionale. Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine on days 1 and 8 in advanced non-small cell lung cancer: a prospective randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale). Lung Cancer. 2008 Sep;61(3):369-77. Epub 2008 Mar 4. link to original article contains dosing details in abstract PubMed
15. SPIRIT I: Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Rodrigues Pereira J, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008 Apr 10;26(11):1886-92. link to original article contains dosing details in manuscript PubMed NCT00050973
16. FLEX: Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains dosing details in manuscript PubMed NCT00148798
17. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains dosing details in manuscript PubMed NCT00144066

Cisplatin, Vinorelbine, Cetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pirker et al. 2009 (FLEX)	2004-2006	Phase 3 (E-esc)	Cisplatin & Vinorelbine	Seems to have superior OS (primary endpoint) Median OS: 11.3 vs 10.1 mo (HR 0.87, 95% CI 0.76-0.996)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Cetuximab (Erbitux) as follows:
  • Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8 & 15
  • Cycles 2 to 6: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

Subsequent treatment

• Cetuximab maintenance

References

1. FLEX: Pirker R, Rodrigues Pereira J, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains dosing details in abstract PubMed NCT00148798

Docetaxel & Vinorelbine

Regimen

Study	Dates of enrollment	Evidence
Miller et al. 2000	1997-1998	Phase 2

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once over 60 minutes, given second
• Vinorelbine (Navelbine) 45 mg/m² IV once over 6 to 10 minutes, given first

Supportive therapy

• Dexamethasone (Decadron) 8 mg PO every 12 hours for 5 doses, starting on day -1
• Filgrastim (Neupogen) 5 mcg/kg SC once per day for at least 6 days, starting on day 3
• Ciprofloxacin (Cipro) (dose note specified) PO twice per day on days 3 to 10

14-day cycles

References

1. Miller VA, Krug LM, Ng KK, Pizzo B, Perez W, Heelan RT, Kris MG. Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Mar;18(6):1346-50. link to original article contains dosing details in manuscript PubMed

Durvalumab & Tremelimumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
de Castro et al. 2022 (NEPTUNE)	2015-NR	Phase 3 (E-switch-ooc)	Platinum doublet chemotherapy	Might have superior OS (primary endpoint) Median OS: 11.7 vs 9.1 mo (HR 0.71, 95% CI 0.49-1.05)

Immunotherapy

• Durvalumab (Imfinzi) 20 mg/kg IV once on day 1
• Tremelimumab (Imjudo) as follows:
  • Cycles 1 up to 4: 1 mg/kg IV once on day 1

28-day cycles

References

1. NEPTUNE: de Castro G Jr, Rizvi NA, Schmid P, Syrigos K, Martin C, Yamamoto N, Cheng Y, Moiseyenko V, Summers Y, Vynnychenko I, Lee SY, Bryl M, Zer A, Erman M, Timcheva C, Raja R, Naicker K, Scheuring U, Walker J, Mann H, Chand V, Mok T; NEPTUNE Investigators. NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC. J Thorac Oncol. 2023 Jan;18(1):106-119. Epub 2022 Oct 12. link to original article contains dosing details in manuscript PubMed NCT02542293

Gemcitabine & Paclitaxel

GT: Gemcitabine & Taxol (Paclitaxel)

Regimen variant #1, 1000/125

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kosmidis et al. 2002	1998-2000	Phase 3 (E-switch-ic)	Carboplatin & Paclitaxel	Did not meet primary endpoint of OS
Kosmidis et al. 2007	2000-2004	Phase 3 (E-switch-ic)	Carboplatin & Gemcitabine	Did not meet primary endpoint of OS
Comella et al. 2006 (SICOG 0101)	2001-2005	Phase 3 (C)	1. GV 2. PGT 3. PGV	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Paclitaxel (Taxol) 125 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 1000/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kosmidis et al. 2010	2004-2008	Phase 3 (C)	Paclitaxel & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycles

References

1. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains dosing details in abstract PubMed
2. SICOG 0101: Comella P, Filippelli G, De Cataldis G, Massidda B, Frasci G, Maiorino L, Putzu C, Mancarella S, Palmeri S, Cioffi R, Roselli M, Buzzi F, Milia V, Gambardella A, Natale D, Bianco M, Ghiani M, Masullo P; Southern Italy Cooperative Oncology Group. Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101). Ann Oncol. 2007 Feb;18(2):324-30. Epub 2006 Oct 27. link to original article contains dosing details in abstract PubMed
3. Kosmidis PA, Fountzilas G, Eleftheraki AG, Kalofonos HP, Pentheroudakis G, Skarlos D, Dimopoulos MA, Bafaloukos D, Pectasides D, Samantas E, Boukovinas J, Lambaki S, Katirtzoglou N, Bakogiannis C, Syrigos KN; Hellenic Cooperative Oncology Group. Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2011 Apr;22(4):827-34. Epub 2010 Sep 29. link to original article contains dosing details in abstract PubMed ACTRN12609000946213

Gemcitabine & Vinorelbine

VG: Vinorelbine & Gemcitabine
GV: Gemcitabine & Vinorelbine
G+V: Gemcitabine & Vinorelbine

Regimen variant #1, 1000/25, 2 weeks out of 3 (IV vinorelbine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Laack et al. 2004	1999-2001	Phase 3 (E-de-esc)	GVP	Did not meet primary endpoint of OS
Tan et al. 2005 (GLOB 2)	2000-2002	Phase 3 (E-switch-ic)	Carboplatin & Vinorelbine	Did not meet primary endpoint of ORR

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Supportive therapy

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycles

Regimen variant #2, 1000/25, 3 weeks out of 4 (IV vinorelbine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Greco et al. 2007 (SCRI LUN 54)	1998-2005	Phase 3 (E-switch-ic)	PCG	Did not meet primary endpoint of OS	Less toxic

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 1000/60 (PO vinorelbine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fløtten et al. 2012	2007-2009	Phase 3 (E-switch-ic)	Carboplatin & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1 & 8

21-day cycle for 3 cycles

Regimen variant #4, 1200/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Frasci et al. 2001	NR	Phase 3 (E-esc)	Vinorelbine	Superior OS

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, DeCataldis G, Belli M, Iannelli N, Massidda B, Mascia V, Comella G, De Lena M; Southern Italy Cooperative Oncology Group. Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer. 2001 Dec;34 Suppl 4:S65-9. link to original article contains dosing details in abstract PubMed
2. NCIC-CTG BR.14: Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F; Italian GEMVIN Investigators; NCIC-CTG. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00004100
3. Laack E, Dickgreber N, Müller T, Knuth A, Benk J, Lorenz C, Gieseler F, Dürk H, Engel-Riedel W, Dalhoff K, Kortsik C, Graeven U, Burk M, Dierlamm T, Welte T, Burkholder I, Edler L, Hossfeld DK; German and Swiss Lung Cancer Study Group. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004 Jun 15;22(12):2348-56. link to original article contains dosing details in abstract PubMed
4. GLOB 2: Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. link to original article contains dosing details in abstract PubMed
5. SCRI LUN 54: Greco FA, Spigel DR, Kuzur ME, Shipley D, Gray JR, Thompson DS, Burris HA, Yardley DA, Pati A, Webb CD, Gandhi JG, Hainsworth JD. Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network. Clin Lung Cancer. 2007 Sep;8(8):483-7. link to original article PubMed NCT00193362
6. Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C; Norwegian Lung Cancer Study Group. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. link to original article link to PMC article contains dosing details in abstract PubMed NCT00737867

Nivolumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carbone et al. 2017 (CheckMate 026)	2014-03 to 2015-04	Phase 3 (E-switch-ooc)	Platinum doublet	Did not meet primary endpoint of PFS

Note: control arm patients in CheckMate 026 received investigator's choice of platinum doublet; the most commonly used regimen was carboplatin & paclitaxel.

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1
  • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

References

1. CheckMate 026: Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. link to original articlecontains dosing details in manuscript link to PMC article PubMed NCT02041533
2. CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02477826

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1a. Carboplatin & Gemcitabine 1b. Carboplatin & Paclitaxel 1c. Carboplatin & Pemetrexed 1d. Cisplatin & Gemcitabine 1e. Cisplatin & Pemetrexed	Superior PFS (primary endpoint) Median PFS: 10.3 vs 6 mo (HR 0.50, 95% CI 0.37-0.68) Superior OS1 (secondary endpoint) Median OS: 26.3 vs 13.4 mo (HR 0.62, 95% CI 0.48-0.81)	Superior HRQoL
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1a. Carboplatin & Paclitaxel 1b. Carboplatin & Pemetrexed	Superior OS2 (co-primary endpoint) Median OS: 16.7 vs 12.1 mo (HR 0.81, 95% CI 0.71-0.93)
Wu et al. 2020 (KEYNOTE-042 China Extension)	2016-08-26 to 2018-01-04	Phase 3 (E-switch-ooc)	Investigator's choice of: 1a. Carboplatin & Paclitaxel 1b. Carboplatin & Pemetrexed	Superior OS2 (co-primary endpoint) Median OS: 24.5 vs 13.8 mo (HR 0.67, 95% CI 0.50-0.89)
Boyer et al. 2021 (KEYNOTE-598)	2018-01-12 to 2019-08-22	Phase 3 (C)	Ipilimumab & Pembrolizumab	Did not meet co-primary endpoints of PFS/OS
Awaiting publication (INTRAPID Lung 037)	2018-2021	Phase 3 (C)	Bintrafusp alfa	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (LEAP-007)	2019-2021	Phase 3 (C)	Lenvatinib & Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (AdvanTIG-302)	2021-ongoing	Phase 3 (C)	Ociperlimab & Tislelizumab	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (MK-7684A-003)	2021-ongoing	Phase 3 (C)	Pembrolizumab & Vibostolimab	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (TROPION-Lung08)	2022-ongoing	Phase 3 (C)	Datopotamab-DXd & Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (EVOKE-03)	2023-ongoing	Phase 3 (C)	Pembrolizumab & Sacituzumab govitecan	TBD if different co-primary endpoints of PFS/OS

¹Reported efficacy for KEYNOTE-024 is based on the 2021 update.
²Reported efficacy for KEYNOTE-042 & KEYNOTE-042 China Extension is for the population with TPS of 1% or more.
KEYNOTE-024 treatment choice for patients in the comparator arm was up to the investigators; most with nonsquamous histology received carboplatin & pemetrexed, whereas most with squamous histology received carboplatin & gemcitabine. Patients could receive a maximum of 35 cycles. ORR was 45% (95% CI: 37-53).
KEYNOTE-042 treatment choice for patients in the comparator arm was carboplatin & paclitaxel for patients with squamous histology, and carboplatin & pemetrexed for patients with nonsquamous histology.

