Non-small cell lung cancer, squamous

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 Eric K. Singhi, MD
MD Anderson Cancer Center
Houston, TX, USA
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 Amit Kulkarni, MBBS
University of Minnesota
Minneapolis, MN, USA
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Note: these are regimens tested in histology-specific populations, please see the main NSCLC page for other regimens.

35 regimens on this page
48 variants on this page


Guidelines

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

ESMO

NCCN

Neoadjuvant therapy

Carboplatin & Gemcitabine (GCb)

GCb: Gemcitabine & Carboplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (C) 1a. CP & Durvalumab
1b. GC & Durvalumab
1c. GCb & Durvalumab 		Inferior EFS (co-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.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Carboplatin & Gemcitabine (GCb) & Durvalumab

GCb & Durvalumab: Gemcitabine, Carboplatin, Durvalumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (E-esc) 1a. CP
1b. GC
1c. GCb 		Superior EFS (co-primary endpoint)
EFS12: 73.4% vs 64.5%
(sHR 0.68, 95% CI 0.53-0.88)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

28-day cycle for up to 12 cycles

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (C) 1a. CP & Durvalumab
1b. GC & Durvalumab
1c. GCb & Durvalumab 		Inferior EFS (co-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.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Carboplatin & Paclitaxel (CP) & Durvalumab

CP & Durvalumab: Carboplatin, Paclitaxel, Durvalumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (E-esc) 1a. CP
1b. GC
1c. GCb 		Superior EFS (co-primary endpoint)
EFS12: 73.4% vs 64.5%
(sHR 0.68, 95% CI 0.53-0.88)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

28-day cycle for up to 12 cycles

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen variant #1, 1000/75 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
1d. GC & Nivolumab 		Inferior EFS

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.

Biomarker eligibility criteria

  • CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 1000/75 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wakelee et al. 2023 (KEYNOTE-671) 2018-04 to 2021-12 Phase 3 (C) GC & Pembrolizumab Inferior EFS

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.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 1250/75 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
1d. GC & Nivolumab 		Inferior EFS

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.

Biomarker eligibility criteria

  • CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #4, 1250/75 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (C) 1a. CP & Durvalumab
1b. GC & Durvalumab
1c. GCb & Durvalumab 		Inferior EFS (co-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.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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. KEYNOTE-671: Wakelee H, Liberman M, Kato T, Tsuboi M, Lee SH, Gao S, Chen KN, Dooms C, Majem M, Eigendorff E, Martinengo GL, Bylicki O, Rodríguez-Abreu D, Chaft JE, Novello S, Yang J, Keller SM, Samkari A, Spicer JD; KEYNOTE-671 Investigators. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):491-503. Epub 2023 Jun 3. link to original article contains dosing details in supplement PubMed NCT03425643
  3. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin & Gemcitabine (GC) & Durvalumab

GC & Durvalumab: Gemcitabine, Cisplatin, Durvalumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (E-esc) 1a. CP
1b. GC
1c. GCb 		Superior EFS (co-primary endpoint)
EFS12: 73.4% vs 64.5%
(sHR 0.68, 95% CI 0.53-0.88)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

28-day cycle for up to 12 cycles

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin & Gemcitabine (GC) & Nivolumab

GC & Nivolumab: Gemcitabine, Cisplatin, Nivolumab

Regimen variant #1, 1000/75/360

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
1d. GC 		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

Immunotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 1250/75/360

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
1d. GC 		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

Immunotherapy

21-day cycle for 3 cycles

Subsequent treatment

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 & Gemcitabine (GC) & Pembrolizumab

GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wakelee et al. 2023 (KEYNOTE-671) 2018-04 to 2021-12 Phase 3 (E-esc) GC Superior EFS (co-primary endpoint)
EFS24: 62.4% vs 40.6%
(HR 0.58, 95% CI 0.46-0.72)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

21-day cycle for up to 13 cycles

References

  1. KEYNOTE-671: Wakelee H, Liberman M, Kato T, Tsuboi M, Lee SH, Gao S, Chen KN, Dooms C, Majem M, Eigendorff E, Martinengo GL, Bylicki O, Rodríguez-Abreu D, Chaft JE, Novello S, Yang J, Keller SM, Samkari A, Spicer JD; KEYNOTE-671 Investigators. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):491-503. Epub 2023 Jun 3. link to original article contains dosing details in supplement PubMed NCT03425643

Adjuvant therapy

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Groen et al. 2019 (NVALT-8) 2007-2013 Phase 3 (C) GC & Nadroparin Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. 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

Advanced or metastatic disease, first-line

Atezolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Herbst et al. 2020 (IMpower110) 2015-2018 Phase 3 (E-RT-switch-ooc) 1a. Carboplatin & Gemcitabine
1b. Cisplatin & Gemcitabine 		Superior OS1 (primary endpoint)
Median OS: 20.2 vs 13.1 mo
(HR 0.59, 95% CI 0.40-0.89)

1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.

Biomarker eligibility criteria

  • PD-L1 expression on at least 1% of tumor cells or tumor-infiltrating immune cells covering at least 1% of the tumor area as determined by the SP142 assay

Immunotherapy

21-day cycles

References

  1. IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains dosing details in manuscript PubMed NCT02409342
    1. Update: Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, Herbst RS. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021 Nov;16(11):1872-1882. Epub 2021 Jul 12. link to original article PubMed

Carboplatin & Gemcitabine (GCb)

Regimen variant #1, 5/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patil et al. 2019 2013-2018 Phase 3 (C) GCb; low-dose Gemcitabine Non-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
Herbst et al. 2020 (IMpower110) 2015-2018 Phase 3 (C) Atezolizumab Inferior OS1

1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.
Note: CrCl in Patil et al. 2019 was calculated using Cockcroft–Gault.

