Non-small cell lung cancer, nonsquamous

Back to Top
Note: these are regimens tested in histology-specific populations, please see the main NSCLC page for other regimens.
Last updated on 2024-12-02:61 regimens on this page
93 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==
*2023: Hendriks et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Non-Small Cell Lung Cancer.
=Perioperative therapy=
==Carboplatin & Paclitaxel (CP) & Nivolumab==
CP & Nivolumab: Carboplatin, Paclitaxel, Nivolumab
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (E-RT-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed1c. CP	Longer EFS (primary endpoint)EFS18: 70.2% vs 50%(HR 0.58, 97.36% CI 0.42-0.81)
===Neoadjuvant===
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
*Paclitaxel (Taxol) 175 or 200 mg/m2 IV once on day 1
====Immunotherapy====
*Nivolumab (Opdivo) 360 mg IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Complete resection
===Adjuvant===
====Immunotherapy====
*Nivolumab (Opdivo) 480 mg IV once on day 1
28-day cycle for 13 cycles (1 year)
===References===
#CheckMate 77T: Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04025879
==Carboplatin, Pemetrexed, Durvalumab==
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Heymach et al. 2023 (AEGEAN)	2019-01-02 to 2022-04-19	Phase 3 (E-RT-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer EFS (co-primary endpoint)EFS12: 73.4% vs 64.5%(sHR 0.68, 95% CI 0.53-0.88)
 	 	Phase 3 (E-RT-esc)	 	
===Neoadjuvant===
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Complete resection
===Adjuvant===
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
28-day cycle for up to 12 cycles
===References===
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT03800134
==Carboplatin, Pemetrexed, Nivolumab==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (E-RT-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed1c. CP	Longer EFS (primary endpoint)EFS18: 70.2% vs 50%(HR 0.58, 97.36% CI 0.42-0.81)
===Neoadjuvant===
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Nivolumab (Opdivo) 360 mg IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Complete resection
===Adjuvant===
====Immunotherapy====
*Nivolumab (Opdivo) 480 mg IV once on day 1
28-day cycle for 13 cycles (1 year)
===References===
#CheckMate 77T: Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04025879
==Cisplatin, Pemetrexed, Durvalumab==
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Heymach et al. 2023 (AEGEAN)	2019-01-02 to 2022-04-19	Phase 3 (E-RT-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer EFS (co-primary endpoint)EFS12: 73.4% vs 64.5%(sHR 0.68, 95% CI 0.53-0.88)
 	 	Phase 3 (E-RT-esc)	 	
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Complete resection
===Adjuvant===
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
28-day cycle for up to 12 cycles
===References===
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT03800134
==Cisplatin, Pemetrexed, Nivolumab==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (E-RT-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed1c. CP	Longer EFS (primary endpoint)EFS18: 70.2% vs 50%(HR 0.58, 97.36% CI 0.42-0.81)
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Nivolumab (Opdivo) 360 mg IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Complete resection
===Adjuvant===
====Immunotherapy====
*Nivolumab (Opdivo) 480 mg IV once on day 1
28-day cycle for 13 cycles (1 year)
===References===
#CheckMate 77T: Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04025879
==Cisplatin, Pemetrexed, Pembrolizumab==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wakelee et al. 2023 (KEYNOTE-671)	2018-04 to 2021-12 	Phase 3 (E-esc)	Cisplatin & Pemetrexed	Longer OS1 (co-primary endpoint)OS36: 71% vs 64%(HR 0.72, 95% CI 0.56-0.93)Longer EFS1 (co-primary endpoint)Median EFS: 47.2 vs 18.3 mo(HR 0.59, 95% CI 0.48-0.72)
1Reported efficacy is based on the 2024 update.
===Neoadjuvant===
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for 4 cycles
===Definitive===
====Local therapy====
*Complete resection
===Adjuvant===
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 13 cycles
===References===
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03425643
##Update: Spicer JD, Garassino MC, Wakelee H, Liberman M, Kato T, Tsuboi M, Lee SH, Chen KN, Dooms C, Majem M, Eigendorff E, Martinengo GL, Bylicki O, Rodríguez-Abreu D, Chaft JE, Novello S, Yang J, Arunachalam A, Keller SM, Samkari A, Gao S; KEYNOTE-671 Investigators. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024 Sep 28;404(10459):1240-1252. Epub 2024 Sep 14. link to original article EuroPMC
=Neoadjuvant therapy=
==Carboplatin & Paclitaxel (CP)==
CP: Carboplatin & Paclitaxel
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab1c. CP & Nivolumab	Shorter EFSEFS18: 50% vs 70.2%(HR 1.72, 97.36% CI 1.23-2.38)
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====
*Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
*Paclitaxel (Taxol) 175 or 200 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Complete resection
===References===
#CheckMate 77T: Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04025879
==Carboplatin & Pemetrexed==
===Regimen variant #1, AUC 5===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 	2019-01-02 to 2022-04-19	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Durvalumab1b. Cisplatin, Pemetrexed, Durvalumab 	Shorter EFS (co-primary endpoint)EFS12: 64.5% vs 73.4%(sHR 1.47, 95% CI 1.14-1.89)
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab1c. CP & Nivolumab	Shorter EFSEFS18: 50% vs 70.2%(HR 1.72, 97.36% CI 1.23-2.38)
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. This was the lower bound of dosing for CheckMate 77T.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Complete resection
===Regimen variant #2, AUC 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab1c. CP & Nivolumab	Shorter EFSEFS18: 50% vs 70.2%(HR 1.72, 97.36% CI 1.23-2.38)
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. This was the upper bound of dosing for CheckMate 77T.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Complete resection
===References===
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT03800134
#CheckMate 77T: Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04025879
==Cisplatin & Pemetrexed==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Forde et al. 2022 (CheckMate 816) 	2017-2019 	Phase 3 (C)	1a. CP & Nivolumab1b. CVb & Nivolumab1c. DC & Nivolumab1d. Cisplatin, Pemetrexed, Nivolumab 	Shorter EFSMedian EFS: 20.8 vs 31.6 mo(HR 1.59, 97.38% CI 1.10-2.33)Lower pCR ratepCR rate: 2.2% vs 24%(OR 0.07, 99% CI 0.02-0.29)
Wakelee et al. 2023 (KEYNOTE-671) 	2018-04 to 2021-12 	Phase 3 (C)	Cisplatin, Pemetrexed, Pembrolizumab 	Shorter OS1 (co-primary endpoint)OS36: 64% vs 71%(HR 1.39, 95% CI 1.08-1.79)Shorter EFS1 (co-primary endpoint)Median EFS: 18.3 vs 47.2 mo(HR 1.69, 95% CI 1.39-2.08)
Heymach et al. 2023 (AEGEAN) 	2019-01-02 to 2022-04-19	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Durvalumab1b. Cisplatin, Pemetrexed, Durvalumab 	Shorter EFS (co-primary endpoint)EFS12: 64.5% vs 73.4%(sHR 1.47, 95% CI 1.14-1.89)
Cascone et al. 2024 (CheckMate 77T)	2019-11 to 2022-04 	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Nivolumab1b. Cisplatin, Pemetrexed, Nivolumab1c. CP & Nivolumab	Shorter EFSEFS18: 50% vs 70.2%(HR 1.72, 97.36% CI 1.23-2.38)
1Reported efficacy for KEYNOTE-671 is based on the 2024 update.
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====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for varying durations: 3 cycles (CheckMate 816); 4 cycles (AEGEAN, CheckMate 77T, KEYNOTE-671)
====Subsequent treatment====
*Complete resection
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02998528
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03425643
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT03800134
#CheckMate 77T: Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04025879
==Cisplatin, Pemetrexed, Nivolumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019 	Phase 3 (E-RT-esc)	1a. CP1b. CVb1c. DC1d. Cisplatin & Pemetrexed	Longer EFS (co-primary endpoint)Median EFS: 31.6 vs 20.8 mo(HR 0.63, 97.38% CI 0.43-0.91)Higher 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====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02998528
=Adjuvant therapy=
==Cisplatin & Pemetrexed==
PemP: Pememetrexed & Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Kenmotsu et al. 2020 (JIPANG)	2012-2016 	Phase 3 (E-switch-ic)	CVb 	Did not meet primary endpoint of RFSMedian RFS: 38.9 vs 37.3 mo(HR 0.98, 95% CI 0.81-1.20)	Fewer grade 3-4 toxicities
====Preceding treatment====
*Complete surgical resection
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
===References===
#JIPANG: Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T, Goto K, Daga H, Ikeda N, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Tsuboi M. Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jul 1;38(19):2187-2196. Epub 2020 May 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000006737
##Update: Kenmotsu H, Yamamoto N, Misumi T, Yoh K, Saito H, Sugawara S, Yamazaki K, Nakagawa K, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Takahashi T, Tsuboi M. Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Dec 1;41(34):5242-5246. Epub 2023 Sep 1. link to original article EuroPMC
==Cisplatin & Vinorelbine (CVb)==
CVb: Cisplatin & Vinorelbine
NP: Navelbine (Vinorelbine) & Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Kenmotsu et al. 2020 (JIPANG)	2012-2016 	Phase 3 (C)	Cisplatin & Pemetrexed	Did not meet primary endpoint of RFSMedian RFS: 37.3 vs 38.9 mo(HR 1.02, 95% CI 0.83-1.23)	More grade 3-4 toxicities
====Preceding treatment====
*Complete surgical resection
====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 4 cycles
===References===
#JIPANG: Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T, Goto K, Daga H, Ikeda N, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Tsuboi M. Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jul 1;38(19):2187-2196. Epub 2020 May 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000006737
##Update: Kenmotsu H, Yamamoto N, Misumi T, Yoh K, Saito H, Sugawara S, Yamazaki K, Nakagawa K, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Takahashi T, Tsuboi M. Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Dec 1;41(34):5242-5246. Epub 2023 Sep 1. link to original article EuroPMC
==UFT monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kato et al. 2004	1994-1997 	Phase 3 (E-esc)	Observation	Seems to have longer OS (primary endpoint)OS60: 88% vs 85%(HR 0.71, 95% CI 0.52-0.98)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Tegafur and uracil (UFT) 250 mg PO once per day
28-day cycle for 26 cycles (2 years)
===References===
#Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
=Definitive therapy for locally advanced disease=
==Cisplatin & Etoposide (EP) & RT==
EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Senan et al. 2016 (PROCLAIM)	2008-2012 	Phase 3 (C)	Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation	Did not meet primary endpoint of OS
====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 to 200 cGy fractions x 30 to 33 fractions (total dose: 6000 to 6600 cGy)
6- to 6.5-week course
====Subsequent treatment====
*Investigator's choice of Carboplatin & Paclitaxel or Cisplatin & Etoposide or Cisplatin & Vinorelbine consolidation
===References===
#PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00686959
##Dataset: Project Data Sphere
=Consolidation after definitive therapy for inoperable disease=
==Carboplatin & Paclitaxel (CP)==
===Regimen===
Study 	Dates of enrollment	Evidence
Senan et al. 2016 (PROCLAIM)	2008-2012 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Definitive EP & 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===
#PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00686959
##Dataset: Project Data Sphere
==Cisplatin & Etoposide (EP)==
===Regimen===
Study 	Dates of enrollment	Evidence
Senan et al. 2016 (PROCLAIM)	2008-2012 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Definitive EP & RT
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
*Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
28-day cycle for 2 cycles
===References===
#PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00686959
##Dataset: Project Data Sphere
==Cisplatin & Vinorelbine (CVb)==
CVb: Cisplatin & Vinorelbine
===Regimen===
Study 	Dates of enrollment	Evidence
Senan et al. 2016 (PROCLAIM)	2008-2012 	Non-randomized part of phase 3 RCT
Note: the dose of cisplatin is not specified for this regimen in Senan et al. 2016; 75 mg/m2 is a common dosing for this regimen in other settings.
====Preceding treatment====
*Definitive EP & RT
====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 2 cycles
===References===
#PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00686959
##Dataset: Project Data Sphere
=Advanced or metastatic disease, first-line=
==ABCP==
ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel
===Regimen variant #1, 1200/15/6/175 x 4===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	1. ACP 	Not reported
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	2. BCP 	Seems to have longer OS1 (co-primary endpoint)Median OS: 19 vs 14.7 mo(HR 0.84, 95% CI 0.71-1.00)Longer PFS (co-primary endpoint)Median PFS: 8.3 vs 6.8 mo(HR 0.62, 95% CI 0.52-0.74)
1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 6 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 4: 175 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 1200/15/6/175 x 6===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	1. ACP 	Not reported
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	2. BCP 	Seems to have longer OS1 (co-primary endpoint)Median OS: 19 vs 14.7 mo(HR 0.84, 95% CI 0.71-1.00)Longer PFS (co-primary endpoint)Median PFS: 8.3 vs 6.8 mo(HR 0.62, 95% CI 0.52-0.74)
1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 6 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 6: 175 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #3, 1200/15/6/200 x 4===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	1. ACP 	Not reported
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	2. BCP 	Seems to have longer OS1 (co-primary endpoint)Median OS: 19 vs 14.7 mo(HR 0.84, 95% CI 0.71-1.00)Longer PFS (co-primary endpoint)Median PFS: 8.3 vs 6.8 mo(HR 0.62, 95% CI 0.52-0.74)
1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====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
21-day cycles
===Regimen variant #4, 1200/15/6/200 x 6===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	1. ACP 	Not reported
Socinski et al. 2018 (IMpower150)	2015-03 to 2016-12 	Phase 3 (E-RT-esc)	2. BCP 	Seems to have longer OS1 (co-primary endpoint)Median OS: 19 vs 14.7 mo(HR 0.84, 95% CI 0.71-1.00)Longer PFS (co-primary endpoint)Median PFS: 8.3 vs 6.8 mo(HR 0.62, 95% CI 0.52-0.74)
1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 6 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 6: 200 mg/m2 IV once on day 1
21-day cycles
===References===
#IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02366143
##PRO analysis: Reck M, Wehler T, Orlandi F, Nogami N, Barone C, Moro-Sibilot D, Shtivelband M, González Larriba JL, Rothenstein J, Früh M, Yu W, Deng Y, Coleman S, Shankar G, Patel H, Kelsch C, Lee A, Piault E, Socinski MA. Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Aug 1;38(22):2530-2542. Epub 2020 May 27. link to original article link to PMC article EuroPMC
##Update: Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, Reck M. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021 Nov;16(11):1909-1924. Epub 2021 Jul 24. link to original article EuroPMC
==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 & Pemetrexed1b. Cisplatin & Pemetrexed	Longer OS1 (primary endpoint)Median OS: 20.2 vs 13.1 mo(HR 0.59, 95% CI 0.40-0.89)
Peters et al. 2022 (B-FAST cohort C)	2017-09-22 to 2019-11-21	Phase 3 (E-switch-ooc) 	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Might have longer PFS (primary endpoint)Median PFS: 20.2 vs 13.1 mo(HR 0.77, 95% CI 0.59-1.00)
1Reported efficacy is for TC3/IC3 only i.e., PD-L1 TC>50%.