Biomarker eligibility criteria

• KEYNOTE-024: PD-L1 to be expressed on at least 50% of tumor cells, no EGFR/ALK mutations
• KEYNOTE-042: PD-L1 to be expressed on at least 1% of tumor cells
• KEYNOTE-042 China Extension: PD-L1 TPS of at least 1%
• KEYNOTE-598 & TROPION-Lung08: PD-L1 TPS of at least 50%; no sensitizing EGFR or ALK mutations

Immunotherapy

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

21-day cycle for up to 35 cycles

References

1. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
   3. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. Epub 2021 Apr 19. link to original article link to PMC article PubMed
2. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed NCT02220894
   1. Update: de Castro G Jr, Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. J Clin Oncol. 2023 Apr 10;41(11):1986-1991. Epub 2022 Oct 28. link to original article link to PMC article PubMed
3. KEYNOTE-042 China Extension: Wu YL, Zhang L, Fan Y, Zhou J, Zhang L, Zhou Q, Li W, Hu C, Chen G, Zhang X, Zhou C, Dang T, Sadowski S, Kush DA, Zhou Y, Li B, Mok T. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study. Int J Cancer. 2021 May 1;148(9):2313-2320. Epub 2020 Dec 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03850444
4. KEYNOTE-598: Boyer M, Şendur MAN, Rodríguez-Abreu D, Park K, Lee DH, Çiçin I, Yumuk PF, Orlandi FJ, Leal TA, Molinier O, Soparattanapaisarn N, Langleben A, Califano R, Medgyasszay B, Hsia TC, Otterson GA, Xu L, Piperdi B, Samkari A, Reck M; KEYNOTE-598 Investigators. Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study. J Clin Oncol. 2021 Jul 20;39(21):2327-2338. Epub 2021 Jan 29. link to original article contains dosing details in manuscript PubMed NCT03302234
5. AdvanTIG-302: NCT04746924
6. EVOKE-03: NCT05609968
7. INTRAPID Lung 037: NCT03631706
8. LEAP-007: NCT03829332
9. MK-7684A-003: NCT04738487
10. TROPION-Lung08: NCT05215340

Advanced or metastatic disease, first-line, elderly or poor performance status

Atezolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2023 (IPSOS)	2017-09-11 to 2019-09-23	Phase 3 (E-switch-ooc)	1a. Gemcitabine 1b. Vinorelbine	Seems to have superior OS (primary endpoint) Median OS: 10.3 vs 9.2 mo (sHR 0.78, 95% CI 0.63-0.97)

Eligibility criteria

• One of the following:
  • ECOG PS 2 or 3
  • Age 70 years or older with an ECOG PS 0-1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. IPSOS: Lee SM, Schulz C, Prabhash K, Kowalski D, Szczesna A, Han B, Rittmeyer A, Talbot T, Vicente D, Califano R, Cortinovis D, Le AT, Huang D, Liu G, Cappuzzo F, Reyes Contreras J, Reck M, Palmero R, Mak MP, Hu Y, Morris S, Höglander E, Connors M, Biggane AM, Vollan HK, Peters S. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. Lancet. 2023 Aug 5;402(10400):451-463. Epub 2023 Jul 6. link to original article PubMed NCT03191786

Carboplatin & Gemcitabine (GCb)

CG: Carboplatin & Gemcitabine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Biesma et al. 2011 (NVALT-3)	2003-2006	Phase 3 (E-switch-ic)	CP	Did not meet secondary endpoint of OS	Similar QoL (primary endpoint)

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 4 cycles

References

1. NVALT-3: Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. link to original article contains dosing details in manuscript PubMed NTR925

Carboplatin & Paclitaxel (CP)

TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel

Regimen variant #1, 5/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Biesma et al. 2011 (NVALT-3)	2003-2006	Phase 3 (E-switch-ic)	CG		Similar QoL

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for up to 4 cycles

Regimen variant #2, 5/90

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (eNERGY)	2018-2021	Phase 3 (C)	Ipilimumab & Nivolumab	Did not meet primary endpoint of OS

Eligibility criteria

• 70 years old or older and PS 0-2, or
• Younger than 70 years old and PS 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Regimen variant #3, 6/90

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Quoix et al. 2011 (IFCT-0501)	2006-2009	Phase 3 (E-esc)	1a. Gemcitabine 1b. Vinorelbine	Superior OS (primary endpoint) Median OS: 10.3 vs 6.2 mo (HR 0.64, 95% CI 0.52-0.78)

Eligibility criteria

• Age 70 to 89 years old and ECOG PS 0–2

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

Supportive therapy

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3-4 neutropenia

28-day cycle for up to 4 cycles

Regimen variant #4, 6/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lilenbaum et al. 2008	2002-2004	Phase 3 (C)	Erlotinib	Seems to have superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 4 cycles

Regimen variant #4, 6/225

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Langer et al. 2008	2002-12 to 2003-12	Phase 3 (C)	Carboplatin & PPX	Did not meet primary endpoint of OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 225 mg/m² IV once on day 1

21-day cycles

References

1. Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. link to original article contains dosing details in abstract PubMed
2. Langer CJ, O'Byrne KJ, Socinski MA, Mikhailov SM, Leśniewski-Kmak K, Smakal M, Ciuleanu TE, Orlov SV, Dediu M, Heigener D, Eisenfeld AJ, Sandalic L, Oldham FB, Singer JW, Ross HJ. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6):623-30. link to original article contains dosing details in abstract PubMed
3. NVALT-3: Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. link to original article contains dosing details in manuscript PubMed NTR925
4. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains dosing details in manuscript PubMed NCT00298415
5. eNERGY: NCT03351361

Carboplatin & Pemetrexed

Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zukin et al. 2013 (INCA-Lung001)	2008-2011	Phase 3 (E-esc)	Pemetrexed	Superior OS (primary endpoint) Median OS: 9.3 vs 5.3 mo (HR 0.62, 95% CI 0.46-0.83)

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

References

1. INCA-Lung001: Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Serodio Da Rocha Baldotto C, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. link to original article contains dosing details in manuscript PubMed NCT01836575

Carboplatin, Pemetrexed, Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Spigel et al. 2018 (ToPPS)	2009-2013	Randomized Phase 2 (E-esc)	1. Pemetrexed 2. Pemetrexed & Bevacizumab	PFS: 4.8 mo

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4: AUC 5 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Targeted therapy

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

Supportive therapy

• Premedications, Folic acid (Folate), and vitamin supplementation per standard guidelines
• Antiemetics per standard guidelines

21-day cycles

References

1. ToPPS: Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains dosing details in manuscript PubMed NCT00892710

Cisplatin & Gemcitabine (GC)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Morabito et al. 2013 (CAPPA-2)	2008-2012	Phase 3 (E-esc)	Gemcitabine	Seems to have superior OS (primary endpoint) Median OS: 5.9 vs 3 mo (HR 0.52, 95% CI 0.28-0.98)
Gridelli et al. 2018 (MILES-3)	2011-2016	Phase 3 (E-esc)	Gemcitabine	Did not meet primary endpoint of OS

Note: MILES-3 involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 4 cycles

References

1. CAPPA-2: Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. link to original article contains dosing details in abstract PubMed NCT00526643
2. MILES-3: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article PubMed NCT01405586

Docetaxel monotherapy

Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 25 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tsukada et al. 2014 (JCOG0207)	2003-2006	Phase 3 (C)	Cisplatin & Docetaxel	Did not meet primary endpoint of OS

Chemotherapy

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

28-day cycles

Regimen variant #2, 36 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 2007	2001-2006	Phase 3 (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 36 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 38 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Karampeazis et al. 2011 (HORG CT/03.07)	2003-2008	Phase 3 (E-switch-ic)	Vinorelbine	Might have superior OS (primary endpoint) Median OS: 6.07 vs 3.87 mo

Chemotherapy

• Docetaxel (Taxotere) 38 mg/m² IV over 60 minutes once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #4, 60 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kudoh et al. 2006 (WJTOG 9904)	2000-2003	Phase 3 (E-switch-ic)	Vinorelbine	Did not meet primary endpoint of OS
Abe et al. 2015 (JCOG0803/WJOG4307L)	2008-2010	Phase 3 (C)	Cisplatin & Docetaxel	Did not meet primary endpoint of OS

Note: This is the PMDA-approved dose.

Chemotherapy

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

21-day cycle for up to 4 cycles (WJTOG 9904) or indefinitely

References

1. WJTOG 9904: Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. link to original article contains dosing details in abstract PubMed NCT00148291
2. Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, Houston GA, Greco FA. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007 Nov 1;110(9):2027-34. link to original article contains dosing details in abstract PubMed
3. HORG CT/03.07: Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. link to original article contains dosing details in manuscript PubMed NCT00441922
4. JCOG0207: Tsukada H, Yokoyama A, Goto K, Shinkai T, Harada M, Ando M, Shibata T, Ohe Y, Tamura T, Saijo N; Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Randomized controlled trial comparing docetaxel-cisplatin combination with weekly docetaxel alone in elderly patients with advanced non-small-cell lung cancer: Japan Clinical Oncology Group (JCOG) 0207. Jpn J Clin Oncol. 2015 Jan;45(1):88-95. Epub 2014 Nov 6. link to original article contains dosing details in abstract PubMed UMIN C000000146
5. JCOG0803/WJOG4307L: Abe T, Takeda K, Ohe Y, Kudoh S, Ichinose Y, Okamoto H, Yamamoto N, Yoshioka H, Minato K, Sawa T, Iwamoto Y, Saka H, Mizusawa J, Shibata T, Nakamura S, Ando M, Yokoyama A, Nakagawa K, Saijo N, Tamura T. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015 Feb 20;33(6):575-81. Epub 2015 Jan 12. link to original article contains dosing details in manuscript PubMed UMIN000001424

Gemcitabine monotherapy

Regimen variant #1, 1000 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2008	2002-2004	Phase 3 (C)	Paclitaxel poliglumex	Did not meet primary endpoint of OS

Chemotherapy

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

28-day cycle for up to 6 cycles

Regimen variant #2, 1150 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Quoix et al. 2011 (IFCT-0501)	2006-2009	Phase 3 (C)	Carboplatin & Paclitaxel	Inferior OS

Eligibility criteria

• Age 70 to 89 years and ECOG PS 0–2

Chemotherapy

• Gemcitabine (Gemzar) 1150 mg/m² IV once per day on days 1 & 8

Supportive therapy

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia

21-day cycle for up to 5 cycles

Regimen variant #3, 1200 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 2003 (MILES)	1997-2000	Phase 3 (E-switch-ic)	1. Gemcitabine & Vinorelbine	Did not meet primary endpoint of OS
			2. Vinorelbine	Did not meet primary endpoint of OS
Reynolds et al. 2009 (USO-03012)	2004-2006	Phase 3 (C)	Carboplatin & Gemcitabine	Did not meet primary endpoint of OS
Morabito et al. 2013 (CAPPA-2)	2008-2012	Phase 3 (C)	Cisplatin & Gemcitabine	Seems to have inferior OS
Gridelli et al. 2018 (MILES-3)	2011-2016	Phase 3 (C)	Cisplatin & Gemcitabine	Did not meet primary endpoint of OS

Note: The MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.