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, 5.5/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Edelman et al. 2017 (CALGB 30801) 2010-2013 Phase 3 (C) GCb & Celecoxib Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

References

  1. CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01041781
  2. Patil V, Noronha V, Joshi A, Chougule A, Kannan S, Bhattacharjee A, Goud S, More S, Chandrasekharan A, Menon N, Srinivas S, Vallathol DH, Dsouza H, Majumdar S, Das S, Zawar A, Khaddar S, Kumar A, Singh G, Kumar KAP, Ravind R, Trivedi V, Behel V, Mahajan A, Janu A, Purandare N, Prabhash K. Phase III non-inferiority study evaluating efficacy and safety of low dose gemcitabine compared to standard dose gemcitabine with platinum in advanced squamous lung cancer. EClinicalMedicine. 2019 Apr 9;9:19-25. link to original article link to PMC article contains dosing details in manuscript PubMed CTRI/2013/02/003422
  3. 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 link to PMC article contains dosing details in supplement PubMed NCT02453282
  4. IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains dosing details in manuscript PubMed NCT02409342
    1. Update: Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, Herbst RS. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021 Nov;16(11):1872-1882. Epub 2021 Jul 12. link to original article PubMed
  5. ORIENT-12: Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, Zhang L, Huang D, Cang S, Yang Z, Zhou J, Zhou C, Li B, Li J, Fan M, Cui J, Li Y, Zhao H, Fang J, Xue J, Hu C, Sun P, Du Y, Zhou H, Wang S, Zhang W. Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12). J Thorac Oncol. 2021 Sep;16(9):1501-1511. Epub 2021 May 25. link to original article PubMed NCT03629925
  6. B-FAST: NCT03178552

Carboplatin & nab-Paclitaxel

CnP: Carboplatin & nab-Paclitaxel

Regimen variant #1, 4 to 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jotte et al. 2020 (IMpower131) 2015-2017 Phase 3 (C) 1. A+CnP Inferior PFS
2. A+CP Not reported
Paz-Ares et al. 2018 (KEYNOTE-407) 2016-08-19 to 2017-12-28 Phase 3 (C) 1a. CP & Pembrolizumab
1b. Carboplatin, nab-Paclitaxel, Pembrolizumab 		Inferior OS

Chemotherapy

21-day cycle for 4 cycles (KEYNOTE-407) or 4 to 6 cycles (IMpower131)


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kogure et al. 2022 (CAPITAL) 2016-2020 Phase 3 (E-esc) Docetaxel Superior OS (primary endpoint)
Median OS: 16.9 vs 10.9 mo
(HR 0.52, 90% CI 0.38-0.70)

Note: this study included patients that were 70 and older.

Chemotherapy

21-day cycles

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02775435
    1. HRQoL analysis: Mazieres J, Kowalski D, Luft A, Vicente D, Tafreshi A, Gümüş M, Laktionov K, Hermes B, Cicin I, Rodríguez-Cid J, Wilson J, Kato T, Ramlau R, Novello S, Reddy S, Kopp HG, Piperdi B, Li X, Burke T, Paz-Ares L. Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jan 20;38(3):271-280. Epub 2019 Nov 21. link to original article PubMed
    2. Update: Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazières J, Hermes B, Cicin I, Medgyasszay B, Rodríguez-Cid J, Okamoto I, Lee S, Ramlau R, Vladimirov V, Cheng Y, Deng X, Zhang Y, Bas T, Piperdi B, Halmos B. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J Thorac Oncol. 2020 Oct;15(10):1657-1669. Epub 2020 Jun 26. link to original article PubMed
    3. Update: Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, Rodríguez-Cid J, Tafreshi A, Cheng Y, Lee KH, Golf A, Sugawara S, Robinson AG, Halmos B, Jensen E, Schwarzenberger P, Pietanza MC, Paz-Ares L. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023 Apr 10;41(11):1999-2006. Epub 2023 Feb 3. link to original article link to PMC article PubMed
  2. IMpower131: Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M, Soo R, Conter HJ, Kozuki T, Huang KC, Graupner V, Sun SW, Hoang T, Jessop H, McCleland M, Ballinger M, Sandler A, Socinski MA. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J Thorac Oncol. 2020 Aug;15(8):1351-1360. Epub 2020 Apr 14. link to original article contains dosing details in manuscript PubMed NCT02367794
  3. CAPITAL: Kogure Y, Iwasawa S, Saka H, Hamamoto Y, Kada A, Hashimoto H, Atagi S, Takiguchi Y, Ebi N, Inoue A, Kurata T, Okamoto I, Yamaguchi M, Harada T, Seike M, Ando M, Saito AM, Kubota K, Takenoyama M, Seto T, Yamamoto N, Gemma A. Efficacy and safety of carboplatin with nab-paclitaxel versus docetaxel in older patients with squamous non-small-cell lung cancer (CAPITAL): a randomised, multicentre, open-label, phase 3 trial. Lancet Healthy Longev. 2021 Dec;2(12):e791-e800. link to original article contains dosing details in manuscript PubMed UMIN000019843

Carboplatin, nab-Paclitaxel, Atezolizumab

A+CnP: Atezolizumab, Carboplatin, nab-Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jotte et al. 2020 (IMpower131) 2015-2017 Phase 3 (E-esc) 1. CnP Superior PFS (co-primary endpoint)
Median PFS: 6.3 vs 5.6 mo
(HR 0.71, 95% CI 0.60-0.85)
2. A+CP Not reported

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMpower131: Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M, Soo R, Conter HJ, Kozuki T, Huang KC, Graupner V, Sun SW, Hoang T, Jessop H, McCleland M, Ballinger M, Sandler A, Socinski MA. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J Thorac Oncol. 2020 Aug;15(8):1351-1360. Epub 2020 Apr 14. link to original article contains dosing details in manuscript PubMed NCT02367794