====Biomarker eligibility criteria====
*IMpower110: 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
*B-FAST cohort C: blood-based TMB of at least 10
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02409342
##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 EuroPMC
#B-FAST cohort C: Peters S, Dziadziuszko R, Morabito A, Felip E, Gadgeel SM, Cheema P, Cobo M, Andric Z, Barrios CH, Yamaguchi M, Dansin E, Danchaivijitr P, Johnson M, Novello S, Mathisen MS, Shagan SM, Schleifman E, Wang J, Yan M, Mocci S, Voong D, Fabrizio DA, Shames DS, Riehl T, Gandara DR, Mok T. Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial. Nat Med. 2022 Sep;28(9):1831-1839. Epub 2022 Aug 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03178552
==Carboplatin & Docetaxel (DCb)==
DCb: Docetaxel & Carboplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380)	2007-2009 	Phase 3 (C)	Carboplatin & Pemetrexed	Did not meet secondary endpoint of OS	Shorter survival without treatment-emergent grade 3/4 toxicity
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 10 minutes once on day 1, given second, 30 minutes after docetaxel
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
21-day cycle for up to 6 cycles
===References===
#H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00520676
==Carboplatin & Gemcitabine (GCb)==
GCb: Gemcitabine & Carboplatin
CG: Carboplatin & Gemcitabine
===Regimen===
Study 	Dates of enrollment	Evidence
Jian et al. 2017	2011-2014 	Non-randomized part of phase 3 RCT
Note: the manuscript does not specify whether gemcitabine is given more than once per cycle.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Gemcitabine (Gemzar) 1250 mg/m2 IV once on day 1
28-day cycle for 2 cycles
====Subsequent treatment====
*Continued GCb x 4 versus GCb & Gefitinib
===References===
#Jian H, Li W, Ma Z, Huang J, Feng J, Song Y, Gao B, Zhu H, Tao M, Bai C, Ma S, Pan H, Qin S, Hua D, Yu Y, Lu S. Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status. Sci Rep. 2017 Aug 16;7(1):8483. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==Carboplatin & nab-Paclitaxel (CnP)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
West et al. 2019 (IMpower130)	2015-2017 	Phase 3 (C)	Carboplatin, nab-Paclitaxel, Atezolizumab	Seems to have shorter OSMedian OS: 13.9 vs 18.6 mo(HR 1.27, 95% CI 1.02-1.56)
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. The length of treatment (4 or 6 cycles) was determined prior to initiation of therapy.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 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 or 6 cycles
====Subsequent treatment====
*Pemetrexed switch maintenance or no further treatment (investigator's choice)
===References===
#IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02367781
==Carboplatin, nab-Paclitaxel, Atezolizumab==
===Regimen variant #1, 4 cycles of platinum doublet===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
West et al. 2019 (IMpower130)	2015-2017 	Phase 3 (E-RT-esc)	Carboplatin & nab-Paclitaxel	Seems to have longer OS (co-primary endpoint)Median OS: 18.6 vs 13.9 mo(HR 0.79, 95% CI 0.64-0.98)
Note: the FDA-recommended dose is specific to the atezolizumab dosing.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycle 1 to 4: AUC 6 IV once on day 1
*Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
**Cycle 1 to 4: 100 mg/m2 IV once per day on days 1, 8, 15
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===Regimen variant #2, 6 cycles of platinum doublet===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
West et al. 2019 (IMpower130)	2015-2017 	Phase 3 (E-RT-esc)	Carboplatin & nab-Paclitaxel	Seems to have longer OS (co-primary endpoint)Median OS: 18.6 vs 13.9 mo(HR 0.79, 95% CI 0.64-0.98)
Note: the FDA-recommended dose is specific to the atezolizumab dosing.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycle 1 to 6: AUC 6 IV once on day 1
*Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
**Cycle 1 to 6: 100 mg/m2 IV once per day on days 1, 8, 15
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===References===
#IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02367781
==Carboplatin & Paclitaxel (CP)==
TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel
===Regimen variant #1, 5/80===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yadav et al. 2021	Not reported in abstract	Phase 3 (C)	Carboplatin & Pemetrexed	Did not meet primary endpoint of PFS6PFS6: 48.64% vs 47.45%(HR 0.88, 95% CI 0.63-1.23)
Note: The full manuscript was not available for review.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 1
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
28-day cycle for 4 cycles
====Subsequent treatment====
*Pemetrexed switch maintenance
===Regimen variant #2, 6/175===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2015 (BEYOND)	2011-05-23 to 2012-05-03	Phase 3 (C)	CP & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 6.5 vs 9.2 mo(HR 2.50, 95% CI 1.85-3.45)Shorter OS (secondary endpoint)Median OS: 17.7 vs 24.3 mo(HR 1.47, 95% CI 1.08-2.00)
====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===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Sandler et al. 2006 (ECOG E4599)	2001-2004 	Phase 3 (C)	PacCBev 	Shorter OSMedian OS: 10.3 vs 12.3 mo(HR 1.27, 95% CI 1.09-1.49)
Mok et al. 2009 (IPASS) 	2006-03 to 2007-10 	Phase 3 (C)	Gefitinib 	Shorter PFS (primary endpoint)PFS12: 6.7% vs 24.9%(HR 1.35, 95% CI 1.18-1.47)Might have shorter OS1 (secondary endpoint)Median OS: 17.4 vs 18.8 mo(HR 1.11, 95% CI 0.98-1.27)
Scagliotti et al. 2012 (MONET1) 	2007-2010 	Phase 3 (C)	TC & Motesanib	Might have shorter OS (primary endpoint)Median OS: 11 vs 13 mo(HR 1.11, 95% CI 0.96-1.28)
Kubota et al. 2017 (MONET-A) 	2012-2015 	Phase 3 (C)	TC & Motesanib	Might have shorter PFSMedian PFS: 5.6 vs 6.1 mo(sHR 1.23, 95% CI 0.97-1.56)
1Reported efficacy for IPASS is based on the 2011 update.
====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 6 cycles
===References===
#ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00021060
##Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00322452
##Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article EuroPMC
##HRQoL analysis: Thongprasert S, Duffield E, Saijo N, Wu YL, Yang JC, Chu DT, Liao M, Chen YM, Kuo HP, Negoro S, Lam KC, Armour A, Magill P, Fukuoka M. Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J Thorac Oncol. 2011 Nov;6(11):1872-1880. link to original article link to EuroPMC
##Dataset: Project Data Sphere
#MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00460317
#BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01364012
#MONET-A: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. Epub 2017 Sep 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-121887
# Yadav A, Malik PS, Khurana S, Jain D, Vishnubhatla S, Yadav M, Pathy S, Mohan A, Kumar L. An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. Oncology. 2021;99(6):389-396. Epub 2021 Mar 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#M14-359: NCT02264990
==Carboplatin & Paclitaxel (CP) & Bevacizumab==
PacCBev: Paclitaxel, Carboplatin, Bevacizumab 
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel
CbTB: Carboplatin, Taxol (Paclitaxel), Bevacizumab
===Regimen variant #1, 6/175/15===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2015 (BEYOND) 	2011-05-23 to 2012-05-03 	Phase 3 (E-esc)	Carboplatin & Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 6.5 mo(HR 0.40, 95% CI 0.29-0.54)Longer OS (secondary endpoint)Median OS: 24.3 vs 17.7 mo(HR 0.68, 95% CI 0.50-0.93)
Stroyakovskiy et al. 2022 (BCD-021-2)	2012-10-27 to not reported	Phase 3 (C) 	CP & Bevacizumab-aveg 	Equivalent ORR (primary endpoint)ORR: 33.82% vs 34.63%
Socinski et al. 2018 (IMpower150) 	2015-03 to 2016-12 	Phase 3 (C) 	1. ACP 	Not reported
Socinski et al. 2018 (IMpower150) 	2015-03 to 2016-12 	Phase 3 (C) 	2. ABCP 	Seems to have shorter OS1 (co-primary endpoint)Median OS: 14.7 vs 19 mo(HR 1.19, 95% CI 1.00-1.41)Shorter PFS (co-primary endpoint)Median PFS: 6.8 vs 8.3 mo(HR 1.61, 95% CI 1.35-1.92)
Yang et al. 2019 (CIBI305A301) 	2016-11-28 to 2018-05-23 	Phase 3 (C) 	CP & Bevacizumab-byva 	Equivalent ORR (primary endpoint)ORR: 46.4% vs 44.3%
1Reported efficacy for IMpower150 is based on the 2021 update.
Note: the total number of chemotherapy cycles in IMpower150 was determined prior to randomization; this dose was used for Asian patients.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for varying durations: 4 cycles (IMpower150); 6 cycles (BCD-021-2, BEYOND, CIBI305A301, IMpower150)
====Subsequent treatment====
*Bevacizumab maintenance
===Regimen variant #2, 6/200/15===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sandler et al. 2006 (ECOG E4599) 	2001-2004 	Phase 3 (E-RT-esc)	CP 	Longer OS (primary endpoint)Median OS: 12.3 vs 10.3 mo(HR 0.79, 95% CI 0.67-0.92)
Patel et al. 2013 (PointBreak) 	2008-2012 	Phase 3 (C) 	PemCBev, then PemBev maint. 	Did not meet primary endpoint of OSMedian OS: 13.4 vs 12.6 mo(HR 1.00, 95% CI 0.86-1.16)
Zinner et al. 2015 (PRONOUNCE) 	2009-2013 	Phase 3 (C) 	Carboplatin & Pemetrexed; with pemetrexed maintenance	Might have shorter G4PFS (primary endpoint)Median G4PFS: 2.86 vs 3.91 mo(HR 1.18, 95% CI 0.96-1.43)
Socinski et al. 2018 (IMpower150) 	2015-03 to 2016-12 	Phase 3 (C) 	1. ACP 	Not reported
Socinski et al. 2018 (IMpower150) 	2015-03 to 2016-12 	Phase 3 (C) 	2. ABCP 	Seems to have shorter OS1 (co-primary endpoint)Median OS: 14.7 vs 19 mo(HR 1.19, 95% CI 1.00-1.41)Shorter PFS (co-primary endpoint)Median PFS: 6.8 vs 8.3 mo(HR 1.61, 95% CI 1.35-1.92)
Reinmuth et al. 2019 (REFLECTIONS B7391003)	2015-05-21 to 2016-11-14	Phase 3 (C) 	CP & Bevacizumab-bvcr 	Equivalent ORR (primary endpoint)ORR: 44.6% vs 45.3%
Sugawara et al. 2021 (TASUKI-52) 	2017-2019 	Phase 3 (C) 	CP, Bevacizumab, Nivolumab 	Shorter PFS2 (primary endpoint)Median PFS: 8.2 vs 10.6 mo(HR 1.69, 95% CI 1.37-2.13)Shorter OS2 (secondary endpoint)Median OS: 24.7 vs 31.6 mo(HR 1.41, 95% CI 1.14-1.75)
Trukhin et al. 2021 (STELLA) 	2018-01-23 to 2019-03-05	Phase 3 (C) 	CP & Bevacizumab-maly 	Equivalent ORR (primary endpoint)ORR: 44.6% vs 40.3%
Syrigos et al. 2021 (AVANA) 	Not reported 	Phase 3 (C) 	CP & Bevacizumab-equi 	Equivalent ORR (primary endpoint)ORR: 53.7% vs 51.6%
Verschraegen et al. 2022 (CT-P16 3.1) 	2019-02-01 to 2021-04-22	Phase 3 (C) 	CP & Bevacizumab-adcd 	Equivalent ORR (primary endpoint)ORR: 42.07% vs 42.4%
1Reported efficacy for IMpower150 is based on the 2021 update.
2Reported efficacy for TASUKI-52 is based on the 2025 update.
Note: the total number of chemotherapy cycles given in IMpower150 was determined prior to randomization.