Chemotherapy

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

Supportive therapy

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for 4 to 6 cycles

References

1. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains dosing details in manuscript PubMed NCT00003447
2. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains dosing details in abstract PubMed
3. O'Brien ME, Socinski MA, Popovich AY, Bondarenko IN, Tomova A, Bilynsky BT, Hotko YS, Ganul VL, Kostinsky IY, Eisenfeld AJ, Sandalic L, Oldham FB, Bandstra B, Sandler AB, Singer JW. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jul;3(7):728-34. link to original article contains dosing details in manuscript PubMed
4. USO-03012: Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O'Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J, Peng G, Monberg MJ, Bepler G. Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009 Dec 1;27(34):5808-15. Epub 2009 Nov 2. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00190710
5. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains dosing details in manuscript PubMed NCT00298415
6. CAPPA-2: Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. link to original article contains dosing details in abstract PubMed NCT00526643
7. MILES-3: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains dosing details in manuscript PubMed NCT01405586
8. IPSOS: Lee SM, Schulz C, Prabhash K, Kowalski D, Szczesna A, Han B, Rittmeyer A, Talbot T, Vicente D, Califano R, Cortinovis D, Le AT, Huang D, Liu G, Cappuzzo F, Reyes Contreras J, Reck M, Palmero R, Mak MP, Hu Y, Morris S, Höglander E, Connors M, Biggane AM, Vollan HK, Peters S. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. Lancet. 2023 Aug 5;402(10400):451-463. Epub 2023 Jul 6. link to original article PubMed NCT03191786

Gemcitabine & Paclitaxel

GT: Gemcitabine & Taxol (Paclitaxel)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Comella et al. 2004 (SICOG 9909)	1999-2003	Phase 3 (E-esc)	1. Gemcitabine 2. Paclitaxel	Seems to have superior OS (primary endpoint)
			3. GV	Not reported

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains dosing details in abstract PubMed

Gemcitabine & Vinorelbine

GV: Gemcitabine & Vinorelbine
VG: Vinorelbine & Gemcitabine

Regimen variant #1, 1000/25

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 2003 (MILES)	1997-2000	Phase 3 (E-esc)	1. Gemcitabine	Did not meet primary endpoint of OS
			2. Vinorelbine	Did not meet primary endpoint of OS

Eligibility criteria

• At least 70 years old

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Supportive therapy

• "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for up to 6 cycles

Regimen variant #2, 1200/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Frasci et al. 2000	1997-1999	Phase 3 (E-esc)	Vinorelbine	Superior OS

Eligibility criteria

• At least 70 years old

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, De Cataldis G, Iannelli A, Bilancia D, Belli M, Massidda B, Piantedosi F, Comella G, De Lena M. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Jul;18(13):2529-36. link to original article contains dosing details in abstract PubMed
2. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains dosing details in manuscript PubMed NCT00003447
3. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains dosing details in abstract PubMed

Pemetrexed monotherapy

Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zukin et al. 2013 (INCA-Lung001)	2008-2011	Phase 3 (C)	Carboplatin & Pemetrexed	Inferior OS

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

21-day cycle for up to 4 cycles

References

1. INCA-Lung001: Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Serodio Da Rocha Baldotto C, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. link to original article contains dosing details in manuscript PubMed NCT01836575
2. ToPPS: Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains dosing details in manuscript PubMed NCT00892710

Pemetrexed & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Spigel et al. 2018 (ToPPS)	2009-2013	Randomized Phase 2 (E-esc)	1. Pemetrexed 2. Carboplatin, Pemetrexed, Bevacizumab	PFS: 4.0 mo

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Targeted therapy

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

Supportive therapy

• Premedications, Folic acid (Folate), and vitamin supplementation per standard guidelines
• Antiemetics per standard guidelines

21-day cycles

References

1. ToPPS: Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains dosing details in manuscript PubMed NCT00892710

Vinorelbine monotherapy

Regimen variant #1, 25 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kudoh et al. 2006 (WJTOG 9904)	2000-2003	Phase 3 (C)	Docetaxel	Did not meet primary endpoint of OS
Karampeazis et al. 2011 (HORG CT/03.07)	2003-2008	Phase 3 (E-switch-ic)	Docetaxel	Might have inferior OS (primary endpoint)
Quoix et al. 2011 (IFCT-0501)	2006-2009	Phase 3 (C)	Carboplatin & Paclitaxel	Inferior OS

Eligibility criteria

• IFCT-0501: Age 70 to 89 years and ECOG PS 0–2

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV over 30 minutes once per day on days 1 & 8

Supportive therapy

• Growth factor support was not recommended as primary prophylaxis during cycle 1, but could be used if the patient develops grade 3 to 4 neutropenia

21-day cycle for up to 4 cycles (WJTOG 9904), 5 cycles (IFCT-0501), or 6 cycles (HORG CT/03.07)

Regimen variant #2, 30 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gridelli et al. 1999 (ELVIS)	1996-04 to 1997-11	Phase 3 (E-esc)	Best supportive care	Seems to have superior OS
Gridelli et al. 2003 (MILES)	1997-2000	Phase 3 (C)	1. Gemcitabine	Did not meet primary endpoint of OS
			2. Gemcitabine & Vinorelbine	Did not meet primary endpoint of OS

Note: These studies involved only patients at least 70 years old

Chemotherapy

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

Supportive therapy

• (varies depending on reference):
• ELVIS: Metoclopramide (Reglan) 20 mg IV bolus once per day on days 1 & 8, prior to vinorelbine
• MILES: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for up to 6 cycles

References

1. ELVIS: Gridelli C, Perrone F, Gallo C; Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains dosing details in manuscript PubMed
2. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains dosing details in manuscript PubMed NCT00003447
3. WJTOG 9904: Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. link to original article contains dosing details in abstract PubMed NCT00148291
4. HORG CT/03.07: Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V; Hellenic Oncology Research Group. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. link to original article contains dosing details in manuscript PubMed NCT00441922
5. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains dosing details in manuscript PubMed NCT00298415
6. IPSOS: Lee SM, Schulz C, Prabhash K, Kowalski D, Szczesna A, Han B, Rittmeyer A, Talbot T, Vicente D, Califano R, Cortinovis D, Le AT, Huang D, Liu G, Cappuzzo F, Reyes Contreras J, Reck M, Palmero R, Mak MP, Hu Y, Morris S, Höglander E, Connors M, Biggane AM, Vollan HK, Peters S. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. Lancet. 2023 Aug 5;402(10400):451-463. Epub 2023 Jul 6. link to original article PubMed NCT03191786

Maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Johnson et al. 2013 (ATLAS-NSCLC)	2006-2009	Phase 3 (C)	Erlotinib & Bevacizumab maintenance	Inferior PFS1	Less toxic

¹While this arm was inferior in ATLAS, the authors noted that, due to toxicity, the "two-drug maintenance regimen will not lead to a new postchemotherapy standard of care."
Note: ATLAS should not be confused with the trials with the same name in breast cancer and in renal cell carcinoma.

Preceding treatment

• First-line DCb & Bevacizumab x 4 or GCb & Bevacizumab x 4 or PacCBev x 4 or DC & Bevacizumab x 4 or GC & Bevacizumab x 4 or CVb & Bevacizumab x 4

Targeted therapy

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

21-day cycles

References

1. ATLAS: Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, Lin CY, Marsland T, Patel T, Polikoff J, Rubin M, White L, Yang JC, Bowden C, Miller V. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013 Nov 1;31(31):3926-34. Epub 2013 Oct 7. link to original article contains dosing details in supplement PubMed NCT00257608

Docetaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhang et al. 2021 (TFINE)	2009-2011	Phase 3 (E-esc)	Observation	Superior PFS (primary endpoint) Median PFS: 5.8 vs 3 mo (HR 0.57, 95% CI 0.40-0.80)

Preceding treatment

• First-line DC; DC60 x 4 versus DC; DC75 x 4

Chemotherapy

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

21-day cycle for up to 6 cycles

References

1. TFINE:' Zhang L, Lu S, Cheng Y, Hu Z, Wu YL, Chen Z, Chen G, Liu X, Yang J, Zhang L, Chen J, Huang M, Tao M, Cheng G, Huang C, Zhou C, Zhang W, Zhao H, Sun Y. Docetaxel maintenance therapy versus best supportive care after first-line chemotherapy with different dose docetaxel plus cisplatin for advanced non-small cell lung cancer (TFINE study, CTONG-0904): an open-label, randomized, phase III trial. Ann Transl Med. 2021 Feb;9(4):338. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01038661

Gemcitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Brodowicz et al. 2006	1999-2002	Phase 3 (E-esc)	Observation	Superior TTP (primary endpoint)
Pérol et al. 2012 (IFCT-GFPC 0502)	2006-2009	Phase 3 (E-esc)	1. Erlotinib	Not reported
			2. Observation	Superior PFS (primary endpoint) Median PFS: 3.8 vs 1.9 mo (HR 0.56, 95% CI 0.44-0.72)

Preceding treatment

• First-line Cisplatin & Gemcitabine x 4

Chemotherapy

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

21-day cycles

References

1. Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 May;52(2):155-63. Epub 2006 Mar 29. link to original article contains dosing details in abstract PubMed
2. IFCT-GFPC 0502: Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original articlecontains dosing details in manuscript PubMed NCT00300586

Ipilimumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Lynch et al. 2012 (CA184-041NSCLC)	2008-2009	Non-randomized part of phase 2 RCT

Preceding treatment

• First-line Carboplatin, Paclitaxel, Ipilimumab x 6

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

12-week cycles

References

1. CA184-041_NSCLC: Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains dosing details in manuscript PubMed NCT00527735

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (ZEAL-1L)	2020-ongoing	Phase 3 (C)	Niraparib & Pembrolizumab	In progress

Preceding treatment

• First-line platinum-based chemotherapy

Immunotherapy

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

21-day cycles

References

1. ZEAL-1L: NCT04475939

Pemetrexed monotherapy

Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ciuleanu et al. 2009 (JMEN)	2005-2007	Phase 3 (E-RT-esc)	Placebo	Superior PFS (primary endpoint) Median PFS: 4.3 vs 2.6 mo (HR 0.50, 95% CI 0.42-0.61) Superior OS (secondary endpoint) Median OS: 13.4 vs 10.6 mo (HR 0.79, 95% CI 0.65-0.95)
Reck et al. 2016 (KEYNOTE-024)	2014-09-19 to 2015-10-29	Non-randomized part of phase 3 RCT
Mok et al. 2019 (KEYNOTE-042)	2014-2017	Non-randomized part of phase 3 RCT

Preceding treatment

• JMEN: First-line platinum-based chemotherapy x 4
• KEYNOTE-024: First-line Carboplatin & Paclitaxel or Carboplatin & Pemetrexed or Cisplatin & Pemetrexed
• KEYNOTE-042: First-line Carboplatin & Pemetrexed x 6

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive therapy

• Folic acid (Folate)
• Cyanocobalamin (Vitamin B12)
• Dexamethasone (Decadron)
• "Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."

21-day cycles

References

1. JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. link to original article contains dosing details in abstract PubMed NCT00102804
2. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
   1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
   2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
   3. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. Epub 2021 Apr 19. link to original article link to PMC article PubMed
3. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed NCT02220894
   1. Update: de Castro G Jr, Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. J Clin Oncol. 2023 Apr 10;41(11):1986-1991. Epub 2022 Oct 28. link to original article link to PMC article PubMed

Advanced or metastatic disease, second-line

Cabozantinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	2013-2014	Randomized Phase 2 (E-switch-ic)	1. Cabozantinib & Erlotinib	Not reported
			2. Erlotinib	Superior PFS (primary endpoint) Median PFS: 4.3 vs 1.8 mo (HR 0.39, 80% CI 0.27-0.55)

Targeted therapy

• Cabozantinib (Cometriq) 60 mg PO once per day on days 1 to 28

28-day cycles

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01708954

Cabozantinib & Erlotinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	2013-2014	Randomized Phase 2 (E-esc)	1. Cabozantinib	Not reported
			2. Erlotinib	Superior PFS (primary endpoint) Median PFS: 4.7 vs 1.8 mo (HR 0.37, 80% CI 0.25-0.53)

Targeted therapy

• Cabozantinib (Cometriq) 40 mg PO once per day
• Erlotinib (Tarceva) 150 mg PO once per day

Continued indefinitely

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01708954

Carboplatin & Pemetrexed

Example orders

• Example orders for Carboplatin (Paraplatin) and Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ardizzoni et al. 2012 (GOIRC 02-2006)	2007-2009	Randomized Phase 2 (E-esc)	Pemetrexed	Did not meet primary endpoint of PFS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (Ardizzoni et al. 2012 contained more details):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for 4 to 6 cycles

References

1. GOIRC 02-2006: Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00786331

Docetaxel monotherapy

Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 33.3 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gebbia et al. 2008 (DISTAL-2)	2005-05 to 2006-12	Phase 3 (C)	1. Capecitabine & Docetaxel 2a. Docetaxel & Gemcitabine 2b. Docetaxel & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 33.3 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 35 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schuette et al. 2005	2000-2003	Phase 3 (E-switch-ic)	Docetaxel; 75 mg/m2, every 3 wks	Might have superior OS
Garassino et al. 2013 (TAILORNSCLC)	2007-2012	Phase 3 (C)	Erlotinib	Seems to have superior OS

Note: there is another trial named TAILOR in colorectal cancer.