Carboplatin, nab-Paclitaxel, Pembrolizumab

Regimen variant #1, AUC 5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tan et al. 2023 (CANOPY-1) 2019-06-25 to 2020-01-17 Phase 3 (C) 1a. CP, Canakinumab, Pembrolizumab
1b. Carboplatin, nab-Paclitaxel, Canakinumab, Pembrolizumab 		Did not meet co-primary endpoints of PFS/OS

Chemotherapy

Immunotherapy

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


Regimen variant #2, AUC 6

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) 2016-08-19 to 2017-12-28 Phase 3 (E-RT-esc) 1a. CP
1b. Carboplatin & nab-Paclitaxel 		Superior OS1 (co-primary endpoint)
Median OS: 17.1 vs 11.6 mo
(HR 0.71, 95% CI 0.58-0.88)
Awaiting publication (KEYVIBE-007) 2022-2025 Phase 3 (C) 1a. CP, Pembrolizumab, Vibostolimab
1b. Carboplatin, nab-Paclitaxel, Pembrolizumab, Vibostolimab 		TBD if different co-primary endpoints of PFS/OS

1Reported efficacy for KEYNOTE-407 is based on the 2021 update.

Chemotherapy

Immunotherapy

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

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02775435
    1. HRQoL analysis: Mazieres J, Kowalski D, Luft A, Vicente D, Tafreshi A, Gümüş M, Laktionov K, Hermes B, Cicin I, Rodríguez-Cid J, Wilson J, Kato T, Ramlau R, Novello S, Reddy S, Kopp HG, Piperdi B, Li X, Burke T, Paz-Ares L. Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jan 20;38(3):271-280. Epub 2019 Nov 21. link to original article PubMed
    2. Update: Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazières J, Hermes B, Cicin I, Medgyasszay B, Rodríguez-Cid J, Okamoto I, Lee S, Ramlau R, Vladimirov V, Cheng Y, Deng X, Zhang Y, Bas T, Piperdi B, Halmos B. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J Thorac Oncol. 2020 Oct;15(10):1657-1669. Epub 2020 Jun 26. link to original article PubMed
    3. Update: Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, Rodríguez-Cid J, Tafreshi A, Cheng Y, Lee KH, Golf A, Sugawara S, Robinson AG, Halmos B, Jensen E, Schwarzenberger P, Pietanza MC, Paz-Ares L. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023 Apr 10;41(11):1999-2006. Epub 2023 Feb 3. link to original article link to PMC article PubMed
  2. CANOPY-1: Tan DSW, Felip E, de Castro G, Solomon BJ, Greystoke A, Cho BC, Cobo M, Kim TM, Ganguly S, Carcereny E, Paz-Ares L, Bennouna J, Garassino MC, Schenker M, Kim SW, Brase JC, Bury-Maynard D, Passos VQ, Deudon S, Dharan B, Song Y, Caparica R, Johnson BE. Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial. J Clin Oncol. 2024 Jan 10;42(2):192-204. Epub 2023 Dec 1. link to original article contains dosing details in supplement PubMed NCT03631199
  3. KEYLYNK-008: NCT03976362
  4. KEYVIBE-007: NCT05226598

Carboplatin & nab-Paclitaxel (CnP) & Tislelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2021 (RATIONALE 307) 2018-07 to 2019-06 Phase 3 (E-esc) 1. CP Superior PFS (primary endpoint)
Median PFS: 7.6 vs 5.5 mo
(HR 0.48, 95% CI 0.34-0.68)
2. CP & Tislelizumab Not reported

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE 307: Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, Zhao J, Yu Y, Hu C, Yang K, Feng G, Ying K, Zhuang W, Zhou J, Wu J, Leaw SJ, Zhang J, Lin X, Liang L, Yang N. Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 May 1;7(5):709-717. Epub 2021 Apr 1. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03594747

Carboplatin & Paclitaxel (CP)

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

Regimen variant #1, 5/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2021 (RATIONALE 307) 2018-07 to 2019-06 Phase 3 (C) 1. CP & Tislelizumab
2. CnP & Tislelizumab 		Inferior PFS
Ren et al. 2021 (CameL-Sq) 2018-11-26 to 2019-12-31 Phase 3 (C) CP & Camrelizumab Inferior OS
Zhou et al. 2022 (GEMSTONE-302) 2018-2020 Phase 3 (C) CP & Sugemalimab Inferior PFS

Chemotherapy

21-day cycle for 4 to 6 cycles


Regimen variant #2, 5/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042) 2014-2017 Phase 3 (C) Pembrolizumab Inferior OS

Note: Patients enrolled in this arm of KEYNOTE-042 had squamous histology.

Chemotherapy

21-day cycle for 4 to 6 cycles


Regimen variant #3, 6/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Govindan et al. 2017 (CA184-104) 2011-2015 Phase 3 (C) TC & Ipilimumab Did not meet primary endpoint of OS

Chemotherapy

Supportive therapy

21-day cycle for up to 6 cycles


Regimen variant #4, 6/200 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) 2016-08-19 to 2017-12-28 Phase 3 (C) 1a. CP & Pembrolizumab
1b. Carboplatin, nab-Paclitaxel, Pembrolizumab 		Inferior OS
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (C) Carboplatin, Paclitaxel, Ipilimumab, Nivolumab Inferior OS

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #5, 6/200 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042) 2014-2017 Phase 3 (C) Pembrolizumab Inferior OS
Ramalingam et al. 2021 (M11-089) 2014-2019 Phase 3 (C) CP & Veliparib Did not meet primary endpoint of OS1
Median OS: 11.1 vs 11.9 mo
(HR 1.10, 95% CI 0.91-1.34)

1The primary endpoint was limited to current smokers, which made up 57% of the cohort.
Note: Patients enrolled in this arm of KEYNOTE-042 had squamous histology.