====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
====Supportive therapy====
*Premedications per paclitaxel label
*Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycle for varying durations: 4 cycles (AVANA, CT-P16 3.1, IMpower150, PointBreak, PRONOUNCE, REFLECTIONS B7391003); 6 cycles (AVANA, CT-P16 3.1, ECOG E4599, IMpower150, REFLECTIONS B7391003, STELLA, TASUKI-52)
====Subsequent treatment====
*Bevacizumab maintenance
===References===
#ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00021060
##Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00762034
##Dataset: Project Data Sphere
#PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00948675
#BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01364012
#IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02366143
##PRO analysis: Reck M, Wehler T, Orlandi F, Nogami N, Barone C, Moro-Sibilot D, Shtivelband M, González Larriba JL, Rothenstein J, Früh M, Yu W, Deng Y, Coleman S, Shankar G, Patel H, Kelsch C, Lee A, Piault E, Socinski MA. Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Aug 1;38(22):2530-2542. Epub 2020 May 27. link to original article link to PMC article EuroPMC
##Update: Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, Reck M. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021 Nov;16(11):1909-1924. Epub 2021 Jul 24. link to original article EuroPMC
# MAPLE: Thatcher N, Goldschmidt JH, Thomas M, Schenker M, Pan Z, Paz-Ares Rodriguez L, Breder V, Ostoros G, Hanes V. Efficacy and Safety of the Biosimilar ABP 215 Compared with Bevacizumab in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (MAPLE): A Randomized, Double-blind, Phase III Study. Clin Cancer Res. 2019 Apr 1;25(7):2088-2095. Epub 2019 Jan 7. Erratum in: Clin Cancer Res. 2019 May 15;25(10):3193. link to original article EuroPMC NCT01966003
#REFLECTIONS B7391003: Reinmuth N, Bryl M, Bondarenko I, Syrigos K, Vladimirov V, Zereu M, Bair AH, Hilton F, Liau K, Kasahara K. PF-06439535 (a Bevacizumab Biosimilar) Compared with Reference Bevacizumab (Avastin®), Both Plus Paclitaxel and Carboplatin, as First-Line Treatment for Advanced Non-Squamous Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Study. BioDrugs. 2019 Oct;33(5):555-570. link to original article link to PMC article EuroPMC NCT02364999
#CIBI305A301: Yang Y, Wu B, Huang L, Shi M, Liu Y, Zhao Y, Wang L, Lu S, Chen G, Li B, Xie C, Fang J, Yang N, Zhang Y, Cui J, Song Y, Zhang C, Mei X, Cao B, Yang L, Cheng Y, Ying K, Sun T, Ren B, Yu Q, Liao Z, Pei Z, Wang M, Zhou J, Yu S, Feng G, Wan H, Wang H, Gao S, Wang J, An G, Geng Y, Ji Y, Yuan Y, Ma S, Jia Z, Hu M, Zhou H, Yu J, Sun X, Zhang L. Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer. Transl Lung Cancer Res. 2019 Dec;8(6):989-999. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02954172
#STELLA: Trukhin D, Poddubskaya E, Andric Z, Makharadze T, Bellala RS, Charoentum C, Yañez Ruiz EP, Fulop A, Hyder Ali IA, Syrigos K, Katgi N, Lopez Chuken YA, Rumyana I, Reyes-Igama J, Costamilan RC, Del Campo García A, Florez A, Paravisini A, Millan S; STELLA Investigators. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03296163
#TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03117049
##Update: Lee KH, Lee JS, Sugawara S, Kang JH, Kim HR, Inui N, Hida T, Yoshida T, Tanaka H, Yang CT, Inoue T, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Takahashi S, Nakagawa K. First-line nivolumab plus platinum chemotherapy and bevacizumab for advanced nonsquamous non-small cell lung cancer: A 3-year follow-up of the phase 3 randomized TASUKI-52 trial. Lung Cancer. 2025 Jan;201:108109. link to original article link to EuroPMC
#AVANA: Syrigos K, Abert I, Andric Z, Bondarenko IN, Dvorkin M, Galic K, Galiulin R, Kuchava V, Sriuranpong V, Trukhin D, Zhavrid E, Fu D, Kassalow LM, Jones S, Bashir Z; AVANA Investigators. Efficacy and Safety of Bevacizumab Biosimilar FKB238 Versus Originator Bevacizumab: Results from AVANA, a Phase III Trial in Patients with Non-Squamous Non-Small-Cell Lung Cancer (non-sq-NSCLC). BioDrugs. 2021 Jul;35(4):417-428. Epub 2021 Jul 15. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT02810457
#BCD-021-2: Stroyakovskiy DL, Fadeeva NV, Matrosova MP, Shelepen KG, Adamchuk GA, Roy B, Nagarkar R, Kalloli M, Zhuravleva D, Voevodin GD, Shustova MS, Kryukov F. Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-021 with reference bevacizumab. BMC Cancer. 2022 Feb 1;22(1):129. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01763645
# CT-P16 3.1: Verschraegen C, Andric Z, Moiseenko F, Makharadze T, Shevnya S, Oleksiienko A, Yañez Ruiz E, Kim S, Ahn K, Park T, Park S, Ju H, Ohe Y. Candidate Bevacizumab Biosimilar CT-P16 versus European Union Reference Bevacizumab in Patients with Metastatic or Recurrent Non-Small Cell Lung Cancer: A Randomized Controlled Trial. BioDrugs. 2022 Nov;36(6):749-760. Epub 2022 Sep 28. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03676192
#SCT510-A301: Cheng Y, Pan Z, Wu L, Zhu B, Yu Y, Zang K, Zhuang W, Liu L, Gu K, Lian J, Chen R, Bian T, Lin D, Sun S, Li W, Hang X, Jiang O, Zhong F, Wang R, Luo H, Shi H, Wei Z, Zhao L, Chen S, Sun H, Li X, Sun D, Ren T, Lei K, He M, Li G, Liu H, Li R, Hu C, Kong L, Sun M, Xie L, Gai W, Chen W, Huang Z, Ren W, Su H. Efficacy and Safety of Biosimilar SCT510 Compared with Bevacizumab for the First-Line Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study. Adv Ther. 2024 Nov;41(11):4032-4048. Epub 2024 Sep 4. link to original article EuroPMC NCT03792074
==Carboplatin & Paclitaxel (CP), Bevacizumab, Nivolumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Sugawara et al. 2021 (TASUKI-52)	2017-2019 	Phase 3 (E-esc)	CP & Bevacizumab	Longer PFS1 (primary endpoint)Median PFS: 10.6 vs 8.2 mo(HR 0.59, 95% CI 0.47-0.73)Longer OS1 (secondary endpoint)Median OS: 31.6 vs 24.7 mo(HR 0.71, 95% CI 0.57-0.88)
1Reported efficacy is based on the 2025 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 6 IV once on day 1
*Paclitaxel (Taxol) as follows:
**Cycles 1 to 6: 200 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Immunotherapy====
*Nivolumab (Opdivo) 360 mg IV once on day 1
21-day cycles
===References===
#TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03117049
##Update: Lee KH, Lee JS, Sugawara S, Kang JH, Kim HR, Inui N, Hida T, Yoshida T, Tanaka H, Yang CT, Inoue T, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Takahashi S, Nakagawa K. First-line nivolumab plus platinum chemotherapy and bevacizumab for advanced nonsquamous non-small cell lung cancer: A 3-year follow-up of the phase 3 randomized TASUKI-52 trial. Lung Cancer. 2025 Jan;201:108109. link to original article link to EuroPMC
==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===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Langer et al. 2016 (KEYNOTE-021) 	2014-2016 	Randomized Phase 2 (C)	See link 	See link
Paz-Ares et al. 2021 (CheckMate 9LA)	2017-2019 	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab1b. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab	Shorter OS1Median OS: 11 vs 15.8 mo(HR 1.39, 95% CI 1.16-1.64)
Yadav et al. 2021 	Not reported in abstract	Phase 3 (E-switch-ic) 	CP 	Did not meet primary endpoint of PFS6PFS6: 47.45% vs 48.64%(HR 1.13, 95% CI 0.81-1.59)
1Reported efficacy for Checkate 9LA is based on the 2021 update.
Note: The full manuscript for Yadav et al. 2021 was not available for review.
====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
====Subsequent treatment====
*CheckMate 9LA & KEYNOTE-021: Optional Pemetrexed maintenance
*Yadav et al. 2021: Pemetrexed maintenance
===Regimen variant #2, 5/500 x 4, then maintenance pem x 2y===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2020 (ORIENT-11) 	2018-08-23 to 2019-07-30	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Sintilimab1b. Cisplatin, Pemetrexed, Sintilimab 	Shorter PFSMedian PFS: 5 vs 8.9 mo(HR 2.08, 95% CI 1.56-2.78)Shorter OS1 (secondary endpoint)Median OS: 16.8 vs 24.2 mo(HR 1.54, 95% CI 1.18-2.00)
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 & Cemiplimab1b. TP & Cemiplimab1c. Carboplatin, Pemetrexed, Cemiplimab1d. Cisplatin, Pemetrexed, Cemiplimab	Shorter OS2 (primary endpoint)Median OS: 12.9 vs 21.1 mo(HR 1.54, 95% CI 1.22-1.96)
1Reported efficacy for ORIENT-11 is based on the 2022 update.
2Reported efficacy for EMPOWER-Lung 3 part 2 is based on the 2023 update.
====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
21-day cycle for up to 36 cycles (2 years)
===Regimen variant #3, 5/500 x 4, then indefinite maintenance pem===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189)	2016-02-26 to 2017-03-06	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab1b. Cisplatin, Pemetrexed, Pembrolizumab	Shorter OS1Median OS: 10.6 vs 22 mo(HR 1.79, 95% CI 1.45-2.17)Shorter PFSMedian PFS: 4.9 vs 8.8 mo(HR 1.92, 95% CI 1.56-2.33)
Zhou et al. 2022 (GEMSTONE-302) 	2018-2020 	Phase 3 (C)	Carboplatin, Pemetrexed, Sugemalimab 	Shorter PFS (primary endpoint)Median PFS: 4.9 vs 9 mo(HR 2.08, 95% CI 1.67-2.56)Shorter OS2 (secondary endpoint)Median OS: 16.9 vs 25.4 mo(HR 1.54, 95% CI 1.19-2.00)
1Reported efficacy for KEYNOTE-189 is based on the 2021 update.
2Reported efficacy for GEMSTONE-302 is based on 2023 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: 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 cycles
===Regimen variant #4, 5/500 x 4-6, then indefinite maintenance pem===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2020 (CameL) 	2017-05-12 to 2018-06-06	Phase 3 (C)	Carboplatin, Pemetrexed, Camrelizumab 	Shorter PFS (co-primary endpoint)Median PFS: 8.3 vs 11.3 mo(HR 1.67, 95% CI 1.27-2.22)Shorter OS1 (secondary endpoint)OS60: 19.3% vs 31.2%(HR 1.35, 95% CI 1.08-1.72)
Lu et al. 2021 (RATIONALE 304)	2018-07-23 to 2019-07-31	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Tislelizumab1b. Cisplatin, Pemetrexed, Tislelizumab	Shorter PFS2Median PFS: 7.6 vs 9.8 mo(sHR 1.59, 95% CI 1.16-2.13)
Wang et al. 2023 (CHOICE-01) 	2019-04-02 to 2020-08-05	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Toripalimab1b. Cisplatin, Pemetrexed, Toripalimab 	Shorter PFS (primary endpoint)Median PFS: 5.6 vs 8.4 mo(HR 2.04, 95% CI 1.64-2.56)Shorter OS (secondary endpoint)Median OS: 17.1 vs NYR mo(HR 1.45, 95% CI 1.09-1.89)
1Reported efficacy for CameL is based on the 2024 update.
2Reported efficacy for RATIONALE 304 is based on the 2024 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4 up to 6: AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #5, 5/500 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380)	2007-2009 	Phase 3 (E-switch-ic)	Carboplatin & Docetaxel	Did not meet secondary endpoint of OS 	Longer survival without treatment-emergent grade 3/4 toxicity
Mok et al. 2019 (KEYNOTE-042) 	2014-2017 	Phase 3 (C) 	Pembrolizumab 	Shorter OS1 (co-primary endpoint)Median OS: 13.8 vs 24.5 mo(HR 1.49, 95% CI 1.12-2.00)	
1Reported efficacy for KEYNOTE-042 is for the population with TPS of 1% or more.
Note: Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.
====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 6 cycles
====Subsequent treatment====
*Optional pemetrexed maintenance
===Regimen variant #6, 6/500 x 4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zinner et al. 2015 (PRONOUNCE) 	2009-2013 	Phase 3 (E-switch-ooc)	See link 	See link
Paz-Ares et al. 2021 (CheckMate 9LA)	2017-2019 	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab1b. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab	Shorter OS1Median OS: 11 vs 15.8 mo(HR 1.39, 95% CI 1.16-1.64)
1Reported efficacy for Checkate 9LA is based on the 2021 update.
====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
====Subsequent treatment====
*Pemetrexed maintenance (optional in CheckMate 9LA)
===Regimen variant #7, 6/500 x 4, then maintenance pem x 2y===
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 & Cemiplimab1b. TP & Cemiplimab1c. Carboplatin, Pemetrexed, Cemiplimab1d. Cisplatin, Pemetrexed, Cemiplimab	Shorter OS1 (primary endpoint)Median OS: 12.9 vs 21.1 mo(HR 1.54, 95% CI 1.22-1.96)
1Reported efficacy is based on the 2023 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for up to 36 cycles (2 years)
===Regimen variant #8, 6/500 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042) 	2014-2017 	Phase 3 (C)	Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 13.8 vs 24.5 mo(HR 1.49, 95% CI 1.12-2.00)
Herbst et al. 2020 (IMpower110)	2015-2018 	Phase 3 (C)	Atezolizumab 	Shorter OS2Median OS: 13.1 vs 20.2 mo(HR 1.69, 95% CI 1.12-2.50)
1Reported efficacy for KEYNOTE-042 is for the population with TPS of 1% or more.
2Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.