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV once per day on days 1, 8, 15

Supportive therapy

• Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to docetaxel
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to docetaxel
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after docetaxel

28-day cycles

Regimen variant #3, 50 mg/m² q2wk, limited duration

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pallis et al. 2010 (HORG CT/04.14)	2004-2008	Phase 3 (C)	Carboplatin & Docetaxel	Did not meet primary endpoint of OS

Prior treatment criteria

• Previous treatment with a platinum-free regimen

Chemotherapy

• Docetaxel (Taxotere) 50 mg/m² IV once per day on days 1 & 15

28-day cycle for up to 6 cycles

Regimen variant #4, 60 mg/m² q3wk, limited duration

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	2006-2008	Phase 3 (C)	Docetaxel & Vandetanib	Inferior PFS

Note: This is the PMDA-approved dose. While statistically inferior, the median PFS difference was only 0.8 months.

Prior treatment criteria

• Platinum-based chemotherapy, with progression

Chemotherapy

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

21-day cycle for up to 6 cycles

Regimen variant #5, 60 mg/m² q3wk, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Takeda et al. 2009 (JCOG 0104)	2002-01 to 2003-09	Phase 3 (C)	Docetaxel & Gemcitabine	Did not meet primary endpoint of OS
Kawaguchi et al. 2014 (DELTANSCLC)	2009-2012	Phase 3 (C)	Erlotinib	Might have superior PFS
Garon et al. 2014 (REVEL)	2010-2013	Phase 3 (C)	Docetaxel & Ramucirumab	Seems to have inferior OS
Gridelli et al. 2018 (AvaALL)	2011-2015	Phase 3 (C)	Investigator's choice of: 1a. Docetaxel & Bevacizumab 1b. Erlotinib & Bevacizumab 1c. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS

Note: This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC. Note that there is another trial named DELTA in indolent lymphoma.

Chemotherapy

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

21-day cycles

Regimen variant #6, 75 mg/m² q3wk, limited duration

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	2006-2008	Phase 3 (C)	Docetaxel & Vandetanib	Inferior PFS

Note: while statistically inferior, the median PFS difference in ZODIAC was only 0.8 months.

Chemotherapy

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

21-day cycle for up to 6 cycles

Regimen variant #7, 75 mg/m² q3wk, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Gridelli et al. 2004 (DISTAL 01)	2000-2002	Phase 3 (C)	Docetaxel; 33.3 mg/m2, 6 out of 8 wks		Did not meet primary endpoint of QoL
Schuette et al. 2005	2000-2003	Phase 3 (C)	Docetaxel; 35 mg/m2, 3 out of 4 wks	Might have inferior OS
Paz-Ares et al. 2008 (STELLAR 2)	2002-2004	Phase 3 (C)	Paclitaxel poliglumex	Did not meet primary endpoint of OS
Krzakowski et al. 2010	2003-2005	Phase 3 (C)	Vinflunine	Non-inferior PFS
Sun et al. 2012 (JMID)	2006-2008	Phase 3 (C)	Pemetrexed	Inconclusive whether non-inferior OS
Ciuleanu et al. 2012 (TITAN)	2006-2010	Phase 3 (C)	Erlotinib	Did not meet primary endpoint of OS
Garassino et al. 2013 (TAILORNSCLC)	2007-2012	Phase 3 (C)	Erlotinib	Seems to have superior OS
Garon et al. 2014 (REVEL)	2010-2013	Phase 3 (C)	Docetaxel & Ramucirumab	Seems to have inferior OS
Gridelli et al. 2018 (AvaALL)	2011-2015	Phase 3 (C)	Investigator's choice of: 1a. Docetaxel & Bevacizumab 1b. Erlotinib & Bevacizumab 1c. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS
Pillai et al. 2019 (GALAXY-2)	2013-2015	Phase 3 (C)	Docetaxel & Ganetespib	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Supportive therapy

• Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)

21-day cycles

References

1. DISTAL 01: Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, Salvagni S, Piantedosi FV, Palazzolo G, Caffo O, Ceribelli A, Falcone A, Mazzanti P, Brancaccio L, Capuano MA, Isa L, Barbera S, Perrone F. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer: the DISTAL 01 study. Br J Cancer. 2004 Dec 13;91(12):1996-2004. link to original article link to PMC article contains dosing details in abstract PubMed
2. Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt EW, Dittrich I, Schweisfurth H, von Weikersthal LF, Raghavachar A, Reissig A, Serke M. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005 Nov 20;23(33):8389-95. link to original article contains dosing details in abstract PubMed
3. STELLAR 2: Paz-Ares L, Ross H, O'Brien M, Riviere A, Gatzemeier U, Von Pawel J, Kaukel E, Freitag L, Digel W, Bischoff H, García-Campelo R, Iannotti N, Reiterer P, Bover I, Prendiville J, Eisenfeld AJ, Oldham FB, Bandstra B, Singer JW, Bonomi P. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br J Cancer. 2008 May 20;98(10):1608-13. Epub 2008 May 13. link to original article link to PMC article contains dosing details in abstract PubMed
4. DISTAL-2: Gebbia V, Gridelli C, Verusio C, Frontini L, Aitini E, Daniele B, Gamucci T, Mancuso G, Di Maio M, Gallo C, Perrone F, Morabito A. Weekly docetaxel vs docetaxel-based combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer patients: the DISTAL-2 randomized trial. Lung Cancer. 2009 Feb;63(2):251-8. Epub 2008 Jul 15. link to original article contains dosing details in abstract PubMed NCT00345059
5. JCOG 0104: Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Yokota S, Matsui K, Semba H, Nakagawa K, Takada Y, Ando M, Shibata T, Saijo N. Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol. 2009 May;20(5):835-41. Epub 2009 Jan 22. link to original article contains dosing details in abstract PubMed
6. Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY. Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol. 2010 May 1;28(13):2167-73. Epub 2010 Mar 29. link to original article contains dosing details in abstract PubMed
7. ZODIAC: Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00312377
   1. Dataset: Project Data Sphere
8. HORG CT/04.14: Pallis AG, Agelaki S, Agelidou A, Varthalitis I, Syrigos K, Kentepozidis N, Pavlakou G, Kotsakis A, Kontopodis E, Georgoulias V. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer. 2010 Nov 19;10:633. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00430651
9. TITAN: Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. link to original article contains dosing details in abstract PubMed NCT00556322
10. JMID: Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. link to original article PubMed NCT00391274
11. TAILOR: Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. link to original article contains dosing details in manuscript PubMed NCT00637910
12. DELTA_NSCLC: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains dosing details in manuscript PubMed
13. REVEL: Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. link to original article contains dosing details in manuscript PubMed NCT01168973
14. AvaALL: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. link to original article link to PMC article contains dosing details in supplement PubMed NCT01351415
15. GALAXY-2: Pillai RN, Fennell DA, Kovcin V, Ciuleanu TE, Ramlau R, Kowalski D, Schenker M, Yalcin I, Teofilovici F, Vukovic VM, Ramalingam SS. Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2). J Clin Oncol. 2020 Feb 20;38(6):613-622. Epub 2019 Dec 12. link to original article contains dosing details in abstract PubMed NCT01798485
16. DUBLIN-3: NCT02504489

Docetaxel & Ramucirumab

Regimen variant #1, 60 mg/m² docetaxel

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2014 (REVEL)	2010-2013	Phase 3 (E-RT-esc)	Docetaxel	Seems to have superior OS (primary endpoint) Median OS: 10.5 vs 9.1 mo (HR 0.86, 95% CI 0.75-0.98)

Note: This is the PMDA-approved dose and the dose recommended for East Asians. The FDA only provides recommendations for ramucirumab dosing.

Chemotherapy

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

Targeted therapy

• Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

Supportive therapy

• Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.

21-day cycles

Regimen variant #2, 75 mg/m² docetaxel

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2014 (REVEL)	2010-2013	Phase 3 (E-RT-esc)	Docetaxel	Seems to have superior OS (primary endpoint) Median OS: 10.5 vs 9.1 mo (HR 0.86, 95% CI 0.75-0.98)

Note: The FDA only provides recommendations for ramucirumab dosing.

Chemotherapy

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

Targeted therapy

• Ramucirumab (Cyramza) 10 mg/kg IV once on day 1

Supportive therapy

• Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.

21-day cycles

References

1. REVEL: Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2. link to original article contains dosing details in manuscript PubMed NCT01168973

Docetaxel & Vandetanib

Regimen variant #1, 60 mg/m² docetaxel

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	2006-2008	Phase 3 (E-esc)	Docetaxel	Superior PFS (primary endpoint) Median PFS: 4 vs 3.2 mo (HR 0.79, 97.58% CI 0.70-0.90)

Note: This is the PMDA-approved dose of docetaxel. While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 up to 6: 60 mg/m² IV once on day 1

Targeted therapy

• Vandetanib (Caprelsa) 100 mg PO once per day on days 1 to 21

21-day cycles

Regimen variant #2, 75 mg/m² docetaxel

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herbst et al. 2010 (ZODIAC)	2006-2008	Phase 3 (E-esc)	Docetaxel	Superior PFS (primary endpoint) Median PFS: 4 vs 3.2 mo (HR 0.79, 97.58% CI 0.70-0.90)

Note: While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Chemotherapy

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

Targeted therapy

• Vandetanib (Caprelsa) 100 mg PO once per day on days 1 to 21

21-day cycles

References

1. ZODIAC: Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00312377

Gefitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sun et al. 2012 (KCSG-LU08-01)	2008-2010	Phase 3 (E-switch-ooc)	Pemetrexed	Superior PFS (primary endpoint) Median PFS: 9 vs 3 mo (HR 0.54, 95% CI 0.37-0.79)

Targeted therapy

• Gefitinib (Iressa) 250 mg PO once per day

Continued indefinitely

References

1. KCSG-LU08-01: Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. link to original article contains dosing details in abstract PubMed NCT01066195

Gemcitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Crinò et al. 1999a	1995-11 to 1997-10	Phase 2

Chemotherapy

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

28-day cycles

References

1. Crinò L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1999 Jul;17(7):2081-5. link to original article contains dosing details in abstract PubMed

Pemetrexed monotherapy

Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cullen et al. 2008 (JMGX)	2004-02 to 2005-11	Phase 3 (C)	Pemetrexed; high-dose	Did not meet primary endpoint of OS
Sun et al. 2012 (JMID)	2006-2008	Phase 3 (E-switch-ic)	Docetaxel	Inconclusive whether non-inferior OS (primary endpoint)
Ciuleanu et al. 2012 (TITAN)	2006-2010	Phase 3 (C)	Erlotinib	Did not meet primary endpoint of OS
de Boer et al. 2011 (ZEAL)	2007-01 to 2008-03	Phase 3 (C)	Pemetrexed & Vandetanib	Did not meet primary endpoint of PFS
Ardizzoni et al. 2012 (GOIRC 02-2006)	2007-2009	Randomized Phase 2 (C)	Carboplatin & Pemetrexed	Did not meet primary endpoint of PFS
Sun et al. 2012 (KCSG-LU08-01)	2008-2010	Phase 3 (C)	Gefitinib	Inferior PFS
Gridelli et al. 2018 (AvaALL)	2011-2015	Phase 3 (C)	Investigator's choice of: 1a. Docetaxel & Bevacizumab 1b. Erlotinib & Bevacizumab 1c. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive therapy

• (per Ardizzoni et al. 2012):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycles GOIRC 02-2006 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.