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains dosing details in manuscript PubMed NCT01285609
  2. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02775435
    1. HRQoL analysis: Mazieres J, Kowalski D, Luft A, Vicente D, Tafreshi A, Gümüş M, Laktionov K, Hermes B, Cicin I, Rodríguez-Cid J, Wilson J, Kato T, Ramlau R, Novello S, Reddy S, Kopp HG, Piperdi B, Li X, Burke T, Paz-Ares L. Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jan 20;38(3):271-280. Epub 2019 Nov 21. link to original article PubMed
    2. Update: Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazières J, Hermes B, Cicin I, Medgyasszay B, Rodríguez-Cid J, Okamoto I, Lee S, Ramlau R, Vladimirov V, Cheng Y, Deng X, Zhang Y, Bas T, Piperdi B, Halmos B. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J Thorac Oncol. 2020 Oct;15(10):1657-1669. Epub 2020 Jun 26. link to original article PubMed
    3. Update: Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, Rodríguez-Cid J, Tafreshi A, Cheng Y, Lee KH, Golf A, Sugawara S, Robinson AG, Halmos B, Jensen E, Schwarzenberger P, Pietanza MC, Paz-Ares L. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023 Apr 10;41(11):1999-2006. Epub 2023 Feb 3. 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
  4. CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains dosing details in manuscript PubMed NCT03215706
    1. Update: Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Reyes F, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, Paz-Ares L, Carbone DP, Memaj A, Marimuthu S, Zhang X, Tran P, John T. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. Epub 2021 Oct 1. Erratum in: ESMO Open. 2021 Dec;6(6):100345. link to original article link to PMC article PubMed
  5. RATIONALE 307: Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, Zhao J, Yu Y, Hu C, Yang K, Feng G, Ying K, Zhuang W, Zhou J, Wu J, Leaw SJ, Zhang J, Lin X, Liang L, Yang N. Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 May 1;7(5):709-717. Epub 2021 Apr 1. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03594747
  6. M11-089: Ramalingam SS, Novello S, Guclu SZ, Bentsion D, Zvirbule Z, Szilasi M, Bernabe R, Syrigos K, Byers LA, Clingan P, Bar J, Vokes EE, Govindan R, Dunbar M, Ansell P, He L, Huang X, Sehgal V, Glasgow J, Bach BA, Mazieres J. Veliparib in Combination With Platinum-Based Chemotherapy for First-Line Treatment of Advanced Squamous Cell Lung Cancer: A Randomized, Multicenter Phase III Study. J Clin Oncol. 2021 Nov 10;39(32):3633-3644. Epub 2021 Aug 26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02106546
  7. CameL-Sq: Ren S, Chen J, Xu X, Jiang T, Cheng Y, Chen G, Pan Y, Fang Y, Wang Q, Huang Y, Yao W, Wang R, Li X, Zhang W, Zhang Y, Hu S, Guo R, Shi J, Wang Z, Cao P, Wang D, Fang J, Luo H, Geng Y, Xing C, Lv D, Zhang Y, Yu J, Cang S, Yang Z, Shi W, Zou J, Zhou C; CameL-sq Study Group. Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial. J Thorac Oncol. 2022 Apr;17(4):544-557. Epub 2021 Dec 16. link to original article contains dosing details in manuscript PubMed NCT03668496
  8. GEMSTONE-302: Zhou C, Wang Z, Sun Y, Cao L, Ma Z, Wu R, Yu Y, Yao W, Chang J, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Wang J, Li P, Qin M, Lu D, Yang J. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial. Lancet Oncol. 2022 Feb;23(2):220-233. Epub 2022 Jan 14. link to original article contains dosing details in abstract PubMed NCT03789604
    1. Update: Zhou C, Wang Z, Sun M, Cao L, Ma Z, Wu R, Yu Y, Yao W, Sun S, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Hu C, Liu J, Liu Y, Wang M, Li X, Sun P, Shu Y, Zhou J, Li J, Gu K, Wang C, Zhao H, Zhang Y, Liu C, Wang J, Chen R, Qin M, Wang H, Yang J. Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC. Nat Cancer. 2023 Jun;4(6):860-871. Epub 2023 Jun 15. link to original article PubMed
  9. ENREACH-L-01: NCT04474119

Carboplatin & Paclitaxel (CP) & Camrelizumab

CP & Camrelizumab: Carboplatin, Paclitaxel, Camrelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ren et al. 2021 (CameL-Sq) 2018-11-26 to 2019-12-31 Phase 3 (E-esc) CP Superior OS (secondary endpoint)
Median OS: NYR vs 14.5 mo
(HR 0.55, 95% CI 0.40-0.75)

Superior PFS (primary endpoint)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. CameL-Sq: Ren S, Chen J, Xu X, Jiang T, Cheng Y, Chen G, Pan Y, Fang Y, Wang Q, Huang Y, Yao W, Wang R, Li X, Zhang W, Zhang Y, Hu S, Guo R, Shi J, Wang Z, Cao P, Wang D, Fang J, Luo H, Geng Y, Xing C, Lv D, Zhang Y, Yu J, Cang S, Yang Z, Shi W, Zou J, Zhou C; CameL-sq Study Group. Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial. J Thorac Oncol. 2022 Apr;17(4):544-557. Epub 2021 Dec 16. link to original article contains dosing details in manuscript PubMed NCT03668496

Carboplatin & Paclitaxel (CP) & Ipilimumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Govindan et al. 2017 (CA184-104) 2011-2015 Phase 3 (E-esc) Carboplatin & Paclitaxel Did not meet primary endpoint of OS
Median OS: 13.4 vs 12.4 mo
(HR 0.91, 95% CI 0.77-1.07)