====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 up to 6 cycles
====Subsequent treatment====
*KEYNOTE-042: Optional pemetrexed maintenance
*IMpower110: pemetrexed maintenance
===Regimen variant #9, 6/500 indefinitely===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Edelman et al. 2017 (CALGB 30801)	2010-2013 	Phase 3 (C)	CP & Celecoxib	Did not meet primary endpoint of PFSMedian PFS: 5.26 vs 5.16 mo(HR 0.93, 95% CI 0.73-1.17)
====Biomarker eligibility criteria====
*COX-2 expression at least 2
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===References===
#H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00520676
#PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00948675
#KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02039674
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01041781
#KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol dosing details in manuscript have been reviewed by our editors EuroPMC NCT02578680
##PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article EuroPMC
##Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article EuroPMC
##Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article EuroPMC
##Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article EuroPMC
#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 EuroPMC NCT02220894
##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 EuroPMC
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT02453282
##PRO analysis: Garon EB, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, Robinet G, Le Moulec S, Natale R, Schneider J, Shepherd FA, Garassino MC, Geater SL, Szekely ZP, Van Ngoc T, Liu F, Scheuring U, Patel N, Peters S, Rizvi NA. Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Clin Lung Cancer. 2021 Jul;22(4):301-312.e8. Epub 2021 Feb 19. link to original article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02409342
##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 EuroPMC
# ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03607539
##Update: Zhang L, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Stefaniak V, Lin Y, Wang S, Zhang W, Sun L, Yang Y. Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study. Lung Cancer. 2022 Sep;171:56-60. Epub 2022 Jul 19. link to original article EuroPMC
##HRQoL analysis: Liu T, He J, Wang Y, Yang Y, Zhang L, Shi M, Liu J, Sun D, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Huang Y, Fang W, Yang Y, Zhao Y, Zhang L. Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial. Lung Cancer. 2025 Jan;200:108108. link to original article link to EuroPMC
#IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article EuroPMC NCT02657434
# CameL: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Zhang T, Shi W, Zou J; CameL Study Group. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2021 Mar;9(3):305-314. Epub 2020 Dec 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03134872
##Update: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Jin F, Gao H, An G, Ding C, Jiang X, Xiong J, Zhou X, Hu S, Lu P, Liu A, Guo S, Huang J, Zhu C, Zhao J, Gao B, Chen Y, Hu C, Zhang J, Zhang H, Zhao H, Tai Y, Ma X, Shi W; CameL Study Group. Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial. J Thorac Oncol. 2023 May;18(5):628-639. Epub 2023 Jan 13. link to original article EuroPMC
##Update: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Jin F, Gao H, An G, Ding C, Jiang X, Xiong J, Zhou X, Hu S, Lu P, Liu A, Guo S, Huang J, Zhu C, Zhao J, Gao B, Chen Y, Hu C, Zhang J, Zhang H, Zhao H, Wang Z, Ma X, Shi W. Camrelizumab plus carboplatin and pemetrexed as first-line therapy for advanced non-squamous non-small-cell lung cancer: 5-year outcomes of the CameL randomized phase 3 study. J Immunother Cancer. 2024 Nov 27;12(11):e009240. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03215706
## 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 EuroPMC
# Yadav A, Malik PS, Khurana S, Jain D, Vishnubhatla S, Yadav M, Pathy S, Mohan A, Kumar L. An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. Oncology. 2021;99(6):389-396. Epub 2021 Mar 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03663205
##HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article EuroPMC
##Update: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ma Z, Li X, He W, Bao Y, Wang M. Tislelizumab plus chemotherapy as first-line treatment of locally advanced or metastatic nonsquamous non-small-cell lung cancer (final analysis of RATIONALE-304: a randomized phase III trial). ESMO Open. 2024 Oct;9(10):103728. Epub 2024 Sep 25. link to original article link to PMC article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT03789604
##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 EuroPMC
#B-FAST cohort C: Peters S, Dziadziuszko R, Morabito A, Felip E, Gadgeel SM, Cheema P, Cobo M, Andric Z, Barrios CH, Yamaguchi M, Dansin E, Danchaivijitr P, Johnson M, Novello S, Mathisen MS, Shagan SM, Schleifman E, Wang J, Yan M, Mocci S, Voong D, Fabrizio DA, Shames DS, Riehl T, Gandara DR, Mok T. Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial. Nat Med. 2022 Sep;28(9):1831-1839. Epub 2022 Aug 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03178552
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03409614
##Update: Makharadze T, Gogishvili M, Melkadze T, Baramidze A, Giorgadze D, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Li S, Li Y, Kaul M, Quek RGW, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol. 2023 Jun;18(6):755-768. Epub 2023 Mar 29. Erratum in: J Thorac Oncol. 2023 Oct 12:S1556-0864(23)00676-7. link to original article EuroPMC
##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 EuroPMC
#CHOICE-01: Wang Z, Wu L, Li B, Cheng Y, Li X, Wang X, Han L, Wu X, Fan Y, Yu Y, Lv D, Shi J, Huang J, Zhou S, Han B, Sun G, Guo Q, Ji Y, Zhu X, Hu S, Zhang W, Wang Q, Jia Y, Wang Z, Song Y, Wu J, Shi M, Li X, Han Z, Liu Y, Yu Z, Liu AW, Wang X, Zhou C, Zhong D, Miao L, Zhang Z, Zhao H, Yang J, Wang D, Wang Y, Li Q, Zhang X, Ji M, Yang Z, Cui J, Gao B, Wang B, Liu H, Nie L, He M, Jin S, Gu W, Shu Y, Zhou T, Feng J, Yang X, Huang C, Zhu B, Yao Y, Tang X, Yu J, Maher E, Feng H, Yao S, Keegan P, Wang J. Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01). J Clin Oncol. 2023 Jan 20;41(3):651-663. Epub 2022 Oct 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03856411
##Update: Zhong J, Fei K, Wu L, Li B, Wang Z, Cheng Y, Li X, Wang X, Han L, Wu X, Fan Y, Yu Y, Lv D, Shi J, Huang J, Zhou S, Han B, Sun G, Guo Q, Ji Y, Zhu X, Hu S, Zhang W, Wang Q, Jia Y, Wang Z, Song Y, Wu J, Shi M, Li X, Han Z, Liu Y, Yu Z, Liu AW, Wang X, Zhou C, Zhong D, Miao L, Zhang Z, Zhao H, Yang J, Wang D, Wang Y, Li Q, Zhang X, Ji M, Yang Z, Cui J, Gao B, Wang B, Liu H, Nie L, He M, Jin S, Gu W, Shu Y, Zhou T, Feng J, Yang X, Huang C, Zhu B, Yao Y, Yao S, Yu J, Cai SL, Cai Y, Xu J, Zhuang W, Luo X, Duan J, Wang J. Toripalimab plus chemotherapy for first line treatment of advanced non-small cell lung cancer (CHOICE-01): final OS and biomarker exploration of a randomized, double-blind, phase 3 trial. Signal Transduct Target Ther. 2024 Dec 24;9(1):369. link to original article link to PMC article EuroPMC
#M14-359: NCT02264990
==Carboplatin, Pemetrexed, Atezolizumab==
APP: Atezolizumab, Platinum (Carboplatin), Pemetrexed
===Regimen variant #1, carboplatin AUC 5===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Shiraishi et al. 2024 (WJOG11218L)	2019-01-20 to 2020-08-12	Phase 3 (C)	APPB 	Did not meet primary endpoint of PFSMedian PFS: 7.7 vs 9.6 mo(HR 1.16, 95% CI 0.93-1.43)
====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
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===Regimen variant #2, carboplatin AUC 6 x 4===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Nishio et al. 2020 (IMpower132)	2016-04-07 to 2017-05-31	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (co-primary endpoint)Median PFS: 8 vs 5 mo (HR 0.60, 95% CI 0.49-0.72)Did not meet co-primary endpoint of OSMedian OS: 17.5 vs 13.6 mo(sHR 0.86, 95% CI 0.71-1.06)
Note: The choice of number of platinum cycles was at the investigator's discretion.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===Regimen variant #3, carboplatin AUC 6 x 6===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Nishio et al. 2020 (IMpower132)	2016-04-07 to 2017-05-31	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (co-primary endpoint)Median PFS: 8 vs 5 mo (HR 0.60, 95% CI 0.49-0.72)Did not meet co-primary endpoint of OSMedian OS: 17.5 vs 13.6 mo(sHR 0.86, 95% CI 0.71-1.06)
Note: The choice of number of platinum cycles was at the investigator's discretion.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===References===
#IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02657434
#WJOG11218L: Shiraishi Y, Kishimoto J, Sugawara S, Mizutani H, Daga H, Azuma K, Matsumoto H, Hataji O, Nishino K, Mori M, Shukuya T, Saito H, Tachihara M, Hayashi H, Tsuya A, Wakuda K, Yanagitani N, Sakamoto T, Miura S, Hata A, Okada M, Kozuki T, Sato Y, Harada T, Takayama K, Yamamoto N, Nakagawa K, Okamoto I. Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2024 Mar 1;10(3):315-324. link to original article contains partial dosing details in abstract link to PMC article EuroPMC jRCT2080224500
#APPLE: JapicCTI-194565
==Carboplatin, Pemetrexed, Bevacizumab==
PemCBev: Pemetrexed, Carboplatin, Bevacizumab
BevCPem: Bevacizumab, Carboplatin, Pemetrexed
===Regimen variant #1, 5/500/7.5===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Schuette et al. 2017 (65Plus)	2009 to not reported	Phase 3 (C)	Pemetrexed & Bevacizumab	Inconclusive whether non-inferior PFS (primary endpoint)Median PFS: 6.8 vs 4.8 mo(HR 0.78, 95% CI 0.59-1.01)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1, given last
21-day cycle for 4 to 6 cycles
====Subsequent treatment====
*65Plus, patients without progression: Bevacizumab or Pemetrexed & Bevacizumab maintenance
===Regimen variant #2, 6/500/15===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Patel et al. 2013 (PointBreak)	2008-2012 	Phase 3 (E-switch-ic) 	PacCBev, then Bev maintenance	Did not meet primary endpoint of OS
Seto et al. 2019 (COMPASS) 	2010-2015 	Non-randomized part of phase 3 RCT	 	
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV over 30 to 60 minutes once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes 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 pemetrexed label
*Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycle for 4 cycles
====Subsequent treatment====
*PointBreak, patients without progression: Pemetrexed & Bevacizumab maintenance
*COMPASS, patients without progression: Bevacizumab versus Pemetrexed & Bevacizumab maintenance
===References===
#PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00762034
##Dataset: Project Data Sphere
#65Plus: Schuette W, Schneider CP, Engel-Riedel W, Schumann C, Kohlhaeufl M, Serke MHU, Hoeffken G, Kortsik C, Reck M. 65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer. Lung Cancer (Auckl). 2017 Nov 6;8:217-229. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00976456
#COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000004194
==Carboplatin, Pemetrexed, Camrelizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2020 (CameL)	2017-05-12 to 2018-06-06	Phase 3 (E-esc)	Carboplatin & Pemetrexed	Longer PFS (co-primary endpoint)Median PFS: 11.3 vs 8.3 mo(HR 0.60, 95% CI 0.45-0.79)Longer OS1 (secondary endpoint)OS60: 31.2% vs 19.3%(HR 0.74, 95% CI 0.58-0.93)
1Reported efficacy is based on the 2024 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4 up to 6: AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycles
===References===
# CameL: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Zhang T, Shi W, Zou J; CameL Study Group. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2021 Mar;9(3):305-314. Epub 2020 Dec 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03134872
##Update: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Jin F, Gao H, An G, Ding C, Jiang X, Xiong J, Zhou X, Hu S, Lu P, Liu A, Guo S, Huang J, Zhu C, Zhao J, Gao B, Chen Y, Hu C, Zhang J, Zhang H, Zhao H, Tai Y, Ma X, Shi W; CameL Study Group. Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial. J Thorac Oncol. 2023 May;18(5):628-639. Epub 2023 Jan 13. link to original article EuroPMC
##Update: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Jin F, Gao H, An G, Ding C, Jiang X, Xiong J, Zhou X, Hu S, Lu P, Liu A, Guo S, Huang J, Zhu C, Zhao J, Gao B, Chen Y, Hu C, Zhang J, Zhang H, Zhao H, Wang Z, Ma X, Shi W. Camrelizumab plus carboplatin and pemetrexed as first-line therapy for advanced non-squamous non-small-cell lung cancer: 5-year outcomes of the CameL randomized phase 3 study. J Immunother Cancer. 2024 Nov 27;12(11):e009240. link to original article link to PMC article EuroPMC
==Carboplatin, Pemetrexed, Cemiplimab==
===Regimen variant #1, 5/500===
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. CP1b. Cisplatin & Paclitaxel1c. Carboplatin & Pemetrexed1d. Cisplatin & Pemetrexed	Longer OS1 (primary endpoint)Median OS: 21.1 vs 12.9 mo(HR 0.65, 95% CI 0.51-0.82)
1Reported efficacy is based on the 2023 update.