References

1. JMGX: Cullen MH, Zatloukal P, Sörenson S, Novello S, Fischer JR, Joy AA, Zereu M, Peterson P, Visseren-Grul CM, Iscoe N. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008 May;19(5):939-45. Epub 2008 Feb 17. link to original article contains dosing details in abstract PubMed NCT00078260
2. ZEAL: de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. Epub 2011 Jan 31. link to original article contains dosing details in abstract PubMed NCT00418886
3. TITAN: Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. link to original article contains dosing details in abstract PubMed NCT00556322
4. KCSG-LU08-01: Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. link to original article contains dosing details in abstract PubMed NCT01066195
5. GOIRC 02-2006: Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00786331
6. JMID: Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. link to original article PubMed NCT00391274
7. AvaALL: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. link to original article link to PMC article contains dosing details in supplement PubMed NCT01351415

Advanced or metastatic disease, third-line

Anlotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Han et al. 2018 (ALTER 0303)	2015-03-01 to 2016-08-31	Phase 3 (E-esc)	Placebo	Superior OS (primary endpoint) Median OS: 9.6 vs 6.3 mo (HR 0.68, 95% CI 0.54-0.87)

Targeted therapy

• Anlotinib (Fukewei) 12 mg PO once per day on days 1 to 14

21-day cycles

References

1. ALTER 0303: Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, Yu H, Zhao Y, Chen W, Luo Y, Wu L, Wang X, Pirker R, Nan K, Jin F, Dong J, Li B, Sun Y. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol. 2018 Nov 1;4(11):1569-1575. link to original article link to PMC article PubMed NCT02388919
   1. HRQoL analysis: Si X, Zhang L, Wang H, Zhang X, Wang M, Han B, Li K, Wang Q, Shi J, Wang Z, Cheng Y, He J, Shi Y, Chen W, Wang X, Luo Y, Nan K, Jin F, Li B, Chen Y, Zhou J, Wang D. Quality of life results from a randomized, double-blinded, placebo-controlled, multi-center phase III trial of anlotinib in patients with advanced non-small cell lung cancer. Lung Cancer. 2018 Aug;122:32-37. Epub 2018 May 18. link to original article PubMed

Cabozantinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	2013-2014	Randomized Phase 2 (E-switch-ic)	1. Cabozantinib & Erlotinib	Not reported
			2. Erlotinib	Superior PFS (primary endpoint)

Targeted therapy

• Cabozantinib (Cometriq) 60 mg PO once per day on days 1 to 28

28-day cycles

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01708954

Cabozantinib & Erlotinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512)	2013-2014	Randomized Phase 2 (E-esc)	1. Cabozantinib	Not reported
			2. Erlotinib	Superior PFS (primary endpoint)

Targeted therapy

• Cabozantinib (Cometriq) 40 mg PO once per day
• Erlotinib (Tarceva) 150 mg PO once per day

Continued indefinitely

References

1. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01708954

Docetaxel monotherapy

Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 60 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kawaguchi et al. 2014 (DELTANSCLC)	2009-2012	Phase 3 (C)	Erlotinib	Might have superior PFS (primary endpoint) Median PFS: 3.2 vs 2 mo (HR 0.82, 95% CI 0.65-1.03)

Note: This is the PMDA-approved dose. Note that there is another trial named DELTA in indolent lymphoma.

Chemotherapy

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

21-day cycles

Regimen variant #2, 75 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al. 2024 (CANOPY-2)	2019-01-29 to 2020-03-30	Phase 3 (C)	Docetaxel & Canakinumab	Did not meet primary endpoint of OS
Awaiting publication (LEAP-008)	2019-ongoing	Phase 3 (C)	1. Lenvatinib & Pembrolizumab 2. Lenvatinib	TBD if different co-primary endpoints of PFS/OS
Borghaei et al. 2023 (SAPPHIRE)	NR	Phase 3 (C)	Sitravantinib & Nivolumab	Might have inferior OS (primary endpoint) Median OS: 10.6 vs 12.2 mo (HR 1.16, 95% CI 0.95-1.43)
Awaiting publication (CONTACT-01)	2020-ongoing	Phase 3 (C)	Cabozantinib & Atezolizumab	TBD if different primary endpoint of OS

Chemotherapy

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

21-day cycles

References

1. DELTA_NSCLC: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains dosing details in manuscript PubMed
2. SAPPHIRE: Borghaei H, de Marinis F, Dumoulin D, Reynolds C, Theelen WSME, Percent I, Gutierrez Calderon V, Johnson ML, Madroszyk-Flandin A, Garon EB, He K, Planchard D, Reck M, Popat S, Herbst RS, Leal TA, Shazer RL, Yan X, Harrigan R, Peters S; SAPPHIRE Investigators. SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2024 Jan;35(1):66-76. Epub 2023 Oct 20. link to original article contains dosing details in manuscript PubMed NCT03906071
3. CANOPY-2: Paz-Ares L, Goto Y, Wan-Teck Lim D, Halmos B, Chul Cho B, Cobo M, Luis González Larriba J, Zhou C, Demedts I, Atmaca A, Baka S, Mookerjee B, Portella S, Zhu Z, Wu J, Demanse D, Dharan B, Reck M. Canakinumab in combination with docetaxel compared with docetaxel alone for the treatment of advanced non-small cell lung cancer following platinum-based doublet chemotherapy and immunotherapy (CANOPY-2): A multicenter, randomized, double-blind, phase 3 trial. Lung Cancer. 2024 Mar;189:107451. Epub 2024 Jan 16. link to original article contains dosing details in manuscript PubMed [NCT03626545
4. CONTACT-01: NCT04471428
5. LEAP-008: NCT03976375

Advanced or metastatic disease, subsequent lines of therapy

Note: this section includes regimens that were tested in second-line and beyond; those tested specifically in the second-line or third-line are to be found above.

Afatinib monotherapy

Regimen variant #1, 30 mg/day

FDA-recommended dose

Note: This is the FDA-recommended dose for patients with "severe renal impairment".

Targeted therapy

• Afatinib (Gilotrif) 30 mg PO once per day

Continued indefinitely

Regimen variant #2, 50 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Miller et al. 2012 (LUX-Lung 1)	2008-05-26 to 2009-09-21	Phase 3 (E-esc)	Placebo	Did not meet primary endpoint of OS
Katakami et al. 2013 (LUX-Lung 4)	2009-2011	Phase 2		ORR: 8% (95% CI: 3-18)

Note: In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.

Targeted therapy

• Afatinib (Gilotrif) 50 mg PO once per day, taken at least 1 hour before eating food

Continued indefinitely

References

1. LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article contains dosing details in manuscript PubMed NCT00656136
   1. HRQoL analysis: Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. link to original article PubMed
2. LUX-Lung 4: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00711594

Afatinib & Paclitaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schuler et al. 2015 (LUX-Lung 5)	2010-04 to 2011-05	Phase 3 (E-esc)	Single-agent chemotherapy	Superior PFS (primary endpoint) Median PFS: 5.6 vs 2.8 mo (HR 0.60, 95% CI 0.43-0.85)

Targeted therapy

• Afatinib (Gilotrif) 40 mg PO once per day on days 1 to 7

Chemotherapy

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

7-day cycles

References

1. LUX-Lung 5: Schuler M, Yang JC, Park K, Kim JH, Bennouna J, Chen YM, Chouaid C, De Marinis F, Feng JF, Grossi F, Kim DW, Liu X, Lu S, Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand VK, Planchard D; LUX-Lung 5 Investigators. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016 Mar;27(3):417-23. Epub 2015 Dec 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01085136

Amrubicin monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshioka et al. 2017 (D0702035)	2010-2012	Phase 3 (E-switch-ic)	Docetaxel	Did not meet primary endpoint of PFS

Chemotherapy

• Amrubicin (Calsed) 35 mg/m² IV over 5 minutes once per day on days 1 to 3

21-day cycles

References

1. D0702035: Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains dosing details in manuscript PubMed NCT01207011

Atezolizumab monotherapy

Regimen variant #1, q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (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.

Immunotherapy

• Atezolizumab (Tecentriq) 840 mg IV over 60 minutes once on day 1

14-day cycles

Regimen variant #2, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fehrenbacher et al. 2016 (POPLAR)	2013-2014	Randomized Phase 2 (E-switch-ooc)	Docetaxel	Seems to have superior OS1 (primary endpoint) Median OS: 12.6 vs 9.7 mo (HR 0.76, 95% CI 0.58-1.00)
Rittmeyer et al. 2016 (OAK)	2014-03-11 to 2015-04-29	Phase 3 (E-RT-switch-ooc)	Docetaxel	Superior OS1 (co-primary endpoint) Median OS: 13.3 vs 9.8 mo (HR 0.78, 95% CI 0.68-0.89)
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (primary endpoint)
Burotto et al. 2023 (IMscin001 Part 2)	2020-12-02 to 2022-03-30	Phase 3 (C)	SC Atezolizumab	Non-inferior trough serum concentration (co-primary endpoint) Non-inferior model-predicted area under the curve from days 0 to 21 (co-primary endpoint)

¹Reported efficacy for POPLAR is based on the 2020 update.
¹Reported efficacy for OAK is based on the 2020 update.

Prior treatment criteria

• OAK: 1 or more platinum-based combination therapies

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1

21-day cycles

Regimen variant #3, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (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.