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

Chemotherapy

Immunotherapy

Supportive therapy

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

21-day cycle for 5 cycles, then 12-week cycles

References

  1. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains dosing details in manuscript PubMed NCT01285609

Carboplatin & Paclitaxel (CP) & Ipilimumab, Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (E-RT-switch-ooc) CP Superior OS1 (primary endpoint)
Median OS: 15.8 vs 11 mo
(HR 0.72, 95% CI 0.61-0.86)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains dosing details in manuscript PubMed NCT03215706
    1. Update: Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Reyes F, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, Paz-Ares L, Carbone DP, Memaj A, Marimuthu S, Zhang X, Tran P, John T. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. Epub 2021 Oct 1. Erratum in: ESMO Open. 2021 Dec;6(6):100345. link to original article link to PMC article PubMed

Carboplatin & Paclitaxel (CP) & Pembrolizumab

Regimen variant #1, AUC 5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tan et al. 2023 (CANOPY-1) 2019-06-25 to 2020-01-17 Phase 3 (C) 1a. CP, Canakinumab, Pembrolizumab
1b. Carboplatin, nab-Paclitaxel, Canakinumab, Pembrolizumab 		Did not meet co-primary endpoints of PFS/OS

Chemotherapy

Immunotherapy

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


Regimen variant #2, AUC 6

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) 2016-08-19 to 2017-12-28 Phase 3 (E-RT-esc) 1a. CP
1b. Carboplatin & nab-Paclitaxel 		Superior OS1 (co-primary endpoint)
Median OS: 17.1 vs 11.6 mo
(HR 0.71, 95% CI 0.58-0.88)
Awaiting publication (KEYVIBE-007) 2022-2025 Phase 3 (C) 1a. CP, Pembrolizumab, Vibostolimab
1b. Carboplatin, nab-Paclitaxel, Pembrolizumab, Vibostolimab 		TBD if different co-primary endpoints of PFS/OS

1Reported efficacy for KEYNOTE-407 is based on the 2021 update.

Chemotherapy

Immunotherapy

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

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains dosing details in manuscript PubMed NCT02775435
    1. HRQoL analysis: Mazieres J, Kowalski D, Luft A, Vicente D, Tafreshi A, Gümüş M, Laktionov K, Hermes B, Cicin I, Rodríguez-Cid J, Wilson J, Kato T, Ramlau R, Novello S, Reddy S, Kopp HG, Piperdi B, Li X, Burke T, Paz-Ares L. Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jan 20;38(3):271-280. Epub 2019 Nov 21. link to original article PubMed
    2. Update: Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazières J, Hermes B, Cicin I, Medgyasszay B, Rodríguez-Cid J, Okamoto I, Lee S, Ramlau R, Vladimirov V, Cheng Y, Deng X, Zhang Y, Bas T, Piperdi B, Halmos B. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J Thorac Oncol. 2020 Oct;15(10):1657-1669. Epub 2020 Jun 26. link to original article PubMed
    3. Update: Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, Rodríguez-Cid J, Tafreshi A, Cheng Y, Lee KH, Golf A, Sugawara S, Robinson AG, Halmos B, Jensen E, Schwarzenberger P, Pietanza MC, Paz-Ares L. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023 Apr 10;41(11):1999-2006. Epub 2023 Feb 3. link to original article link to PMC article PubMed
  2. CANOPY-1: Tan DSW, Felip E, de Castro G, Solomon BJ, Greystoke A, Cho BC, Cobo M, Kim TM, Ganguly S, Carcereny E, Paz-Ares L, Bennouna J, Garassino MC, Schenker M, Kim SW, Brase JC, Bury-Maynard D, Passos VQ, Deudon S, Dharan B, Song Y, Caparica R, Johnson BE. Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial. J Clin Oncol. 2024 Jan 10;42(2):192-204. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03631199
  3. KEYLYNK-008: NCT03976362
  4. KEYVIBE-007: NCT05226598

Carboplatin & Paclitaxel (CP) & Sugemalimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2022 (GEMSTONE-302) 2018-2020 Phase 3 (E-esc) CP Superior OS1 (secondary endpoint)
Median OS: 25.4 vs 16.9 mo
(HR 0.65, 95% CI 0.50-0.84)

Superior PFS (primary endpoint)
Median PFS: 9 vs 4.9 mo
(HR 0.48, 95% CI 0.39-0.60)

1Reported efficacy is based on 2023 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. GEMSTONE-302: Zhou C, Wang Z, Sun Y, Cao L, Ma Z, Wu R, Yu Y, Yao W, Chang J, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Wang J, Li P, Qin M, Lu D, Yang J. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial. Lancet Oncol. 2022 Feb;23(2):220-233. Epub 2022 Jan 14. link to original article contains dosing details in abstract PubMed NCT03789604
    1. Update: Zhou C, Wang Z, Sun M, Cao L, Ma Z, Wu R, Yu Y, Yao W, Sun S, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Hu C, Liu J, Liu Y, Wang M, Li X, Sun P, Shu Y, Zhou J, Li J, Gu K, Wang C, Zhao H, Zhang Y, Liu C, Wang J, Chen R, Qin M, Wang H, Yang J. Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC. Nat Cancer. 2023 Jun;4(6):860-871. Epub 2023 Jun 15. link to original article PubMed

Carboplatin & Paclitaxel (CP) & Tislelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2021 (RATIONALE 307) 2018-07 to 2019-06 Phase 3 (E-esc) 1. CP Superior PFS (primary endpoint)
Median PFS: 7.6 vs 5.5 mo
(HR 0.52, 95% CI 0.37-0.74)
2. CnP & Tislelizumab Not reported