====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
====Immunotherapy====
*Cemiplimab (Libtayo) 350 mg IV once on day 1
21-day cycle for up to 36 cycles (2 years)
===Regimen variant #2, 6/500===
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. CP1b. Cisplatin & Paclitaxel1c. Carboplatin & Pemetrexed1d. Cisplatin & Pemetrexed	Longer OS1 (primary endpoint)Median OS: 21.1 vs 12.9 mo(HR 0.65, 95% CI 0.51-0.82)
1Reported efficacy is based on the 2023 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 6 IV once on day 1
*Pemetrexed (Alimta) 500 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===
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03409614
##Update: Makharadze T, Gogishvili M, Melkadze T, Baramidze A, Giorgadze D, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Li S, Li Y, Kaul M, Quek RGW, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol. 2023 Jun;18(6):755-768. Epub 2023 Mar 29. Erratum in: J Thorac Oncol. 2023 Oct 12:S1556-0864(23)00676-7. link to original article EuroPMC
##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 EuroPMC
==Carboplatin, Pemetrexed, Ipilimumab, Nivolumab==
===Regimen variant #1, AUC 5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Paz-Ares et al. 2021 (CheckMate 9LA)	2017-2019 	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer 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====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 & 2: AUC 5 IV once on day 1
*Pemetrexed (Alimta) as follows:
**Cycles 1 & 2: 500 mg/m2 IV once on day 1
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Odd cycles: 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 360 mg IV once on day 1, given first
21-day cycles 
===Regimen variant #2, AUC 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Paz-Ares et al. 2021 (CheckMate 9LA)	2017-2019 	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer 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====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 & 2: AUC 6 IV once on day 1
*Pemetrexed (Alimta) as follows:
**Cycles 1 & 2: 500 mg/m2 IV once on day 1
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Odd cycles: 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 360 mg IV once on day 1, given first
21-day cycles 
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03215706
## 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 EuroPMC
==Carboplatin, Pemetrexed, Pembrolizumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Langer et al. 2016 (KEYNOTE-021) 	2014-2016 	Randomized Phase 2 (E-esc)	Carboplatin & Pemetrexed 	Higher ORR (primary endpoint)
Gandhi et al. 2018 (KEYNOTE-189) 	2016-02-26 to 2017-03-06	Phase 3 (E-RT-esc) 	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed 	Longer OS1 (co-primary endpoint)Median OS: 22 vs 10.6 mo(HR 0.56, 95% CI 0.46-0.69)Longer PFS (co-primary endpoint)Median PFS: 8.8 vs 4.9 mo(HR 0.52, 95% CI 0.43-0.64)
Tan et al. 2023 (CANOPY-1) 	2019-06-25 to 2020-01-17	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Canakinumab, Pembrolizumab1b. Cisplatin, Pemetrexed, Canakinumab, Pembrolizumab 	Did not meet co-primary endpoint of PFSMedian PFS: 6.8 vs 6.8 mo(HR 1.18, 95% CI 0.92-1.49)Did not meet co-primary endpoint of OSMedian OS: 20.2 vs 20.8 mo(HR 1.15, 95% CI 0.91-1.43)
Shiraishi et al. 2024 (JCOG2007) 	2021-04-06 to 2023-03-30	Phase 3 (C) 	Carboplatin, Pemetrexed, Ipilimumab, Nivolumab 	Did not meet primary endpoint of OSMedian OS: 20.5 vs 23.7 mo(HR 1.02, 95% CI 0.75-1.39)
Awaiting publication (TROPION-Lung07)	2023-ongoing 	Phase 3 (C) 	1. Datopotamab-DXd & Pembrolizumab2a. Carboplatin, Pemeterexed, Datopotamab-DXd, Pembrolizumab2b. Cisplatin, Pemeterexed, Datopotamab-DXd, Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
1Reported efficacy for KEYNOTE-189 is based on the 2021 update.
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 5 IV over 15 to 60 minutes once on day 1, given third
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given second
====Immunotherapy====
*Pembrolizumab (Keytruda) as follows:
**Cycles 1 to 35: 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy
====Supportive therapy====
*"Premedication with folic acid, vitamin B12, and corticosteroids was administered according to local guidelines."
21-day cycles
===References===
# KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article dosing details in manuscript have been reviewed by our editors supplementary appendix link to PMC article EuroPMC NCT02039674
#KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol dosing details in manuscript have been reviewed by our editors EuroPMC NCT02578680
##PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article EuroPMC
##Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article EuroPMC
##Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article EuroPMC
##Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03631199
#JCOG2007: Shiraishi Y, Nomura S, Sugawara S, Horinouchi H, Yoneshima Y, Hayashi H, Azuma K, Hara S, Niho S, Morita R, Yamaguchi M, Yokoyama T, Yoh K, Kurata T, Okamoto H, Okamoto M, Kijima T, Kasahara K, Fujiwara Y, Murakami S, Kanda S, Akamatsu H, Takemoto S, Kaneda H, Kozuki T, Ando M, Sekino Y, Fukuda H, Ohe Y, Okamoto I. Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): an open-label, multicentre, randomised, phase 3 trial. Lancet Respir Med. 2024 Nov;12(11):877-887. Epub 2024 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC jRCTs031210013
#KEYLYNK-006: NCT03976323
#KEYVIBE-007: NCT05226598
#TROPION-Lung07: NCT05555732
==Carboplatin, Pemetrexed, Sintilimab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2020 (ORIENT-11)	2018-08-23 to 2019-07-30	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 8.9 vs 5 mo(HR 0.48, 95% CI 0.36-0.64)Longer OS1 (secondary endpoint)Median OS: 24.2 vs 16.8 mo(HR 0.65, 95% CI 0.50-0.85)
1Reported efficacy is based on the 2022 update.
====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
====Immunotherapy====
*Sintilimab (Tyvyt) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03607539
##Update: Zhang L, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Stefaniak V, Lin Y, Wang S, Zhang W, Sun L, Yang Y. Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study. Lung Cancer. 2022 Sep;171:56-60. Epub 2022 Jul 19. link to original article EuroPMC
##HRQoL analysis: Liu T, He J, Wang Y, Yang Y, Zhang L, Shi M, Liu J, Sun D, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Huang Y, Fang W, Yang Y, Zhao Y, Zhang L. Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial. Lung Cancer. 2025 Jan;200:108108. link to original article link to EuroPMC
==Carboplatin, Pemetrexed, Sugemalimab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zhou et al. 2022 (GEMSTONE-302)	2018-2020 	Phase 3 (E-esc)	Carboplatin & Pemetrexed	Longer OS1 (secondary endpoint)Median OS: 25.4 vs 16.9 mo(HR 0.65, 95% CI 0.50-0.84)Longer 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====
*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
====Immunotherapy====
*Sugemalimab (Cejemly) 1200 mg IV once on day 1
21-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT03789604
##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 EuroPMC
==Carboplatin, Pemetrexed, Tislelizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lu et al. 2021 (RATIONALE 304)	2018-07-23 to 2019-07-31	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS1 (primary endpoint)Median PFS: 9.8 vs 7.6 mo(sHR 0.63, 95% CI 0.47-0.86)
1Reported efficacy is based on the 2024 update.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4 up to 6: AUC 5 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
# RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03663205
##HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article EuroPMC
##Update: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ma Z, Li X, He W, Bao Y, Wang M. Tislelizumab plus chemotherapy as first-line treatment of locally advanced or metastatic nonsquamous non-small-cell lung cancer (final analysis of RATIONALE-304: a randomized phase III trial). ESMO Open. 2024 Oct;9(10):103728. Epub 2024 Sep 25. link to original article link to PMC article EuroPMC
==Cisplatin & Docetaxel (DC)==
DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Park et al. 2017 (TRAIL)	2011-2013 	Phase 3 (C)	Cisplatin & Pemetrexed	Inconclusive whether non-inferior PFS (primary endpoint)
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV once on day 1
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
===References===
#TRAIL: Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01282151
==Cisplatin & Gemcitabine (GC)==
GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)
===Regimen variant #1, 75/1250===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Han et al. 2012 (First-SIGNAL)	2005-2007 	Phase 3 (C)	Gefitinib 	Did not meet primary endpoint of OSMedian OS: 22.9 vs 22.3 mo(HR 1.07, 95% CI 0.82-1.40)
Paz-Ares et al. 2012 (NExUS) 	2007-2009 	Phase 3 (C)	GC & Sorafenib	Did not meet primary endpoint of OSMedian OS: 12.5 vs 12.4 mo(HR 1.02, 95% CI 0.86-1.20)
Note: There is a discrepancy in the cisplatin dosing between the abstract and the manuscript in Han et al. 2012; the authors have been contacted but are unlikely to respond as this was published more than 10 years ago.
====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 varying durations: 6 cycles (NExUS); 9 cycles (First-SIGNAL)
===Regimen variant #2, 80/1250 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-02 to 2006-08 	Phase 3 (C)	1. GC & Bevacizumab; low-dose 	Shorter PFS
Reck et al. 2009 (AVAil)	2005-02 to 2006-08 	Phase 3 (C)	2. GC & Bevacizumab; standard-dose	Seems to have shorter PFS
====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
===References===
#AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00806923
##Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article EuroPMC
#First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00455936
#NExUS: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Lemarie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non–small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. Epub 2012 Jul 30. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00449033
##Dataset: Project Data Sphere
==Cisplatin & Gemcitabine (GC) & Bevacizumab==
===Regimen variant #1, low-dose bev===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-02 to 2006-08 	Phase 3 (E-RT-esc)	1. Cisplatin & Gemcitabine 	Longer PFS1 (primary endpoint)(HR 0.75, 95% CI 0.64-0.87)
Reck et al. 2009 (AVAil)	2005-02 to 2006-08 	Phase 3 (E-RT-esc)	2. GC & Bevacizumab; standard-dose	Not reported
1Reported efficacy is based on the 2010 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 80 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) as follows:
**Cycles 1 to 6: 1250 mg/m2 IV once per day on days 1 & 8
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, standard-dose bev===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Reck et al. 2009 (AVAil)	2005-02 to 2006-08 	Phase 3 (E-RT-esc)	1. Cisplatin & Gemcitabine 	Seems to have longer PFS1 (primary endpoint)(HR 0.85, 95% CI 0.73-1.00)
Reck et al. 2009 (AVAil)	2005-02 to 2006-08 	Phase 3 (E-RT-esc)	2. GC & Bevacizumab; low-dose	Not reported
1Reported efficacy is based on the 2010 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 80 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) as follows:
**Cycles 1 to 6: 1250 mg/m2 IV once per day on days 1 & 8
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00806923
##Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article EuroPMC
==Cisplatin & Pemetrexed==
Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed
===Regimen variant #1, 70/500 x 4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Park et al. 2017 (TRAIL)	2011-2013 	Phase 3 (E-switch-ic)	Cisplatin & Docetaxel	Inconclusive whether non-inferior PFS (primary endpoint)
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
===Regimen variant #2, 75/500 x 4-6===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Paz-Ares et al. 2012 (PARAMOUNT) 	2008-2010 	Non-randomized part of phase 3 RCT	 	 	
Wu et al. 2014 (JMIL) 	2009-11 to 2010-10 	Phase 3 (C) 	GC 	Did not meet primary endpoint of OSMedian OS: 17.54 vs 15.51 mo(HR 1.00, 95% CI 0.75-1.35) 	
Paz-Ares et al. 2015 (INSPIRE) 	2009-2011 	Phase 3 (C) 	Pem-Cis & Necitumumab 	Did not meet primary endpoint of OSMedian OS: 11.5 vs 11.3 mo(HR 0.99, 95% CI 0.83-1.19) 	
Reck et al. 2016 (KEYNOTE-024) 	2014-09-19 to 2015-10-29	Phase 3 (C) 	Pembrolizumab 	Shorter PFS (primary endpoint)Median PFS: 6 vs 10.3 mo(HR 2.00, 95% CI 1.47-2.70)Shorter OS1 (secondary endpoint)Median OS: 13.4 vs 26.3 mo(HR 1.61, 95% CI 1.23-2.08)	Worse HRQoL
Rizvi et al. 2020 (MYSTIC) 	2015-07-21 to 2016-06-08	Phase 3 (C) 	1. Durvalumab 	Might have shorter OS 	
Rizvi et al. 2020 (MYSTIC) 	2015-07-21 to 2016-06-08	Phase 3 (C) 	2. Durvalumab & Tremelimumab 	Did not meet co-primary endpoints of PFS/OS 	
Herbst et al. 2020 (IMpower110) 	2015-2018 	Phase 3 (C) 	Atezolizumab 	Shorter OS2Median OS: 13.1 vs 20.2 mo(HR 1.69, 95% CI 1.12-2.50) 	
Paz-Ares et al. 2021 (CheckMate 9LA)	2017-2019 	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab1b. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab	Shorter OS3Median OS: 11 vs 15.8 mo(HR 1.39, 95% CI 1.16-1.64) 	
Lu et al. 2021 (RATIONALE 304) 	2018-07-23 to 2019-07-31	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Tislelizumab1b. Cisplatin, Pemetrexed, Tislelizumab 	Shorter PFS4Median PFS: 7.6 vs 9.8 mo(sHR 1.59, 95% CI 1.16-2.13) 	Worse HRQoL
Wang et al. 2023 (CHOICE-01) 	2019-04-02 to 2020-08-05	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Toripalimab1b. Cisplatin, Pemetrexed, Toripalimab 	Shorter PFS (primary endpoint)Median PFS: 5.6 vs 8.4 mo(HR 2.04, 95% CI 1.64-2.56)Shorter OS (secondary endpoint)Median OS: 17.1 vs NYR mo(HR 1.45, 95% CI 1.09-1.89) 	
1Reported OS efficacy for KEYNOTE-024 is based on the 2021 update.
2Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.
3Reported efficacy for Checkate 9LA is based on the 2021 update.
4Reported efficacy for RATIONALE 304 is based on the 2024 update.
Note: Selection of platinum agent in IMpower110, KEYNOTE-189, and MYSTIC was per investigator choice.
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given second
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
====Supportive therapy====
*(as described in JMDB):
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
*Folic acid (Folate) 1 mg PO once per day
*In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for pemetrexed."