Immunotherapy

• Atezolizumab (Tecentriq) 1680 mg IV over 60 minutes once on day 1

28-day cycles

References

1. POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains dosing details in abstract PubMed NCT01903993
   1. Pooled update: Mazieres J, Rittmeyer A, Gadgeel S, Hida T, Gandara DR, Cortinovis DL, Barlesi F, Yu W, Matheny C, Ballinger M, Park K. Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials. J Thorac Oncol. 2021 Jan;16(1):140-150. Epub 2020 Nov 6. link to original article PubMed
2. OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. link to original article link to PMC article PubMed NCT02008227
   1. Update: Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. link to original article PubMed
   2. PRO analysis: Bordoni R, Ciardiello F, von Pawel J, Cortinovis D, Karagiannis T, Ballinger M, Sandler A, Yu W, He P, Matheny C, Felizzi F, Rittmeyer A. Patient-Reported Outcomes in OAK: A Phase III Study of Atezolizumab Versus Docetaxel in Advanced Non-Small-cell Lung Cancer. Clin Lung Cancer. 2018 Sep;19(5):441-449.e4. Epub 2018 May 31. link to original article PubMed
   3. Update: von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. link to original article PubMed
   4. Pooled update: Mazieres J, Rittmeyer A, Gadgeel S, Hida T, Gandara DR, Cortinovis DL, Barlesi F, Yu W, Matheny C, Ballinger M, Park K. Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials. J Thorac Oncol. 2021 Jan;16(1):140-150. Epub 2020 Nov 6. link to original article PubMed
3. IMscin001 Part 2: Burotto M, Zvirbule Z, Mochalova A, Runglodvatana Y, Herraez-Baranda L, Liu SN, Chan P, Shearer-Kang E, Liu X, Tosti N, Zanghi JA, Leutgeb B, Felip E. IMscin001 Part 2: a randomised phase III, open-label, multicentre study examining the pharmacokinetics, efficacy, immunogenicity, and safety of atezolizumab subcutaneous versus intravenous administration in previously treated locally advanced or metastatic non-small-cell lung cancer and pharmacokinetics comparison with other approved indications. Ann Oncol. 2023 Aug;34(8):693-702. Epub 2023 Jun 1. link to original article contains dosing details in manuscript PubMed NCT03735121
4. LUNAR: Leal T, Kotecha R, Ramlau R, Zhang L, Milanowski J, Cobo M, Roubec J, Petruzelka L, Havel L, Kalmadi S, Ward J, Andric Z, Berghmans T, Gerber DE, Kloecker G, Panikkar R, Aerts J, Delmonte A, Pless M, Greil R, Rolfo C, Akerley W, Eaton M, Iqbal M, Langer C; LUNAR Study Investigators. Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study. Lancet Oncol. 2023 Sep;24(9):1002-1017. link to original article contains dosing details in manuscript PubMed NCT02973789

Docetaxel monotherapy

Example orders

• Example orders for Docetaxel (Taxotere) in non-small cell lung cancer

Regimen variant #1, 35 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chen et al. 2006	2002-2004	Phase 3 (E-switch-ic)	1. Docetaxel; 40 mg/m2, 2 out of 3 wks	Did not meet efficacy endpoint
			2. Docetaxel; 75 mg/m2, every 3 wks	Did not meet efficacy endpoint

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV once per day on days 1, 8, 15

Supportive therapy

• Dexamethasone (Decadron) as follows:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to docetaxel
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to docetaxel
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after docetaxel

28-day cycles

Regimen variant #2, 60 mg/m² q3wk, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Maruyama et al. 2008 (V-15-32)	2003-2006	Phase 3 (C)	Gefitinib	Inconclusive whether non-inferior OS
Atagi et al. 2023 (JMTO LC09-01)	2009-05 to 2014-09	Phase 3 (C)	Docetaxel & S-1	Did not meet primary endpoint of OS
Yoshioka et al. 2017 (D0702035)	2010-2012	Phase 3 (C)	Amrubicin	Did not meet primary endpoint of PFS
Nokihara et al. 2017 (EAST-LC)	2010-2014	Phase 3 (C)	S-1	Non-inferior OS
Yoneshima et al. 2021 (J-AXEL)	2015-2018	Phase 3 (C)	nab-Paclitaxel	Non-inferior OS

Note: This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC.

Chemotherapy

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

21-day cycles

Regimen variant #3, 75 mg/m² q3wk, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shepherd et al. 2000 (TAX 317)	1994-1998	Phase 3 (E-RT-esc)	Best supportive care	Seems to have superior OS (primary endpoint) Median OS: 7 vs 4.6 mo
Fossella et al. 2000 (TAX 320)	1995-1998	Phase 3 (E-RT-switch-ic)	1. Docetaxel; 100 mg/m2	Did not meet primary endpoint of OS
			2. Ifosfamide 3. Vinorelbine	Did not meet primary endpoint of OS
Camps et al. 2005	2000-2003	Phase 3 (C)	Docetaxel; 36 mg/m2, 6 out of 8 wks	Might have superior OS
Hanna et al. 2004 (JMEI)	2001-03 to 2002-02	Phase 3 (C)	Pemetrexed	Inconclusive whether non-inferior OS
Ramlau et al. 2006 (GSK 104864-A/387)	2001-2003	Phase 3 (C)	Topotecan	Might have superior OS
Chen et al. 2006	2002-2004	Phase 3 (C)	1. Docetaxel; 35 mg/m2, 3 out of 4 wks	Did not meet efficacy endpoint
			2. Docetaxel; 40 mg/m2, 2 out of 3 wks	Did not meet efficacy endpoint
Fidias et al. 2008	2002-2005	Phase 3 (C)	Docetaxel consolidation	Might have inferior OS
Kim et al. 2008 (INTEREST)	2004-2006	Phase 3 (C)	Gefitinib	Seems to have non-inferior OS
Lee et al. 2010 (ISTANA)	2005-09 to 2006-09	Phase 3 (C)	Gefitinib	Seems to have inferior PFS
Ramlau et al. 2012 (EFC10261)	2007-2010	Phase 3 (C)	Docetaxel & Ziv-aflibercept	Did not meet primary endpoint of OS Median OS: 10.4 vs 10.1 mo (HR 0.99, 95% CI 0.85-1.15)
Reck et al. 2014 (LUME-Lung 1)	2008-2011	Phase 3 (C)	Docetaxel & Nintedanib	Inferior PFS
Nokihara et al. 2017 (EAST-LC)	2010-2014	Phase 3 (C)	S-1	Non-inferior OS
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase 3 (C)	Eribulin	Might have superior OS Median OS: 9.5 vs 9.5 mo (HR 0.86, 95% CI 0.71-1.05)
Fehrenbacher et al. 2016 (POPLAR)	2013-2014	Randomized Phase 2 (C)	Atezolizumab	Seems to have inferior OS
Herbst et al. 2015 (KEYNOTE-010)	2013-2015	Phase 2/3 (C)	1. Pembrolizumab; 2 mg/kg 2. Pembrolizumab; 10 mg/kg	Inferior OS
Rittmeyer et al. 2016 (OAK)	2014-03-11 to 2015-04-29	Phase 3 (C)	Atezolizumab	Inferior OS
Wu et al. 2019 (CheckMate 078)	2015-12 to 2016-11	Phase 3 (C)	Nivolumab	Inferior OS
Barlesi et al. 2018 (JAVELIN Lung 200)	2015-2017	Phase 3 (C)	Avelumab	Did not meet primary endpoint of OS
Ren et al. 2023 (KEYNOTE-033)	2016-09-08 to 2018-10-17	Phase 3 (C)	Pembrolizumab	Did not meet co-primary endpoint of OS1 Median OS: 10.9 vs 12.3 mo (HR 1.20, 95% CI 0.88-1.64)
Zhou et al. 2022 (RATIONALE-303)	2017-2020	Phase 3 (C)	Tislelizumab	Inferior OS
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (primary endpoint)
Awaiting publication (TROPION-Lung01)	2020-ongoing	Phase 3 (C)	Datopotamab-DXd	TBD if different co-primary endpoints of PFS/OS
Awaiting publication (EVOKE-01)	2021-ongoing	Phase 3 (C)	Sacituzumab govitecan	TBD if different primary endpoint of OS
Awaiting publication (KN046-302)	2021-ongoing	Phase 2/3 (C)	1. Lenvatinib 2. Lenvatinib & KN-046	TBD if different co-primary endpoints of PFS/OS

¹KEYNOTE-033 was designed to look first at patients with TPS at least 50%; this result is reported here.

Biomarker eligibility criteria

• KEYNOTE-010 & KEYNOTE-033: PD-L1 expression of at least 1% on tumor cells

Prior treatment criteria

• OAK: 1 or more platinum-based combination therapies
• CheckMate 078 & JAVELIN Lung 200: Failure of a platinum doublet
• RATIONALE-303: Progression after a platinum doublet, with up to 2 SACT for metastatic disease
• KEYNOTE-033: Progression after 2+ cycles of platinum doublet per RECIST 1.1, and an appropriate TKI for those with an ALK gene rearrangement
• KN046-302: Progression after first- or second-line PD-1 or PD-L1 inhibitor and platinum-containing dual-agent chemotherapy

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Supportive therapy

• Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)

21-day cycles

Regimen variant #4, 100 mg/m² q3wk

Study	Dates of enrollment	Evidence
Fossella et al. 1995	1992-07 to 1993-06	Phase 2