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE 307: Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, Zhao J, Yu Y, Hu C, Yang K, Feng G, Ying K, Zhuang W, Zhou J, Wu J, Leaw SJ, Zhang J, Lin X, Liang L, Yang N. Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 May 1;7(5):709-717. Epub 2021 Apr 1. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03594747

Carboplatin & S-1

Regimen

Study Dates of enrollment Evidence
Tanaka et al. 2020 (WJOG7512L) 2013-2017 Non-randomized part of phase 3 RCT

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. WJOG7512L: Tanaka K, Morita S, Ando M, Yokoyama T, Nakamura A, Yoshioka H, Ishiguro T, Miura S, Toyozawa R, Oguri T, Daga H, Ko R, Bessho A, Tachihara M, Iwamoto Y, Hirano K, Nakanishi Y, Nakagawa K, Yamamoto N, Okamoto I. A randomized phase 3 study of maintenance therapy with S-1 plus best supportive care versus best supportive care after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell carcinoma of the lung (WJOG7512L). Cancer. 2020 Aug 15;126(16):3648-3656. Epub 2020 Jun 2. link to original article contains dosing details in abstract PubMed UMIN000010396

Cisplatin & Docetaxel (DC)

DC: Docetaxel & Cisplatin
CD: Cisplatin & Docetaxel

Regimen variant #1, 75/75

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2018 (5501068) 2013-2015 Phase 3 (C) Docetaxel & Nedaplatin Might have inferior PFS

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, 80/60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shukuya et al. 2015 (WJOG5208L) 2009-2012 Phase 3 (C) Docetaxel & Nedaplatin Might have inferior OS

Chemotherapy

21-day cycle for 4 to 6 cycles

References

  1. WJOG5208L: Shukuya T, Yamanaka T, Seto T, Daga H, Goto K, Saka H, Sugawara S, Takahashi T, Yokota S, Kaneda H, Kawaguchi T, Nagase S, Oguri T, Iwamoto Y, Nishimura T, Hattori Y, Nakagawa K, Nakanishi Y, Yamamoto N; West Japan Oncology Group. Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1630-8. Epub 2015 Oct 28. link to original article contains dosing details in abstract PubMed UMIN000002015
  2. 5501068: Lu S, Chen Z, Hu C, Zhang J, Chen Y, Song Y, Zhao Q, Fan Y, Wu G, Ma Z, Fang J, Yu Q, Liu Z. Nedaplatin plus docetaxel versus cisplatin plus docetaxel as first-line chemotherapy for advanced squamous cell carcinoma of the lung - a multicenter, open-label, randomized, phase III trial. J Thorac Oncol. 2018 Nov;13(11):1743-1749. Epub 2018 Jul 11. link to original article contains dosing details in manuscript PubMed NCT02088515

Cisplatin & Gemcitabine (GC)

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thatcher et al. 2015 (SQUIRE) 2010-2012 Phase 3 (C) Cisplatin, Gemcitabine, Necitumumab Seems to have 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
Herbst et al. 2020 (IMpower110) 2015-2018 Phase 3 (C) Atezolizumab Inferior OS1

1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. SQUIRE: Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. Epub 2015 Jun 1. link to original article contains dosing details in abstract PubMed NCT00981058
    1. Dataset: Project Data Sphere
  2. 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 link to PMC article PubMed NCT02453282
  3. IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains dosing details in manuscript PubMed NCT02409342
    1. Update: Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, Herbst RS. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021 Nov;16(11):1872-1882. Epub 2021 Jul 12. link to original article PubMed
  4. ORIENT-12: Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, Zhang L, Huang D, Cang S, Yang Z, Zhou J, Zhou C, Li B, Li J, Fan M, Cui J, Li Y, Zhao H, Fang J, Xue J, Hu C, Sun P, Du Y, Zhou H, Wang S, Zhang W. Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12). J Thorac Oncol. 2021 Sep;16(9):1501-1511. Epub 2021 May 25. link to original article PubMed NCT03629925
  5. B-FAST: NCT03178552

Cisplatin & Gemcitabine (GC) & Necitumumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thatcher et al. 2015 (SQUIRE) 2010-2012 Phase 3 (E-RT-esc) Cisplatin & Gemcitabine Seems to have superior OS (primary endpoint)
Median OS: 11.5 vs 9.9 mo
(HR 0.84, 95% CI 0.74-0.96)

Chemotherapy

Targeted therapy

Supportive therapy

  • Antiemetic premedications for gemcitabine and cisplatin "according to local practice."
  • "Pre-emptive treatment for skin toxicity was allowed only after the first cycle."

21-day cycles

References

  1. SQUIRE: Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. Epub 2015 Jun 1. link to original article contains dosing details in manuscript PubMed NCT00981058
    1. Dataset: Project Data Sphere

Docetaxel monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kogure et al. 2022 (CAPITAL) 2016-2020 Phase 3 (C) CnP Inferior OS

Note: This trial enrolled patients who were 70 or older.

Chemotherapy

21-day cycles

References

  1. CAPITAL: Kogure Y, Iwasawa S, Saka H, Hamamoto Y, Kada A, Hashimoto H, Atagi S, Takiguchi Y, Ebi N, Inoue A, Kurata T, Okamoto I, Yamaguchi M, Harada T, Seike M, Ando M, Saito AM, Kubota K, Takenoyama M, Seto T, Yamamoto N, Gemma A. Efficacy and safety of carboplatin with nab-paclitaxel versus docetaxel in older patients with squamous non-small-cell lung cancer (CAPITAL): a randomised, multicentre, open-label, phase 3 trial. Lancet Healthy Longev. 2021 Dec;2(12):e791-e800. link to original article contains dosing details in manuscript PubMed UMIN000019843

Docetaxel & Nedaplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shukuya et al. 2015 (WJOG5208L) 2009-2012 Phase 3 (E-switch-ic) Cisplatin & Docetaxel Might have superior OS (primary endpoint)
Median OS: 13.6 vs 11.4 mo
(HR 0.81, 95% CI 0.65-1.02)