21-day cycle for varying durations: 4 cycles (CheckMate 9LA, PARAMOUNT); 4 to 6 cycles (CHOICE-01, IMpower110, KEYNOTE-024, MYSTIC, RATIONALE 304); 6 cycles (INSPIRE, JMIL)
====Subsequent treatment====
*PARAMOUNT: Placebo versus pemetrexed maintenance
*CHOICE-01, IMpower110, RATIONALE 304: Pemetrexed maintenance
*KEYNOTE-024, MYSTIC, CheckMate 9LA: Optional Pemetrexed maintenance
===Regimen variant #3, 75/500 x 4, then maintenance pem x 2y===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2020 (ORIENT-11) 	2018-08-23 to 2019-07-30	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Sintilimab1b. Cisplatin, Pemetrexed, Sintilimab 	Shorter PFSMedian PFS: 5 vs 8.9 mo(HR 2.08, 95% CI 1.56-2.78)Shorter OS1 (secondary endpoint)Median OS: 16.8 vs 24.2 mo(HR 1.54, 95% CI 1.18-2.00)
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 & Cemiplimab1b. TP & Cemiplimab1c. Carboplatin, Pemetrexed, Cemiplimab1d. Cisplatin, Pemetrexed, Cemiplimab	Shorter OS2 (primary endpoint)Median OS: 12.9 vs 21.1 mo(HR 1.54, 95% CI 1.22-1.96)
1Reported efficacy for ORIENT-11 is based on the 2022 update.
2Reported efficacy for EMPOWER-Lung 3 part 2 is based on the 2023 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===Regimen variant #4, 75/500 x 4, then indefinite maintenance pem===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189)	2016-02-26 to 2017-03-06	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab1b. Cisplatin, Pemetrexed, Pembrolizumab	Shorter OS1Median OS: 10.6 vs 22 mo(HR 1.79, 95% CI 1.45-2.17)Shorter PFSMedian PFS: 4.9 vs 8.8 mo(HR 1.92, 95% CI 1.56-2.33)
Nishio et al. 2020 (IMpower132) 	2016-04-07 to 2017-05-31	Phase 3 (C)	1a. APP (carboplatin)1b. APP (cisplatin) 	Shorter PFSMedian PFS: 5 vs 8 mo(HR 1.67, 95% CI 1.39-2.04)Did not meet co-primary endpoint of OSMedian OS: 13.6 vs 17.5 mo(sHR 1.16, 95% CI 0.94-1.41)
1Reported efficacy for KEYNOTE-189 is based on the 2021 update.
Note: Selection of platinum agent in KEYNOTE-189 was per investigator choice.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1, given second
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
====Supportive therapy====
*(as described in JMDB):
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
*Folic acid (Folate) 1 mg PO once per day
*In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for pemetrexed."
21-day cycles
===Regimen variant #5, 75/500 x 6, then indefinite maintenance pem===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Nishio et al. 2020 (IMpower132)	2016-04-07 to 2017-05-31	Phase 3 (C)	1a. APP (carboplatin)1b. APP (cisplatin)	Shorter PFSMedian PFS: 5 vs 8 mo(HR 1.67, 95% CI 1.39-2.04)Did not meet co-primary endpoint of OSMedian OS: 13.6 vs 17.5 mo(sHR 1.16, 95% CI 0.94-1.41)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Supportive therapy====
*(as described in JMDB):
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to pemetrexed
*Folic acid (Folate) 1 mg PO once per day
21-day cycles
===References===
#PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00789373
##HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article EuroPMC
##Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##HRQoL analysis: Pujol JL, Paz-Ares L, de Marinis F, Dediu M, Thomas M, Bidoli P, Corral J, San Antonio B, Chouaki N, John W, Zimmermann A, Visseren-Grul C, Gridelli C. Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2014 Nov;15(6):418-25. Epub 2014 Jun 21. link to original article EuroPMC
#JMIL: Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M. Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2014 Sep;85(3):401-7. Epub 2014 Jul 17. link to original article EuroPMC NCT01005680
#INSPIRE: Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA; INSPIRE investigators. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015 Mar;16(3):328-37. Epub 2015 Feb 18. link to original article EuroPMC NCT00982111
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02142738
##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 EuroPMC
##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 EuroPMC
#TRAIL: Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01282151
#KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol dosing details in manuscript have been reviewed by our editors EuroPMC NCT02578680
##PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article EuroPMC
##Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article EuroPMC
##Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article EuroPMC
##Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article EuroPMC
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT02453282
##PRO analysis: Garon EB, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, Robinet G, Le Moulec S, Natale R, Schneider J, Shepherd FA, Garassino MC, Geater SL, Szekely ZP, Van Ngoc T, Liu F, Scheuring U, Patel N, Peters S, Rizvi NA. Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Clin Lung Cancer. 2021 Jul;22(4):301-312.e8. Epub 2021 Feb 19. link to original article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02409342
##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 EuroPMC
# ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03607539
##Update: Zhang L, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Stefaniak V, Lin Y, Wang S, Zhang W, Sun L, Yang Y. Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study. Lung Cancer. 2022 Sep;171:56-60. Epub 2022 Jul 19. link to original article EuroPMC
##HRQoL analysis: Liu T, He J, Wang Y, Yang Y, Zhang L, Shi M, Liu J, Sun D, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Huang Y, Fang W, Yang Y, Zhao Y, Zhang L. Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial. Lung Cancer. 2025 Jan;200:108108. link to original article link to EuroPMC
#IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02657434
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03215706
## 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 EuroPMC
# RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03663205
##HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article EuroPMC
##Update: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ma Z, Li X, He W, Bao Y, Wang M. Tislelizumab plus chemotherapy as first-line treatment of locally advanced or metastatic nonsquamous non-small-cell lung cancer (final analysis of RATIONALE-304: a randomized phase III trial). ESMO Open. 2024 Oct;9(10):103728. Epub 2024 Sep 25. link to original article link to PMC article EuroPMC
#B-FAST cohort C: Peters S, Dziadziuszko R, Morabito A, Felip E, Gadgeel SM, Cheema P, Cobo M, Andric Z, Barrios CH, Yamaguchi M, Dansin E, Danchaivijitr P, Johnson M, Novello S, Mathisen MS, Shagan SM, Schleifman E, Wang J, Yan M, Mocci S, Voong D, Fabrizio DA, Shames DS, Riehl T, Gandara DR, Mok T. Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial. Nat Med. 2022 Sep;28(9):1831-1839. Epub 2022 Aug 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03178552
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03409614
##Update: Makharadze T, Gogishvili M, Melkadze T, Baramidze A, Giorgadze D, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Li S, Li Y, Kaul M, Quek RGW, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol. 2023 Jun;18(6):755-768. Epub 2023 Mar 29. Erratum in: J Thorac Oncol. 2023 Oct 12:S1556-0864(23)00676-7. link to original article EuroPMC
##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 EuroPMC
#CHOICE-01: Wang Z, Wu L, Li B, Cheng Y, Li X, Wang X, Han L, Wu X, Fan Y, Yu Y, Lv D, Shi J, Huang J, Zhou S, Han B, Sun G, Guo Q, Ji Y, Zhu X, Hu S, Zhang W, Wang Q, Jia Y, Wang Z, Song Y, Wu J, Shi M, Li X, Han Z, Liu Y, Yu Z, Liu AW, Wang X, Zhou C, Zhong D, Miao L, Zhang Z, Zhao H, Yang J, Wang D, Wang Y, Li Q, Zhang X, Ji M, Yang Z, Cui J, Gao B, Wang B, Liu H, Nie L, He M, Jin S, Gu W, Shu Y, Zhou T, Feng J, Yang X, Huang C, Zhu B, Yao Y, Tang X, Yu J, Maher E, Feng H, Yao S, Keegan P, Wang J. Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01). J Clin Oncol. 2023 Jan 20;41(3):651-663. Epub 2022 Oct 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03856411
##Update: Zhong J, Fei K, Wu L, Li B, Wang Z, Cheng Y, Li X, Wang X, Han L, Wu X, Fan Y, Yu Y, Lv D, Shi J, Huang J, Zhou S, Han B, Sun G, Guo Q, Ji Y, Zhu X, Hu S, Zhang W, Wang Q, Jia Y, Wang Z, Song Y, Wu J, Shi M, Li X, Han Z, Liu Y, Yu Z, Liu AW, Wang X, Zhou C, Zhong D, Miao L, Zhang Z, Zhao H, Yang J, Wang D, Wang Y, Li Q, Zhang X, Ji M, Yang Z, Cui J, Gao B, Wang B, Liu H, Nie L, He M, Jin S, Gu W, Shu Y, Zhou T, Feng J, Yang X, Huang C, Zhu B, Yao Y, Yao S, Yu J, Cai SL, Cai Y, Xu J, Zhuang W, Luo X, Duan J, Wang J. Toripalimab plus chemotherapy for first line treatment of advanced non-small cell lung cancer (CHOICE-01): final OS and biomarker exploration of a randomized, double-blind, phase 3 trial. Signal Transduct Target Ther. 2024 Dec 24;9(1):369. link to original article link to PMC article EuroPMC
#M14-359: NCT02264990
==Cisplatin, Pemetrexed, Atezolizumab==
APP: Atezolizumab, Platinum (Cisplatin), Pemetrexed
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Nishio et al. 2020 (IMpower132)	2016-04-07 to 2017-05-31	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (co-primary endpoint)Median PFS: 8 vs 5 mo (HR 0.60, 95% CI 0.49-0.72)Did not meet co-primary endpoint of OSMedian OS: 17.5 vs 13.6 mo(sHR 0.86, 95% CI 0.71-1.06)
Note: The choice of number of platinum cycles was at the investigator's discretion.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Nishio et al. 2020 (IMpower132)	2016-04-07 to 2017-05-31	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (co-primary endpoint)Median PFS: 8 vs 5 mo (HR 0.60, 95% CI 0.49-0.72)Did not meet co-primary endpoint of OSMedian OS: 17.5 vs 13.6 mo(sHR 0.86, 95% CI 0.71-1.06)
Note: The choice of number of platinum cycles was at the investigator's discretion.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
===References===
#IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02657434
==Cisplatin, Pemetrexed, Bevacizumab==
===Regimen variant #1, maintenance bevacizumab only===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Barlesi et al. 2013 (AVAPERL)	2009-08 to 2010-07 	Phase 3 (C)	Cisplatin, Pemetrexed, Bevacizumab; with pem/bev maintenance	Shorter PFSMedian PFS: 3.7 vs 7.4 mo(HR 2.08, 95% CI 1.52-2.86)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV over 2 hours once on day 1
*Pemetrexed (Alimta) as follows:
**Cycles 1 to 4: 500 mg/m2 IV over 10 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV over 90 minutes once on day 1
**If well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes
====Supportive therapy====
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
*Folic acid (Folate) 350 to 1000 mcg PO once per day, given throughout therapy
*Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
21-day cycles 
===Regimen variant #2, maintenance pemetrexed & bevacizumab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Barlesi et al. 2013 (AVAPERL)	2009-08 to 2010-07 	Phase 3 (E-esc)	Cisplatin, Pemetrexed, Bevacizumab; with bev maintenance	Longer PFS (primary endpoint)Median PFS: 7.4 vs 3.7 mo(HR 0.48, 95% CI 0.35-0.66)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV over 2 hours once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
====Supportive therapy====
*Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, given throughout therapy
*Folic acid (Folate) 350 to 1000 mcg PO once per day, given throughout therapy
*Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
21-day cycles
===References===
#AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00961415
##HRQoL analysis: Rittmeyer A, Gorbunova V, Vikström A, Vikström A, Scherpereel A, Kim JH, Ahn MJ, Chella A, Chouaid C, Campbell AK, Barlesi F. Health-related quality of life in patients with advanced nonsquamous non-small-cell lung cancer receiving bevacizumab or bevacizumab-plus-pemetrexed maintenance therapy in AVAPERL (MO22089). J Thorac Oncol. 2013 Nov;8(11):1409-1416. link to original article link to EuroPMC
##Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article EuroPMC
==Cisplatin, Pemetrexed, 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. CP1b. Cisplatin & Paclitaxel1c. Carboplatin & Pemetrexed1d. Cisplatin & Pemetrexed	Longer OS1 (primary endpoint)Median OS: 21.1 vs 12.9 mo(HR 0.65, 95% CI 0.51-0.82)
1Reported efficacy is based on the 2023 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 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===
#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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03409614
##Update: Makharadze T, Gogishvili M, Melkadze T, Baramidze A, Giorgadze D, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Li S, Li Y, Kaul M, Quek RGW, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol. 2023 Jun;18(6):755-768. Epub 2023 Mar 29. Erratum in: J Thorac Oncol. 2023 Oct 12:S1556-0864(23)00676-7. link to original article EuroPMC
##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 EuroPMC
==Cisplatin, Pemetrexed, 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)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer 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====
*Cisplatin (Platinol) as follows:
**Cycles 1 & 2: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) as follows:
**Cycles 1 & 2: 500 mg/m2 IV once on day 1
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Odd cycles: 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 360 mg IV once on day 1, given first
21-day cycles 
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03215706
## 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 EuroPMC
==Cisplatin, Pemetrexed, Pembrolizumab==
===Regimen variant #1, limited pemetrexed===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (LEAP-006)	2019-ongoing 	Phase 3 (C)	1a. Carboplatin, Lenvatinib, Pemetrexed, Pembrolizumab1b. Cisplatin, Lenvatinib, Pemetrexed, Pembrolizumab	TBD if different co-primary endpoints of PFS/OS
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) as follows:
**Cycles 1 to 4: 500 mg/m2 IV once on day 1
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===Regimen variant #2, indefinite pemetrexed===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189)	2016-02-26 to 2017-03-06	Phase 3 (E-RT-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed 	Longer OS1 (co-primary endpoint)Median OS: 22 vs 10.6 mo(HR 0.56, 95% CI 0.46-0.69)Longer PFS (co-primary endpoint)Median PFS: 8.8 vs 4.9 mo(HR 0.52, 95% CI 0.43-0.64)
Tan et al. 2023 (CANOPY-1) 	2019-06-25 to 2020-01-17	Phase 3 (C) 	1a. Carboplatin, Pemetrexed, Canakinumab, Pembrolizumab1b. Cisplatin, Pemetrexed, Canakinumab, Pembrolizumab	Did not meet co-primary endpoint of PFSMedian PFS: 6.8 vs 6.8 mo(HR 1.18, 95% CI 0.92-1.49)Did not meet co-primary endpoint of OSMedian OS: 20.2 vs 20.8 mo(HR 1.15, 95% CI 0.91-1.43)
1Reported efficacy for KEYNOTE-189 is based on the 2021 update.