Chemotherapy

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

21-day cycles

References

1. Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, Murphy WK, Lippman S, Benner S, Glisson B, Chasen M, Hong WK, Raber M. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol. 1995 Mar;13(3):645-51. link to original article contains dosing details in abstract PubMed
2. TAX 317: Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. link to original article contains dosing details in abstract PubMed
3. TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains dosing details in manuscript PubMed
4. JMEI: Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains dosing details in manuscript PubMed
5. Camps C, Massuti B, Jiménez A, Maestu I, Gómez RG, Isla D, González JL, Almenar D, Blasco A, Rosell R, Carrato A, Viñolas N, Batista N, Girón CG, Galán A, López M, Blanco R, Provencio M, Diz P, Felip E; Spanish Lung Cancer Group. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol. 2006 Mar;17(3):467-72. Epub 2005 Dec 21. link to original article contains dosing details in abstract PubMed
6. Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. link to original article contains dosing details in manuscript PubMed
7. GSK 104864-A/387: Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, Dharan B, Grotzinger KM, Ross G, Dane G, Shepherd FA. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006 Jun 20;24(18):2800-7. Epub 2006 May 8. link to original article contains dosing details in abstract PubMed NCT00049998
8. V-15-32: Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Inoue A, Tomii K, Harada M, Masuda N, Jiang H, Itoh Y, Ichinose Y, Saijo N, Fukuoka M. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008 Sep 10;26(26):4244-52. link to original article contains dosing details in manuscript PubMed NCT00252707
   1. HRQoL analysis: Sekine I, Ichinose Y, Nishiwaki Y, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Itoh Y, Tamura T, Saijo N, Fukuoka M. Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel. Ann Oncol. 2009 Sep;20(9):1483-8. Epub 2009 Mar 12. link to original article PubMed
9. INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains dosing details in abstract PubMed NCT00076388
   1. Dataset: Project Data Sphere
10. Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, Hristova-Kazmierski M, Treat J, Obasaju CK, Marciniak M, Gill J, Schiller JH. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1;27(4):591-8. Epub 2008 Dec 15. link to original articlecontains dosing details in manuscript PubMed
11. ISTANA: Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. link to original article contains dosing details in abstract PubMed NCT00478049
12. EFC10261: Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Le-Guennec S, Rey A, Miller V, Thatcher N, Scagliotti G. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10;30(29):3640-7. Epub 2012 Sep 10. link to original article contains dosing details in abstract PubMed NCT00532155
    1. Dataset: Project Data Sphere
13. LUME-Lung 1: Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. link to original article contains dosing details in abstract PubMed NCT00805194
14. KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains dosing details in abstract PubMed NCT01905657
    1. Update: Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. Epub 2020 Feb 20. link to original article PubMed
15. POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains dosing details in abstract PubMed NCT01903993
    1. Pooled update: Mazieres J, Rittmeyer A, Gadgeel S, Hida T, Gandara DR, Cortinovis DL, Barlesi F, Yu W, Matheny C, Ballinger M, Park K. Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials. J Thorac Oncol. 2021 Jan;16(1):140-150. Epub 2020 Nov 6. link to original article PubMed
16. OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. link to original article contains dosing details in abstract link to PMC article PubMed NCT02008227
    1. Update: Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, Han JY, Gadgeel SM, Hida T, Cortinovis DL, Cobo M, Kowalski DM, De Marinis F, Gandhi M, Danner B, Matheny C, Kowanetz M, He P, Felizzi F, Patel H, Sandler A, Ballinger M, Barlesi F. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 Aug;13(8):1156-1170. Epub 2018 May 17. Erratum in: J Thorac Oncol. 2018 Nov;13(11):1800. link to original article PubMed
    2. PRO analysis: Bordoni R, Ciardiello F, von Pawel J, Cortinovis D, Karagiannis T, Ballinger M, Sandler A, Yu W, He P, Matheny C, Felizzi F, Rittmeyer A. Patient-Reported Outcomes in OAK: A Phase III Study of Atezolizumab Versus Docetaxel in Advanced Non-Small-cell Lung Cancer. Clin Lung Cancer. 2018 Sep;19(5):441-449.e4. Epub 2018 May 31. link to original article PubMed
    3. Update: von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, Rittmeyer A, Gandhi M, Yu W, Matheny C, Patel H, Sandler A, Ballinger M, Kowanetz M, Park K. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study. Eur J Cancer. 2019 Jan;107:124-132. Epub 2018 Dec 17. link to original article PubMed
    4. Pooled update: Mazieres J, Rittmeyer A, Gadgeel S, Hida T, Gandara DR, Cortinovis DL, Barlesi F, Yu W, Matheny C, Ballinger M, Park K. Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials. J Thorac Oncol. 2021 Jan;16(1):140-150. Epub 2020 Nov 6. link to original article PubMed
17. D0702035: Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains dosing details in manuscript PubMed NCT01207011
18. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01454934
19. EAST-LC: Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article contains dosing details in manuscript PubMed JapicCTI-101155
20. JAVELIN Lung 200: Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, Özgüroğlu M, Szczesna A, Polychronis A, Uslu R, Krzakowski M, Lee JS, Calabrò L, Arén Frontera O, Ellers-Lenz B, Bajars M, Ruisi M, Park K. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1468-79. Epub 2018 Sep 21. link to original article contains dosing details in abstract PubMed NCT02395172
    1. Update: Park K, Özgüroğlu M, Vansteenkiste J, Spigel D, Yang JCH, Ishii H, Garassino M, de Marinis F, Szczesna A, Polychronis A, Uslu R, Krzakowski M, Lee JS, Calabrò L, Arén Frontera O, Xiong H, Bajars M, Ruisi M, Barlesi F. Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial. J Thorac Oncol. 2021 Aug;16(8):1369-1378. Epub 2021 Apr 9. link to original article PubMed
21. CheckMate 078: Wu YL, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu HY, Wu L, Feng J, Zhang Y, Luft AV, Zhou J, Ma Z, Lu Y, Hu C, Shi Y, Baudelet C, Cai J, Chang J. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol. 2019 May;14(5):867-875. Epub 2019 Jan 17. link to original article contains dosing details in abstract PubMed NCT02613507
    1. Update: Lu S, Wang J, Cheng Y, Mok T, Chang J, Zhang L, Feng J, Tu HY, Wu L, Zhang Y, Luft A, Zhou JY, Ma Z, Lu Y, Hu C, Shi Y, Ying K, Zhong H, Poddubskaya E, Soo RA, Chia YH, Li A, Li A, Wu YL. Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer: 2-year follow-up from a randomized, open-label, phase 3 study (CheckMate 078). Lung Cancer. 2021 Feb;152:7-14. Epub 2020 Nov 24. link to original article PubMed
22. J-AXEL: Yoneshima Y, Morita S, Ando M, Nakamura A, Iwasawa S, Yoshioka H, Goto Y, Takeshita M, Harada T, Hirano K, Oguri T, Kondo M, Miura S, Hosomi Y, Kato T, Kubo T, Kishimoto J, Yamamoto N, Nakanishi Y, Okamoto I. Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC. J Thorac Oncol. 2021 Sep;16(9):1523-1532. Epub 2021 Apr 27. link to original article contains dosing details in manuscript PubMed UMIN000017487
23. RATIONALE-303: Zhou C, Huang D, Fan Y, Yu X, Liu Y, Shu Y, Ma Z, Wang Z, Cheng Y, Wang J, Hu S, Liu Z, Poddubskaya E, Disel U, Akopov A, Dvorkin M, Zheng W, Ma Y, Wang Y, Li S, Yu C, Rivalland G. Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label, Randomized Controlled Trial. J Thorac Oncol. 2023 Jan;18(1):93-105. Epub 2022 Sep 29. link to original article contains dosing details in manuscript PubMed NCT03358875
24. KEYNOTE-033: Ren S, Feng J, Ma S, Chen H, Ma Z, Huang C, Zhang L, He J, Wang C, Zhou J, Danchaivijtr P, Wang CC, Vynnychenko I, Wang K, Orlandi F, Sriuranpong V, Li B, Ge J, Dang T, Zhou C. KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC. Int J Cancer. 2023 Aug 1;153(3):623-634. Epub 2023 May 4. link to original article PubMed NCT02864394
25. JMTO LC09-01: Atagi S, Daimon T, Okishio K, Komuta K, Okano Y, Minato K, Kim YH, Usui R, Tabata C, Tamura A, Kawahara M. A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01. Thorac Cancer. 2023 Oct;14(29):2941-2949. Epub 2023 Aug 23. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000001826
26. LUNAR: Leal T, Kotecha R, Ramlau R, Zhang L, Milanowski J, Cobo M, Roubec J, Petruzelka L, Havel L, Kalmadi S, Ward J, Andric Z, Berghmans T, Gerber DE, Kloecker G, Panikkar R, Aerts J, Delmonte A, Pless M, Greil R, Rolfo C, Akerley W, Eaton M, Iqbal M, Langer C; LUNAR Study Investigators. Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study. Lancet Oncol. 2023 Sep;24(9):1002-1017. link to original article contains dosing details in manuscript PubMed NCT02973789
27. EVOKE-01: NCT05089734
28. KN046-302: NCT05001724
29. TROPION-Lung01: NCT04656652

Docetaxel & Nintedanib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Reck et al. 2014 (LUME-Lung 1)	2008-2011	Phase 3 (E-esc)	Docetaxel	Superior PFS (primary endpoint) Median PFS: 3.4 vs 2.7 mo (HR 0.79, 95% CI 0.68-0.92) Might have superior OS1 (secondary endpoint) Median OS: 10.1 vs 9.1 mo (HR 0.94, 95% CI 0.83-1.05)

¹Reported OS is for the overall population.

Chemotherapy

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

Targeted therapy

• Nintedanib (Vargatef) 200 mg PO twice per day on days 2 to 21

21-day cycles

References

1. LUME-Lung 1: Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. link to original article contains dosing details in abstract PubMed NCT00805194

Docetaxel & Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Taniguchi et al. 2022 (TORG1630)	2017-2021	Phase 2/3 (E-esc)	Nivolumab	Seems to have superior OS1 (primary endpoint) Median OS: 23.1 vs 14.7 mo (HR 0.63, 90% CI 0.42-0.95)

¹This trial was terminated early; the authors recommend interpreting the results with caution.

Prior treatment criteria

• One or two previous chemotherapy regimens, excluding EGFR or ALK TKIs; no prior docetaxel or ICI. Switch maintenance counted as 2 chemotherapy regimens.

Chemotherapy

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

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

28-day cycles

References

1. TORG1630: Taniguchi Y, Shimokawa T, Takiguchi Y, Misumi T, Nakamura Y, Kawashima Y, Furuya N, Shiraishi Y, Harada T, Tanaka H, Miura S, Uchiyama A, Nakahara Y, Tokito T, Naoki K, Bessho A, Goto Y, Seike M, Okamoto H. A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non-Small Cell Lung Cancer: TORG1630. Clin Cancer Res. 2022 Oct 14;28(20):4402-4409. link to original article contains dosing details in manuscript link to PMC article PubMed jRCTs031180331

Gefitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kris et al. 2003 (IDEAL2)	2000-2001	Randomized Phase 2 (E-RT-de-esc)	Gefitinib; 500 mg/day	Did not meet primary endpoint of ORR
Thatcher et al. 2005 (ISEL)	NR	Phase 3 (E-RT-esc)	Placebo	Might have superior OS (primary endpoint) Median OS: 5.6 vs 5.1 mo (HR 0.89, 95% CI 0.77-1.02)
Kim et al. 2008 (INTEREST)	2004-2006	Phase 3 (E-switch-ooc)	Docetaxel	Non-inferior OS (co-primary endpoint) Median OS: 7.6 vs 8.0 mo (HR 1.02, 96% CI 0.905-1.15)
Lee et al. 2010 (ISTANA)	2005-09 to 2006-09	Phase 3 (E-switch-ooc)	Docetaxel	Seems to have superior PFS (primary endpoint) Median PFS: 3.3 vs 3.4 mo (HR 0.73, 90% CI 0.533-0.99) Did not meet secondary endpoint of OS Median OS: 14.1 vs 12.2 mo (HR 0.87, 95% CI 0.61-1.24)
Han et al. 2011 (NCCCTS-06-177)	2006-2008	Randomized Phase 2 (C)	Gefitinib & Simvastatin	Did not meet primary endpoint of ORR
Shi et al. 2013 (ICOGEN)	2009-02-26 to 2009-11-13	Phase 3 (C)	Icotinib	Seems to have non-inferior PFS

Note: IDEAL2 was the basis of initial FDA approval in 2003.

Targeted therapy

• Gefitinib (Iressa) 250 mg PO once per day

Continued indefinitely

References

1. IDEAL2: Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22;290(16):2149-58. link to original article PubMed
2. ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article PubMed NCT00242801
3. INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains dosing details in manuscript PubMed NCT00076388
   1. Dataset: Project Data Sphere
4. ISTANA: Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. link to original article contains dosing details in abstract PubMed NCT00478049
5. NCCCTS-06-177: Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. link to orinigal article contains dosing details in abstract PubMed NCT00452244
6. ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article PubMed NCT01040780

Gemcitabine monotherapy

Regimen variant #1, 1000 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase 3 (C)	Eribulin	Might have superior OS Median OS: 9.5 vs 9.5 mo (HR 0.86, 95% CI 0.71-1.05)
Planchard et al. 2020 (ARCTIC)	2015-01-13 to 2016-09-13	Phase 3 (C)	1. Durvalumab & Tremelimumab	Might have inferior PFS
			2. Durvalumab 3. Tremelimumab	Not reported

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, 15

28-day cycles

Regimen variant #2, 1250 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase 3 (C)	Eribulin	Might have superior OS Median OS: 9.5 vs 9.5 mo (HR 0.86, 95% CI 0.71-1.05)

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) 1250 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01454934
2. ARCTIC: Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. Epub 2020 Feb 20. link to original article contains dosing details in supplement PubMed NCT02352948

Icotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shi et al. 2013 (ICOGEN)	2009-02-26 to 2009-11-13	Phase 3 (E-switch-ic)	Gefitinib	Seems to have non-inferior PFS (primary endpoint) Median PFS: 4.6 vs 3.4 mo (HR 0.84, 95% CI 0.67-1.05)

Note: this drug is only approved in China.