Chemotherapy

21-day cycle for 4 to 6 cycles

References

  1. WJOG5208L: Shukuya T, Yamanaka T, Seto T, Daga H, Goto K, Saka H, Sugawara S, Takahashi T, Yokota S, Kaneda H, Kawaguchi T, Nagase S, Oguri T, Iwamoto Y, Nishimura T, Hattori Y, Nakagawa K, Nakanishi Y, Yamamoto N; West Japan Oncology Group. Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1630-8. Epub 2015 Oct 28. link to original article contains dosing details in abstract PubMed UMIN000002015
  2. 5501068: Lu S, Chen Z, Hu C, Zhang J, Chen Y, Song Y, Zhao Q, Fan Y, Wu G, Ma Z, Fang J, Yu Q, Liu Z. Nedaplatin plus docetaxel versus cisplatin plus docetaxel as first-line chemotherapy for advanced squamous cell carcinoma of the lung - a multicenter, open-label, randomized, phase III trial. J Thorac Oncol. 2018 Nov;13(11):1743-1749. Epub 2018 Jul 11. link to original article contains dosing details in manuscript PubMed NCT02088515

Ipilimumab & Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hellmann et al. 2018 (CheckMate 227) 2015-08 to 2016-11 Phase 3 (E-RT-switch-ooc) 1. Nivolumab Not reported
2a. GC
2b. GCb 		Superior OS (co-primary endpoint)1
OS60: 24% vs 14%

1Reported efficacy is based on the 2022 update. Note that the proportional hazards assumption was not met; HR is therefore not reported here.

Biomarker eligibility criteria

  • PD-L1 expression of 1% or more

Immunotherapy

42-day cycles

References

  1. 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
    1. PRO analysis: Reck M, Schenker M, Lee KH, Provencio M, Nishio M, Lesniewski-Kmak K, Sangha R, Ahmed S, Raimbourg J, Feeney K, Corre R, Franke FA, Richardet E, Penrod JR, Yuan Y, Nathan FE, Bhagavatheeswaran P, DeRosa M, Taylor F, Lawrance R, Brahmer J. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur J Cancer. 2019 Jul;116:137-147. Epub 2019 Jun 11. link to original article PubMed
    2. Update: Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. Epub 2019 Sep 28. link to original article PubMed
    3. Update: Paz-Ares LG, Ramalingam SS, Ciuleanu TE, Lee JS, Urban L, Caro RB, Park K, Sakai H, Ohe Y, Nishio M, Audigier-Valette C, Burgers JA, Pluzanski A, Sangha R, Gallardo C, Takeda M, Linardou H, Lupinacci L, Lee KH, Caserta C, Provencio M, Carcereny E, Otterson GA, Schenker M, Zurawski B, Alexandru A, Vergnenegre A, Raimbourg J, Feeney K, Kim SW, Borghaei H, O'Byrne KJ, Hellmann MD, Memaj A, Nathan FE, Bushong J, Tran P, Brahmer JR, Reck M. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thorac Oncol. 2022 Feb;17(2):289-308. Epub 2021 Oct 12. link to original article PubMed
    4. Update: Brahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, Audigier-Valette C, Lupinacci L, Sangha R, Pluzanski A, Burgers J, Mahave M, Ahmed S, Schoenfeld AJ, Paz-Ares LG, Reck M, Borghaei H, O'Byrne KJ, Gupta RG, Bushong J, Li L, Blum SI, Eccles LJ, Ramalingam SS. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023 Feb 20;41(6):1200-1212. Epub 2022 Oct 12. link to original article link to PMC article PubMed

Maintenance after first-line therapy

S-1 monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tanaka et al. 2020 (WJOG7512L) 2013-2017 Phase 3 (E-esc) Observation Superior PFS (primary endpoint)
Median PFS: 1.6 vs 1 mo
(HR 0.55, 95% CI 0.37-0.80)

Preceding treatment

Chemotherapy

21-day cycles

References

  1. WJOG7512L: Tanaka K, Morita S, Ando M, Yokoyama T, Nakamura A, Yoshioka H, Ishiguro T, Miura S, Toyozawa R, Oguri T, Daga H, Ko R, Bessho A, Tachihara M, Iwamoto Y, Hirano K, Nakanishi Y, Nakagawa K, Yamamoto N, Okamoto I. A randomized phase 3 study of maintenance therapy with S-1 plus best supportive care versus best supportive care after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell carcinoma of the lung (WJOG7512L). Cancer. 2020 Aug 15;126(16):3648-3656. Epub 2020 Jun 2. link to original article contains dosing details in manuscript PubMed UMIN000010396

Advanced or metastatic disease, second-line

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

Continued indefinitely


Regimen variant #2, 40 mg/day

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Soria et al. 2015 (LUX-Lung 8) 2012-2014 Phase 3 (E-RT-switch-ic) Erlotinib Seems to have superior PFS (primary endpoint)
Median PFS: 2.4 vs 1.9 mo
(HR 0.82, 95% CI 0.68-1.00)

Seems to have superior OS1 (secondary endpoint)
Median OS: 7.8 vs 6.8 mo
(HR 0.84, 95% CI 0.73-0.97)

1Reported efficacy for OS is based on the 2021 update.