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1, given third
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given second
====Immunotherapy====
*Pembrolizumab (Keytruda) as follows:
**Cycles 1 to 35: 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy
====Supportive therapy====
*"Premedication with folic acid, vitamin B12, and corticosteroids was administered according to local guidelines."
21-day cycles
===References===
#KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol dosing details in manuscript have been reviewed by our editors EuroPMC NCT02578680
##PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article EuroPMC
##Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article EuroPMC
##Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article EuroPMC
##Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03631199
#KEYLYNK-006: NCT03976323
#KEYVIBE-007: NCT05226598
#LEAP-006: NCT03829319
#TROPION-Lung07: NCT05555732
==Cisplatin, Pemetrexed, Sintilimab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2020 (ORIENT-11)	2018-08-23 to 2019-07-30	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS (primary endpoint)Median PFS: 8.9 vs 5 mo(HR 0.48, 95% CI 0.36-0.64)Longer OS1 (secondary endpoint)Median OS: 24.2 vs 16.8 mo(HR 0.65, 95% CI 0.50-0.85)
1Reported efficacy is based on the 2022 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Sintilimab (Tyvyt) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03607539
##Update: Zhang L, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Stefaniak V, Lin Y, Wang S, Zhang W, Sun L, Yang Y. Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study. Lung Cancer. 2022 Sep;171:56-60. Epub 2022 Jul 19. link to original article EuroPMC
##HRQoL analysis: Liu T, He J, Wang Y, Yang Y, Zhang L, Shi M, Liu J, Sun D, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Huang Y, Fang W, Yang Y, Zhao Y, Zhang L. Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial. Lung Cancer. 2025 Jan;200:108108. link to original article link to EuroPMC
==Cisplatin, Pemetrexed, Tislelizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lu et al. 2021 (RATIONALE 304)	2018-07-23 to 2019-07-31	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed1b. Cisplatin & Pemetrexed	Longer PFS1 (primary endpoint)Median PFS: 9.8 vs 7.6 mo(sHR 0.63, 95% CI 0.47-0.86)
1Reported efficacy is based on the 2024 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 4 up to 6: 75 mg/m2 IV once on day 1
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
# RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03663205
##HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article EuroPMC
##Update: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ma Z, Li X, He W, Bao Y, Wang M. Tislelizumab plus chemotherapy as first-line treatment of locally advanced or metastatic nonsquamous non-small-cell lung cancer (final analysis of RATIONALE-304: a randomized phase III trial). ESMO Open. 2024 Oct;9(10):103728. Epub 2024 Sep 25. link to original article link to PMC article EuroPMC
==Gefitinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Han et al. 2012 (First-SIGNAL)	2005-2007 	Phase 3 (E-switch-ooc) 	Cisplatin & Gemcitabine 	Did not meet primary endpoint of OSMedian OS: 22.3 vs 22.9 mo(HR 0.932, 95% CI 0.72-1.21)
Mok et al. 2009 (IPASS) 	2006-03 to 2007-10 	Phase 3 (E-RT-switch-ooc)	Carboplatin & Paclitaxel 	Longer PFS (primary endpoint)PFS12: 24.9% vs 6.7%(HR 0.74, 95% CI 0.68-0.85)Might have longer OS1 (secondary endpoint)Median OS: 18.8 vs 17.4 mo(HR 0.90, 95% CI 0.79-1.02)
Yang et al. 2014 (H3E-CR-S131)	2009-2012 	Phase 3 (C) 	Cisplatin & Pemetrexed, then Gefitinib maint.	Did not meet primary endpoint of PFSMedian PFS: 8.38 vs 9.63 mo(HR 1.18, 95% CI 0.88-1.59)
1Reported efficacy for IPASS is based on the 2011 update.
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
===References===
#IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00322452
##Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article EuroPMC
##HRQoL analysis: Thongprasert S, Duffield E, Saijo N, Wu YL, Yang JC, Chu DT, Liao M, Chen YM, Kuo HP, Negoro S, Lam KC, Armour A, Magill P, Fukuoka M. Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J Thorac Oncol. 2011 Nov;6(11):1872-1880. link to original article link to EuroPMC
##Dataset: Project Data Sphere
#First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00455936
#H3E-CR-S131: Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, Kim DW, Tsai CM, Barraclough H, Altug S, Orlando M, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer. 2014 Sep;50(13):2219-30. Epub 2014 Jun 18. link to original article EuroPMC NCT01017874
##Update: Yang JC, Srimuninnimit V, Ahn MJ, Lin CC, Kim SW, Tsai CM, Mok T, Orlando M, Puri T, Wang X, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol. 2016 Mar;11(3):370-9. Epub 2015 Dec 25. link to original article EuroPMC
==Ipilimumab & Nivolumab==
===Regimen===
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|Evidence
!style="width: 20%"|Comparator
!style="width: 20%"|Comparative Efficacy
|-
| rowspan="2" |Hellmann et al. 2018 (CheckMate 227)
|rowspan=2|2015-08 to 2016-11
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
|1. Nivolumab
| style="background-color:#d3d3d3" |Not reported
|-
|2a. Cisplatin & Pemetrexed2b. Carboplatin & Pemetrexed
| style="background-color:#002f73; color:white" |Longer OS (co-primary endpoint)1OS60: 24% vs 14%1</sup>Reported efficacy is based on the 2022 update. Note that the proportional hazards assumption was not met.
====Biomarker eligibility criteria====
*PD-L1 expression of 1% or more
====Immunotherapy====
*Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 3 mg/kg IV once per day on days 1, 15, 29
42-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02477826
##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 EuroPMC
##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 EuroPMC
##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 EuroPMC
##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 EuroPMC
=Advanced or metastatic disease, first-line, elderly or poor performance status=
==Carboplatin & Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Okamoto et al. 2020 (JCOG1210/WJOG7813L)	2013-08 to 2017-02 	Phase 3 (E-esc)	Docetaxel 	Non-inferior OS (primary endpoint)Median OS: 18.7 vs 15.5 mo(sHR 0.85, 95% CI 0.68-1.06)
====Eligibility criteria====
*At least 75 years old
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 4: AUC 5 IV over 30 minutes once on day 1, given second
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
21-day cycles
===References===
#JCOG1210/WJOG7813L: Okamoto I, Nokihara H, Nomura S, Niho S, Sugawara S, Horinouchi H, Azuma K, Yoneshima Y, Murakami H, Hosomi Y, Atagi S, Ozaki T, Horiike A, Fujita Y, Okamoto H, Ando M, Yamamoto N, Ohe Y, Nakagawa K. Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):e196828. Epub 2020 May 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000011460
==Docetaxel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Okamoto et al. 2020 (JCOG1210/WJOG7813L)	2013-08 to 2017-02 	Phase 3 (C)	Carboplatin & Pemetrexed	Non-inferior OS (primary endpoint)Median OS: 15.5 vs 18.7 mo(sHR 1.18, 95% CI 0.94-1.47)
====Eligibility criteria====
*At least 75 years old
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
#JCOG1210/WJOG7813L: Okamoto I, Nokihara H, Nomura S, Niho S, Sugawara S, Horinouchi H, Azuma K, Yoneshima Y, Murakami H, Hosomi Y, Atagi S, Ozaki T, Horiike A, Fujita Y, Okamoto H, Ando M, Yamamoto N, Ohe Y, Nakagawa K. Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):e196828. Epub 2020 May 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000011460
==Gemcitabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gridelli et al. 2018 (MILES-4)	2011-2016 	Phase 3 (C)	1. Cisplatin & Gemcitabine2. Cisplatin & Pemetrexed	Did not meet primary endpoint of OS
Gridelli et al. 2018 (MILES-4)	2011-2016 	Phase 3 (C)	3. Pemetrexed 	Not reported
====Eligibility criteria====
*At least 70 years old
====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===
#MILES-4: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01656551
##HRQoL analysis: Morabito A, Piccirillo MC, Maione P, Luciani A, Cavanna L, Bonanno L, Filipazzi V, Leo S, Cinieri S, Morgillo F, Burgio MA, Ferrara D, Rosetti F, Bianco R, Artioli F, Cortinovis D, Gebbia V, Fregoni V, Mencoboni M, Sandomenico C, Rossi A, Montanino A, Manzo A, Rocco G, Arenare L, Daniele G, Signoriello S, Gallo C, Perrone F, Gridelli C. Effect on quality of life of cisplatin added to single-agent chemotherapy as first-line treatment for elderly patients with advanced non-small cell lung cancer: Joint analysis of MILES-3 and MILES-4 randomised phase 3 trials. Lung Cancer. 2019 Jul;133:62-68. Epub 2019 May 9. link to original article EuroPMC
==Pemetrexed monotherapy==
===Example orders===
*Example orders for Pemetrexed (Alimta) in non-small cell lung cancer
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gridelli et al. 2018 (MILES-4)	2011-2016 	Phase 3 (E-switch-ic)	1. Cisplatin & Gemcitabine2. Cisplatin & Pemetrexed	Did not meet primary endpoint of OS
Gridelli et al. 2018 (MILES-4)	2011-2016 	Phase 3 (E-switch-ic)	3. Gemcitabine 	Not reported
====Chemotherapy====
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
21-day cycle for up to 6 cycles
===References===
#MILES-4: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01656551
##HRQoL analysis: Morabito A, Piccirillo MC, Maione P, Luciani A, Cavanna L, Bonanno L, Filipazzi V, Leo S, Cinieri S, Morgillo F, Burgio MA, Ferrara D, Rosetti F, Bianco R, Artioli F, Cortinovis D, Gebbia V, Fregoni V, Mencoboni M, Sandomenico C, Rossi A, Montanino A, Manzo A, Rocco G, Arenare L, Daniele G, Signoriello S, Gallo C, Perrone F, Gridelli C. Effect on quality of life of cisplatin added to single-agent chemotherapy as first-line treatment for elderly patients with advanced non-small cell lung cancer: Joint analysis of MILES-3 and MILES-4 randomised phase 3 trials. Lung Cancer. 2019 Jul;133:62-68. Epub 2019 May 9. link to original article EuroPMC
=Maintenance after first-line therapy=
==Bevacizumab monotherapy==
===Regimen variant #1, 7.5 mg/kg===
Study 	Dates of enrollment 	Evidence
Yang et al. 2019 (CIBI305A301)	2016-11-28 to 2018-05-23	Non-randomized part of phase 3 RCT
====Preceding treatment====
*First-line PacCBev x 6
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, 15 mg/kg===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sandler et al. 2006 (ECOG E4599) 	2001-2004 	Non-randomized part of phase 3 RCT	 	
Patel et al. 2013 (PointBreak) 	2008-2012 	Non-randomized part of phase 3 RCT	 	
Zinner et al. 2015 (PRONOUNCE) 	2009-2013 	Non-randomized part of phase 3 RCT	 	
Ramalingam et al. 2019 (ECOG-ACRIN E5508) 	2010-2015 	Phase 3 (C) 	1. Pemetrexed2. Pemetrexed & Bevacizumab	Did not meet primary endpoint of OS
Seto et al. 2019 (COMPASS) 	2010-2015 	Phase 3 (C) 	Pemetrexed & Bevacizumab 	Might have shorter OSMedian OS: 19.6 vs 23.3 mo(HR 1.15, 95% CI 0.95-1.37)
Zhou et al. 2015 (BEYOND) 	2011-05-23 to 2012-05-03 	Non-randomized part of phase 3 RCT	 	
Stroyakovskiy et al. 2022 (BCD-021-2) 	2012-10-27 to not reported	Non-randomized part of phase 3 RCT	 	
Socinski et al. 2018 (IMpower150) 	2015-03 to 2016-12 	Non-randomized part of phase 3 RCT	 	
Reinmuth et al. 2019 (REFLECTIONS B7391003)	2015-05-21 to 2016-11-14 	Non-randomized part of phase 3 RCT	 	
Sugawara et al. 2021 (TASUKI-52) 	2017-2019 	Non-randomized part of phase 3 RCT	 	
Trukhin et al. 2021 (STELLA) 	2018-01-23 to 2019-03-05 	Non-randomized part of phase 3 RCT	 	
Syrigos et al. 2021 (AVANA) 	Not reported 	Non-randomized part of phase 3 RCT	 	
Verschraegen et al. 2022 (CT-P16 3.1) 	2019-02-01 to 2021-04-22 	Non-randomized part of phase 3 RCT	 	
====Preceding treatment====
*AVANA, COMPASS, CT-P16 3.1, ECOG-ACRIN E5508, IMpower150, PointBreak, PRONOUNCE, REFLECTIONS B7391003: First-line PacCBev x 4
*AVANA, BCD-021-2, BEYOND, CT-P16 3.1, ECOG E4599, IMpower150, REFLECTIONS B7391003, STELLA, TASUKI-52: First-line PacCBev x 6
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00021060
##Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00762034
##Dataset: Project Data Sphere
#PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00948675
#BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01364012
#IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02366143
##PRO analysis: Reck M, Wehler T, Orlandi F, Nogami N, Barone C, Moro-Sibilot D, Shtivelband M, González Larriba JL, Rothenstein J, Früh M, Yu W, Deng Y, Coleman S, Shankar G, Patel H, Kelsch C, Lee A, Piault E, Socinski MA. Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Aug 1;38(22):2530-2542. Epub 2020 May 27. link to original article link to PMC article EuroPMC