Targeted therapy

• Icotinib (Conmana) 125 mg PO three times per day

Continued indefinitely

References

1. ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article contains dosing details in abstract PubMed NCT01040780

Nivolumab monotherapy

Regimen variant #1, weight-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wu et al. 2019 (CheckMate 078)	2015-12 to 2016-11	Phase 3 (E-switch-ooc)	Docetaxel	Superior OS1 (primary endpoint) Median OS: 11.9 vs 9.5 mo (HR 0.75, 95% CI 0.61-0.93)

¹Reported efficacy is based on the 2020 update.

Prior treatment criteria

• Failure of a platinum doublet

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1
  • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

Regimen variant #2, q2wk flat dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Taniguchi et al. 2022 (TORG1630)	2017-2021	Phase 2/3 (C)	Docetaxel & Nivolumab	Seems to have inferior OS1
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (primary endpoint)

¹TORG1630 was terminated early; the authors recommend interpreting the results with caution. 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.

Prior treatment criteria

• One or two previous chemotherapy regimens, excluding EGFR or ALK TKIs; no prior docetaxel or ICI. Switch maintenance counted as 2 chemotherapy regimens.

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycles

Regimen variant #3, q4wk flat dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (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.

Immunotherapy

• Nivolumab (Opdivo) 480 mg IV once on day 1

28-day cycles

References

1. CheckMate 078: Wu YL, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu HY, Wu L, Feng J, Zhang Y, Luft AV, Zhou J, Ma Z, Lu Y, Hu C, Shi Y, Baudelet C, Cai J, Chang J. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol. 2019 May;14(5):867-875. Epub 2019 Jan 17. link to original article contains dosing details in abstract PubMed NCT02613507
   1. Update: Lu S, Wang J, Cheng Y, Mok T, Chang J, Zhang L, Feng J, Tu HY, Wu L, Zhang Y, Luft A, Zhou JY, Ma Z, Lu Y, Hu C, Shi Y, Ying K, Zhong H, Poddubskaya E, Soo RA, Chia YH, Li A, Li A, Wu YL. Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer: 2-year follow-up from a randomized, open-label, phase 3 study (CheckMate 078). Lung Cancer. 2021 Feb;152:7-14. Epub 2020 Nov 24. link to original article PubMed
2. TORG1630: Taniguchi Y, Shimokawa T, Takiguchi Y, Misumi T, Nakamura Y, Kawashima Y, Furuya N, Shiraishi Y, Harada T, Tanaka H, Miura S, Uchiyama A, Nakahara Y, Tokito T, Naoki K, Bessho A, Goto Y, Seike M, Okamoto H. A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non-Small Cell Lung Cancer: TORG1630. Clin Cancer Res. 2022 Oct 14;28(20):4402-4409. link to original article contains dosing details in manuscript link to PMC article PubMed jRCTs031180331
3. LUNAR: Leal T, Kotecha R, Ramlau R, Zhang L, Milanowski J, Cobo M, Roubec J, Petruzelka L, Havel L, Kalmadi S, Ward J, Andric Z, Berghmans T, Gerber DE, Kloecker G, Panikkar R, Aerts J, Delmonte A, Pless M, Greil R, Rolfo C, Akerley W, Eaton M, Iqbal M, Langer C; LUNAR Study Investigators. Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study. Lancet Oncol. 2023 Sep;24(9):1002-1017. link to original article contains dosing details in manuscript PubMed NCT02973789

nab-Paclitaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoneshima et al. 2021 (J-AXEL)	2015-2018	Phase 3 (E-switch-ic)	Docetaxel	Non-inferior OS (primary endpoint) Median OS: 16.2 vs 13.6 mo (HR 0.85, 95.2% CI 0.68-1.07)

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once on day 1

7-day cycles

References

1. J-AXEL: Yoneshima Y, Morita S, Ando M, Nakamura A, Iwasawa S, Yoshioka H, Goto Y, Takeshita M, Harada T, Hirano K, Oguri T, Kondo M, Miura S, Hosomi Y, Kato T, Kubo T, Kishimoto J, Yamamoto N, Nakanishi Y, Okamoto I. Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC. J Thorac Oncol. 2021 Sep;16(9):1523-1532. Epub 2021 Apr 27. link to original article contains dosing details in manuscript PubMed UMIN000017487

Pembrolizumab monotherapy

Regimen variant #1, 2 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2015 (KEYNOTE-001NSCLC)	2012-2014	Phase 1, >20 pts in dosing cohort
Herbst et al. 2015 (KEYNOTE-010)	2013-2015	Phase 2/3 (E-RT-switch-ooc)	1. Docetaxel	Superior OS (co-primary endpoint) Median OS: 10.4 vs 8.5 mo (HR 0.71, 95% CI 0.58-0.88)
			2. Pembrolizumab; 10 mg/kg	Not reported

Note: patients had previously received chemotherapy.

Biomarker eligibility criteria

• KEYNOTE-010: PD-L1 expression of at least 1% on tumor cells

Immunotherapy

• Pembrolizumab (Keytruda) 2 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, q3wk; 10 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garon et al. 2015 (KEYNOTE-001NSCLC)	2012-2014	Phase 1, >20 pts in dosing cohort
Herbst et al. 2015 (KEYNOTE-010)	2013-2015	Phase 2/3 (E-RT-switch-ooc)	1. Docetaxel	Superior OS (co-primary endpoint) Median OS: 12.7 vs 8.5 mo (HR 0.61, 95% CI 0.49-0.75)
			2. Pembrolizumab; 2 mg/kg	Not reported

Note: patients had previously received chemotherapy.

Biomarker eligibility criteria

• KEYNOTE-010: PD-L1 expression of at least 1% on tumor cells

Immunotherapy

• Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, q3wk, flat dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (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.

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #4, q6wk, flat dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leal et al. 2023 (LUNAR)	2017-02-13 to 2021-11-19	Phase 3 (C)	1a. Atezolizumab & TTFields 1b. Docetaxel & TTFields 1c. Nivolumab & TTFields 1d. Pembrolizumab & TTFields	Seems to have inferior OS (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.

Immunotherapy

• Pembrolizumab (Keytruda) 400 mg IV over 30 minutes once on day 1

42-day cycles

References

1. KEYNOTE-001_NSCLC: Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. link to original article PubMed NCT01295827
2. KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains dosing details in abstract PubMed NCT01905657
   1. Update: Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. Epub 2020 Feb 20. link to original article PubMed
3. LUNAR: Leal T, Kotecha R, Ramlau R, Zhang L, Milanowski J, Cobo M, Roubec J, Petruzelka L, Havel L, Kalmadi S, Ward J, Andric Z, Berghmans T, Gerber DE, Kloecker G, Panikkar R, Aerts J, Delmonte A, Pless M, Greil R, Rolfo C, Akerley W, Eaton M, Iqbal M, Langer C; LUNAR Study Investigators. Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study. Lancet Oncol. 2023 Sep;24(9):1002-1017. link to original article contains dosing details in manuscript PubMed NCT02973789

Pemetrexed monotherapy

Example orders

• Example orders for Pemetrexed (Alimta) in non-small cell lung cancer

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hanna et al. 2004 (JMEI)	2001-03 to 2002-02	Phase 3 (E-RT-switch-ic)	Docetaxel	Inconclusive whether non-inferior OS (primary endpoint)
Kim et al. 2013 (JXBC)	2005-2010	Phase 3 (C)	Pemetrexed & Cetuximab	Did not meet primary endpoint of PFS Median PFS: 2.8 vs 2.9 mo (HR 0.97, 95% CI 0.83-1.15)
Karampeazis et al. 2013 (CT/06.05)	2006-2010	Phase 3 (E-switch-ooc)	Erlotinib	Did not meet primary endpoint of TTP
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase 3 (C)	Eribulin	Might have superior OS Median OS: 9.5 vs 9.5 mo (HR 0.86, 95% CI 0.71-1.05)

Note: JXBC also evaluated docetaxel versus docetaxel & cetuximab, but did not report the efficacy of this comparison; see paper for details.

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive therapy

• (per Ardizzoni et al. 2012):
• Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
• Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
  • JMEI used Folic acid (Folate) 1 mg PO once per day
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycles

References

1. JMEI: Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains dosing details in abstract PubMed
2. CT/06.05: Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, Agelaki S, Vamvakas L, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013 Aug 1;119(15):2754-64. Epub 2013 May 9. link to original article contains dosing details in manuscript PubMed NCT00440414
3. JXBC: Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. Epub 2013 Nov 12. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article contains dosing details in abstract PubMed NCT00095199
4. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01454934

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nokihara et al. 2017 (EAST-LC)	2010-2014	Phase 3 (E-switch-ic)	Docetaxel	Non-inferior OS (primary endpoint) Median OS: 12.75 vs 12.52 mo (HR 0.945, 95% CI 0.83-1.07)

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
  • Less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

References

1. EAST-LC: Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article contains dosing details in manuscript PubMed JapicCTI-101155

Tislelizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhou et al. 2022 (RATIONALE-303)	2017-2020	Phase 3 (E-switch-ooc)	Docetaxel	Superior OS (co-primary endpoint) Median OS: 17.2 vs 11.9 mo (HR 0.64, 95% CI 0.53-0.78)

Prior treatment criteria

• RATIONALE-303: Progression after a platinum doublet, with up to 2 SACT for metastatic disease

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

21-day cycles

References

1. RATIONALE-303: Zhou C, Huang D, Fan Y, Yu X, Liu Y, Shu Y, Ma Z, Wang Z, Cheng Y, Wang J, Hu S, Liu Z, Poddubskaya E, Disel U, Akopov A, Dvorkin M, Zheng W, Ma Y, Wang Y, Li S, Yu C, Rivalland G. Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label, Randomized Controlled Trial. J Thorac Oncol. 2023 Jan;18(1):93-105. Epub 2022 Sep 29. link to original article contains dosing details in manuscript PubMed NCT03358875

Vinorelbine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fossella et al. 2000 (TAX 320)	1995-1998	Phase 3 (C)	1. Docetaxel 100 mg/m2	Did not meet primary endpoint of OS
			2. Docetaxel 75 mg/m2	Did not meet primary endpoint of OS
Katakami et al. 2017 (E7389-G000-302)	2011-2014	Phase 3 (C)	Eribulin	Might have superior OS Median OS: 9.5 vs 9.5 mo (HR 0.86, 95% CI 0.71-1.05)
Planchard et al. 2020 (ARCTIC)	2015-01-13 to 2016-09-13	Phase 3 (C)	1. Durvalumab & Tremelimumab	Might have inferior PFS
			2. Durvalumab 3. Tremelimumab	Not reported

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

• Vinorelbine (Navelbine) 30 mg/m² IV over 5 to 10 minutes once on day 1

Supportive therapy

• Per TAX 320:
• Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive G-CSF (dose/schedule/duration not specified)
• Metoclopramide (Reglan) (dose/schedule/route not specified) used first for nausea
• Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as Ondansetron (Zofran) or Granisetron (dose/schedule/route not specified) prn nausea

7-day cycles

References

1. TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains dosing details in manuscript PubMed
2. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01454934
3. ARCTIC: Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. Epub 2020 Feb 20. link to original article contains dosing details in supplement PubMed NCT02352948