Targeted therapy

Continued indefinitely

References

  1. LUX-Lung 8: Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains dosing details in abstract PubMed NCT01523587
    1. PRO analysis: Felip E, Hirsh V, Popat S, Cobo M, Fülöp A, Dayen C, Trigo JM, Gregg R, Waller CF, Soria JC, Goss GD, Gordon J, Wang B, Palmer M, Ehrnrooth E, Gadgeel SM. Symptom and Quality of Life Improvement in LUX-Lung 8, an Open-Label Phase III Study of Second-Line Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung After First-Line Platinum-Based Chemotherapy. Clin Lung Cancer. 2018 Jan;19(1):74-83.e11. Epub 2017 Jun 23. link to original article PubMed
    2. Update: Goss GD, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Isla D, Morabito A, Min YJ, Ardizzoni A, Bender S, Cseh A, Felip E. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung: Final analysis of the randomised phase 3 LUX-Lung 8 trial. EClinicalMedicine. 2021 Jun 18;37:100940. link to original article link to PMC article PubMed

Docetaxel monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shi et al. 2022 (ORIENT-3) 2017-08-25 to 2018-11-07 Phase 3 (C) Sintilimab Seems to have inferior OS

Prior treatment criteria

Chemotherapy

21-day cycles

References

  1. ORIENT-3: Shi Y, Wu L, Yu X, Xing P, Wang Y, Zhou J, Wang A, Shi J, Hu Y, Wang Z, An G, Fang Y, Sun S, Zhou C, Wang C, Ye F, Li X, Wang J, Wang M, Liu Y, Zhao Y, Yuan Y, Feng J, Chen Z, Shi J, Sun T, Wu G, Shu Y, Guo Q, Zhang Y, Song Y, Zhang S, Chen Y, Li W, Niu H, Hu W, Wang L, Huang J, Zhang Y, Cheng Y, Wu Z, Peng B, Sun J, Mancao C, Wang Y, Sun L. Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer: an open-label, randomized controlled phase 3 trial (ORIENT-3). Cancer Commun (Lond). 2022 Dec;42(12):1314-1330. Epub 2022 Nov 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03150875

Sintilimab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shi et al. 2022 (ORIENT-3) 2017-08-25 to 2018-11-07 Phase 3 (E-switch-ooc) Docetaxel Seems to have superior OS (primary endpoint)
Median OS: 11.79 vs 8.25 mo
(HR 0.74, 95% CI 0.56-0.96)

Prior treatment criteria

Immunotherapy

21-day cycles

References

  1. ORIENT-3: Shi Y, Wu L, Yu X, Xing P, Wang Y, Zhou J, Wang A, Shi J, Hu Y, Wang Z, An G, Fang Y, Sun S, Zhou C, Wang C, Ye F, Li X, Wang J, Wang M, Liu Y, Zhao Y, Yuan Y, Feng J, Chen Z, Shi J, Sun T, Wu G, Shu Y, Guo Q, Zhang Y, Song Y, Zhang S, Chen Y, Li W, Niu H, Hu W, Wang L, Huang J, Zhang Y, Cheng Y, Wu Z, Peng B, Sun J, Mancao C, Wang Y, Sun L. Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer: an open-label, randomized controlled phase 3 trial (ORIENT-3). Cancer Commun (Lond). 2022 Dec;42(12):1314-1330. Epub 2022 Nov 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03150875

Advanced or metastatic disease, subsequent lines of therapy

Note: this section includes regimens that were tested in second-line and beyond.

Docetaxel monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brahmer et al. 2015 (CheckMate 017) 2012-10 to 2013-12 Phase 3 (C) Nivolumab Inferior OS

Prior treatment criteria

Chemotherapy

21-day cycles

References

  1. CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01642004
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article link to PMC article PubMed
    2. HRQoL analysis: Reck M, Taylor F, Penrod JR, DeRosa M, Morrissey L, Dastani H, Orsini L, Gralla RJ. Impact of nivolumab versus docetaxel on health-related quality of life and symptoms in patients with advanced squamous non-small cell lung cancer: results from the CheckMate 017 study. J Thorac Oncol. 2018 Feb;13(2):194-204. Epub 2017 Nov 10. link to original article PubMed
    3. Pooled update: Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wójcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, García MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Mar 1;39(7):723-733. Epub 2021 Jan 15. link to original article link to PMC article PubMed

Nivolumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rizvi et al. 2015 (CheckMate 063) 2012-2013 Phase 2
Brahmer et al. 2015 (CheckMate 017) 2012-10 to 2013-12 Phase 3 (E-RT-switch-ooc) Docetaxel Superior OS (primary endpoint)
Median OS: 9 vs 6 mo
(HR 0.59, 95% CI 0.44-0.79)
Gettinger et al. 2021 (Lung-MAP) 2015-2018 Phase 3 (C) Ipilimumab & Nivolumab Did not meet primary endpoint of OS

Note: On 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Prior treatment criteria

Immunotherapy

14-day cycles

References

  1. CheckMate 063: Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257-65. Epub 2015 Feb 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01721759
  2. CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01642004
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article link to PMC article PubMed
    2. HRQoL analysis: Reck M, Taylor F, Penrod JR, DeRosa M, Morrissey L, Dastani H, Orsini L, Gralla RJ. Impact of nivolumab versus docetaxel on health-related quality of life and symptoms in patients with advanced squamous non-small cell lung cancer: results from the CheckMate 017 study. J Thorac Oncol. 2018 Feb;13(2):194-204. Epub 2017 Nov 10. link to original article PubMed
    3. Pooled update: Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wójcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, García MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Mar 1;39(7):723-733. Epub 2021 Jan 15. link to original article link to PMC article PubMed
  3. Lung-MAP: Gettinger SN, Redman MW, Bazhenova L, Hirsch FR, Mack PC, Schwartz LH, Bradley JD, Stinchcombe TE, Leighl NB, Ramalingam SS, Tavernier SS, Yu H, Unger JM, Minichiello K, Highleyman L, Papadimitrakopoulou VA, Kelly K, Gandara DR, Herbst RS. Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Sep 1;7(9):1368-1377. link to original article link to PMC article contains dosing details in abstract PubMed NCT02785952
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