##Update: Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, Reck M. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021 Nov;16(11):1909-1924. Epub 2021 Jul 24. link to original article EuroPMC
# MAPLE: Thatcher N, Goldschmidt JH, Thomas M, Schenker M, Pan Z, Paz-Ares Rodriguez L, Breder V, Ostoros G, Hanes V. Efficacy and Safety of the Biosimilar ABP 215 Compared with Bevacizumab in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (MAPLE): A Randomized, Double-blind, Phase III Study. Clin Cancer Res. 2019 Apr 1;25(7):2088-2095. Epub 2019 Jan 7. Erratum in: Clin Cancer Res. 2019 May 15;25(10):3193. link to original article EuroPMC NCT01966003
#ECOG-ACRIN E5508: Ramalingam SS, Dahlberg SE, Belani CP, Saltzman JN, Pennell NA, Nambudiri GS, McCann JC, Winegarden JD, Kassem MA, Mohamed MK, Rothman JM, Lyss AP, Horn L, Stinchcombe TE, Schiller JH. Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508. J Clin Oncol. 2019 Sep 10;37(26):2360-2367. Epub 2019 Jul 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01107626
#REFLECTIONS B7391003: Reinmuth N, Bryl M, Bondarenko I, Syrigos K, Vladimirov V, Zereu M, Bair AH, Hilton F, Liau K, Kasahara K. PF-06439535 (a Bevacizumab Biosimilar) Compared with Reference Bevacizumab (Avastin®), Both Plus Paclitaxel and Carboplatin, as First-Line Treatment for Advanced Non-Squamous Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Study. BioDrugs. 2019 Oct;33(5):555-570. link to original article link to PMC article EuroPMC NCT02364999
#CIBI305A301: Yang Y, Wu B, Huang L, Shi M, Liu Y, Zhao Y, Wang L, Lu S, Chen G, Li B, Xie C, Fang J, Yang N, Zhang Y, Cui J, Song Y, Zhang C, Mei X, Cao B, Yang L, Cheng Y, Ying K, Sun T, Ren B, Yu Q, Liao Z, Pei Z, Wang M, Zhou J, Yu S, Feng G, Wan H, Wang H, Gao S, Wang J, An G, Geng Y, Ji Y, Yuan Y, Ma S, Jia Z, Hu M, Zhou H, Yu J, Sun X, Zhang L. Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer. Transl Lung Cancer Res. 2019 Dec;8(6):989-999. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02954172
#COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000004194
#STELLA: Trukhin D, Poddubskaya E, Andric Z, Makharadze T, Bellala RS, Charoentum C, Yañez Ruiz EP, Fulop A, Hyder Ali IA, Syrigos K, Katgi N, Lopez Chuken YA, Rumyana I, Reyes-Igama J, Costamilan RC, Del Campo García A, Florez A, Paravisini A, Millan S; STELLA Investigators. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03296163
#TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03117049
##Update: Lee KH, Lee JS, Sugawara S, Kang JH, Kim HR, Inui N, Hida T, Yoshida T, Tanaka H, Yang CT, Inoue T, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Takahashi S, Nakagawa K. First-line nivolumab plus platinum chemotherapy and bevacizumab for advanced nonsquamous non-small cell lung cancer: A 3-year follow-up of the phase 3 randomized TASUKI-52 trial. Lung Cancer. 2025 Jan;201:108109. link to original article link to EuroPMC
#AVANA: Syrigos K, Abert I, Andric Z, Bondarenko IN, Dvorkin M, Galic K, Galiulin R, Kuchava V, Sriuranpong V, Trukhin D, Zhavrid E, Fu D, Kassalow LM, Jones S, Bashir Z; AVANA Investigators. Efficacy and Safety of Bevacizumab Biosimilar FKB238 Versus Originator Bevacizumab: Results from AVANA, a Phase III Trial in Patients with Non-Squamous Non-Small-Cell Lung Cancer (non-sq-NSCLC). BioDrugs. 2021 Jul;35(4):417-428. Epub 2021 Jul 15. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT02810457
#BCD-021-2: Stroyakovskiy DL, Fadeeva NV, Matrosova MP, Shelepen KG, Adamchuk GA, Roy B, Nagarkar R, Kalloli M, Zhuravleva D, Voevodin GD, Shustova MS, Kryukov F. Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-021 with reference bevacizumab. BMC Cancer. 2022 Feb 1;22(1):129. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01763645
# CT-P16 3.1: Verschraegen C, Andric Z, Moiseenko F, Makharadze T, Shevnya S, Oleksiienko A, Yañez Ruiz E, Kim S, Ahn K, Park T, Park S, Ju H, Ohe Y. Candidate Bevacizumab Biosimilar CT-P16 versus European Union Reference Bevacizumab in Patients with Metastatic or Recurrent Non-Small Cell Lung Cancer: A Randomized Controlled Trial. BioDrugs. 2022 Nov;36(6):749-760. Epub 2022 Sep 28. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03676192
==Pemetrexed monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Paz-Ares et al. 2012 (PARAMOUNT) 	2008-2010 	Phase 3 (E-RT-esc) 	Placebo 	Longer PFS (primary endpoint)Median PFS: 4.1 vs 2.8 mo(HR 0.62, 95% CI 0.49-0.79)
Zinner et al. 2015 (PRONOUNCE) 	2009-2013 	Phase 3 (E-switch-ooc)	See link 	See link
Souquet et al. 2021 (IFCT-GFPC-1101)	2012-2016 	Phase 3 (C) 	Response-adapted maintenance	Did not meet primary endpoint of OS
====Preceding treatment====
*PARAMOUNT: First-line Cisplatin & Pemetrexed x 4; maintenance therapy started 21 to 42 days after cycle 4 day 1 of induction chemotherapy
*PRONOUNCE: First-line Carboplatin & Pemetrexed x 4
====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===
#PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00789373
##HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article EuroPMC
##Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##HRQoL analysis: Pujol JL, Paz-Ares L, de Marinis F, Dediu M, Thomas M, Bidoli P, Corral J, San Antonio B, Chouaki N, John W, Zimmermann A, Visseren-Grul C, Gridelli C. Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2014 Nov;15(6):418-25. Epub 2014 Jun 21. link to original article EuroPMC
#PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00948675
#IFCT-GFPC-1101: Souquet PJ, Audigier-Valette C, Molinier O, Cortot A, Margery J, Moreau L, Gervais R, Barlesi F, Pichon E, Zalcman G, Dumont P, Girard N, Poudenx M, Mazières J, Cadranel J, Debieuvre D, Dauba J, Langlais A, Morin F, Moro-Sibilot D, Westeel V, Pérol M. Tailoring maintenance chemotherapy upon response to induction chemotherapy as compared with pemetrexed continuation maintenance in advanced non-squamous NSCLC patients: Results of the IFCT-GFPC-1101 multicenter randomized phase III trial. Lung Cancer. 2022 Feb;164:84-90. Epub 2021 Nov 30. link to original article EuroPMC NCT01631136
==Pemetrexed & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Patel et al. 2013 (PointBreak)	2008-2012 	Non-randomized part of phase 3 RCT	 	
Seto et al. 2019 (COMPASS) 	2010-2015 	Phase 3 (E-esc) 	Bevacizumab	Might have longer OS (primary endpoint)Median OS: 23.3 vs 19.6 mo(HR 0.87, 95% CI 0.73-1.05)
====Preceding treatment====
*First-line PemCBev (AUC 6) x 4
====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 pemetrexed label
*Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycles
===References===
#PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00762034
##Dataset: Project Data Sphere
#COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000004194
=Advanced or metastatic disease, subsequent lines of therapy=
Note: this section includes regimens that were tested in second-line and beyond.
==Docetaxel monotherapy==
===Regimen variant #1, 75 mg/m2 q3wk, limited duration===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gerber et al. 2018 (SUNRISE)	2013-2016 	Phase 3 (C)	Docetaxel & Bavituximab	Did not meet primary endpoint of OSMedian OS: 10.9 vs 10.5 mo(HR 0.94, 95% CI 0.78-1.14)
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
===Regimen variant #2, 75 mg/m2 q3wk, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Borghaei et al. 2015 (CheckMate 057)	2012-2015 	Phase 3 (C)	Nivolumab 	Shorter OSMedian OS: 9.4 vs 12.2 mo(HR 1.37, 96% CI 1.12-1.69)
Cortot et al. 2020 (ULTIMATE) 	2013-05-31 to 2014-08-13	Phase 3 (C)	Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 3.9 vs 5.4 mo(HR 1.64, 95% CI 1.16-2.27)
Steendam et al. 2021 (NVALT-18) 	2016-2018 	Phase 3 (C)	Docetaxel & Erlotinib 	Longer PFS (primary endpoint)Median PFS: 4 vs 1.9 mo(aHR 0.40, 95% CI 0.18-0.86)Longer OS (secondary endpoint)Median OS: 10.6 vs 4.7 mo(aHR 0.27, 95% CI 0.11-0.68)
Awaiting publication (CARMEN-LC03) 	2020-ongoing 	Phase 3 (C)	Tusamitamab ravtansine 	TBD if different co-primary endpoints of PFS/OS
====Biomarker eligibility criteria====
*CARMEN-LC03: CEACAM5+
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
#CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01673867
##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 EuroPMC
##HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article EuroPMC
##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 EuroPMC
#SUNRISE: Gerber DE, Horn L, Boyer M, Sanborn R, Natale R, Palmero R, Bidoli P, Bondarenko I, Germonpre P, Ghizdavescu D, Kotsakis A, Lena H, Losonczy G, Park K, Su WC, Tang M, Lai J, Kallinteris NL, Shan JS, Reck M, Spigel DR. Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer. Ann Oncol. 2018 Jul 1;29(7):1548-1553. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01999673
# ULTIMATE: Cortot AB, Audigier-Valette C, Molinier O, Le Moulec S, Barlesi F, Zalcman G, Dumont P, Pouessel D, Poulet C, Fontaine-Delaruelle C, Hiret S, Dixmier A, Renault PA, Becht C, Raffy O, Dayen C, Mazieres J, Pichon E, Langlais A, Morin F, Moro-Sibilot D, Besse B. Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study. Eur J Cancer. 2020 May;131:27-36. Epub 2020 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01763671
# NVALT-18: Steendam CMJ, Peric R, van Walree NC, Youssef M, Schramel FMNH, Brocken P, van Putten JWG, van der Noort V, Veerman GDM, Koolen SLW, Groen HJM, Dingemans AC, Mathijssen RHJ, Smit EF, Aerts JGJV; NVALT Study Group. Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma. Lung Cancer. 2021 Oct;160:44-49. Epub 2021 Aug 4. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02775006
#CARMEN-LC03: NCT04154956
==Gefitinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Urata et al. 2016 (WJOG 5108L)	2009-2012 	Phase 3 (E-switch-ic)	Erlotinib 	Inconclusive whether non-inferior PFS
====Targeted therapy====
*Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
===References===
#WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000002014
==Nintedanib & Pemetrexed==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hanna et al. 2016 (LUME-Lung 2)	2008-2011 	Phase 3 (E-esc)	Pemetrexed	Seems to have longer PFS (primary endpoint)Median PFS: 4.4 vs 3.6 mo(HR 0.83, 95% CI 0.70-0.99)
====Targeted therapy====
*Nintedanib (Vargatef) 200 mg PO twice per day on days 2 to 21, taken after food
====Chemotherapy====
*Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
===References===
#LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00806819
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Borghaei et al. 2015 (CheckMate 057)	2012-2015 	Phase 3 (E-RT-switch-ooc)	Docetaxel 	Longer OS (primary endpoint)Median OS: 12.2 vs 9.4 mo(HR 0.73, 96% CI 0.59-0.89)
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
**Notably, 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.
14-day cycles
===References===
#CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01673867
##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 EuroPMC
##HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article EuroPMC
##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 EuroPMC
==Paclitaxel & Bevacizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Cortot et al. 2020 (ULTIMATE)	2013-05-31 to 2014-08-13	Phase 3 (E-esc)	Docetaxel 	Longer PFS (primary endpoint)Median PFS: 5.4 vs 3.9 mo(HR 0.61, 95% CI 0.44-0.86)
====Chemotherapy====
*Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
===References===
# ULTIMATE: Cortot AB, Audigier-Valette C, Molinier O, Le Moulec S, Barlesi F, Zalcman G, Dumont P, Pouessel D, Poulet C, Fontaine-Delaruelle C, Hiret S, Dixmier A, Renault PA, Becht C, Raffy O, Dayen C, Mazieres J, Pichon E, Langlais A, Morin F, Moro-Sibilot D, Besse B. Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study. Eur J Cancer. 2020 May;131:27-36. Epub 2020 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01763671
==Pemetrexed monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hanna et al. 2016 (LUME-Lung 2)	2008-2011 	Phase 3 (C)	Nintedanib & Pemetrexed	Seems to have shorter PFSMedian PFS: 3.6 vs 4.4 mo(HR 1.20, 95% CI 1.01-1.43)
====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===
#LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00806819
==Sorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Paz-Ares et al. 2015 (MISSION)	2009 to not reported	Phase 3 (E-esc)	Placebo 	Did not meet primary endpoint of OS
Note: although the primary endpoinat (OS) was negative overall, the authors note that the subgroup of patients with known EGFR mutations treated with sorafenib had significantly longer survival (p=0.002).
====Targeted therapy====
*Sorafenib (Nexavar) 400 mg PO twice per day
Continued indefinitely
===References===
#MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00863746
Category:Non-small cell lung cancer regimens
Category:Histology-specific pages
Category:Non-small cell lung cancers