Non-small cell lung cancer - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main NSCLC page for regimens that include active anticancer treatment.
=Neoadjuvant therapy=
==No neoadjuvant therapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mattson et al. 2003 	1995-1999 	Phase 3 (C)	Docetaxel 	Did not meet primary endpoint of OS
Gilligan et al. 2007 (MRC LU22) 	1997-2005 	Phase 3 (C)	Platinum doublet 	Did not meet primary endpoint of OS
Pisters et al. 2010 (SWOG S9900)	1999-2004 	Phase 3 (C)	Carboplatin & Paclitaxel (CP)	Did not meet primary endpoint of OS
Scagliotti et al. 2011 (CHEST) 	2000-2004 	Phase 3 (C)	Cisplatin & Gemcitabine 	Seems to have shorter PFS (primary endpoint)Median PFS: 2.2 vs 4 y(aHR 1.43, 95% CI 1.03-2.00)Shorter OS (secondary endpoint)Median OS: 4.8 vs 7.8 y(aHR 1.59, 95% CI 1.09-2.33)
These trials included patients with Stage IB to IIIA NSCLC. No preoperative therapy is given.
====Subsequent treatment====
*Complete resection
===References===
# Mattson KV, Abratt RP, ten Velde G, Krofta K. Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomised phase III study. Ann Oncol. 2003 Jan;14(1):116-22. link to original article EuroPMC
# MRC LU22: Gilligan D, Nicolson M, Smith I, Groen H, Dalesio O, Goldstraw P, Hatton M, Hopwood P, Manegold C, Schramel F, Smit H, van Meerbeeck J, Nankivell M, Parmar M, Pugh C, Stephens R. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007 Jun 9;369(9577):1929-37. link to original article EuroPMC NCT00003159
# SWOG S9900: Pisters KM, Vallières E, Crowley JJ, Franklin WA, Bunn PA Jr, Ginsberg RJ, Putnam JB Jr, Chansky K, Gandara D. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol. 2010 Apr 10;28(11):1843-9. Epub 2010 Mar 15. link to original article link to PMC article EuroPMC NCT00004011
# CHEST: Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. link to original article EuroPMC NCT00191126
=Adjuvant therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
McKneally et al. 1976 	1973 to not reported	Phase 3 (C)	Intrapleural BCG 	Shorter OS
Feld et al. 1993 (LCSG 801) 	1980-1986 	Phase 3 (C)	CAP 	Did not meet endpoint of OS
Ohta et al. 1993 (JCOG8601) 	1986-10 to 1989-01 	Phase 3 (C)	Cisplatin & Vindesine 	Did not meet endpoint of OS
Figlin & Piantodosi 1994 (LCSG 853) 	Not reported 	Phase 3 (C)	CAP 	Did not meet endpoint of OS
Nakagawa et al. 2005 (WJSG4) 	1991-1994 	Phase 3 (C)	UFT 	Did not meet primary endpoint of OS
Kato et al. 2004 	1994-1997 	Phase 3 (C)	UFT 	Seems to have shorter OSOS60: 85% vs 88%(HR 1.41, 95% CI 1.02-1.92)
Tada et al. 2004 (JCOG9304) 	1994-1998 	Phase 3 (C)	Cisplatin & Vindesine 	Did not meet endpoint of OS50%
Scagliotti et al. 2003 (ALPI) 	1994-1999 	Phase 3 (C)	MVP 	Did not meet primary endpoint of OS
Douillard et al. 2006 (ANITA) 	1994-2000 	Phase 3 (C)	Cisplatin & Vinorelbine 	Seems to have shorter OS (primary endpoint)Median OS: 43.7 vs 65.7 mo(aHR 1.25, 95% CI 1.04-1.52)
Winton et al. 2005 (JBR.10) 	1994-2001 	Phase 3 (C)	Cisplatin & Vinorelbine 	Shorter OSMedian OS: 73 vs 94 mo(HR 1.45, 95% CI 1.10-1.92)
Arriagada et al. 2004 (IALT) 	1995-2000 	Phase 3 (C)	1a. Cisplatin & Etoposide1b. Cisplatin & Vinblastine1c. Cisplatin & Vindesine1d. Cisplatin & Vinorelbine	Seems to have shorter OS (primary endpoint)OS60: 40.4% vs 44.5%(HR 1.16, 95% CI 1.02-1.32)
Strauss et al. 2008 (CALGB 9633) 	1996-2003 	Phase 3 (C)	Carboplatin & Paclitaxel 	Did not meet primary endpoint of OSMedian OS: 78 vs 95 mo(HR 1.20, 90% CI 0.93-1.56)
Felip et al. 2010 (NATCH) 	2000-2007 	Phase 3 (C)	1. Carboplatin & Paclitaxel; adjuvant2. Carboplatin & Paclitaxel; neoadjuvant 	Did not meet primary endpoint of DFS
Awaiting publication (ECOG-ACRIN E4512)	2014-ongoing 	Phase 3 (C)	Crizotinib 	TBD if different primary endpoint of OS
Felip et al. 2021 (IMpower010) 	2015-2018 	Phase 3 (C)	Atezolizumab 	Seems to have shorter DFS (primary endpoint)Median DFS: 37.2 vs NYR mo(HR 1.23, 95% CI 1.01-1.49)
Awaiting publication (ANVIL) 	2016-ongoing 	Phase 3 (C)	Nivolumab 	TBD if different co-primary endpoints of DFS/OS
No systemic treatment after surgery.
====Preceding treatment====
*Surgery
===References===
# McKneally MF, Maver C, Kausel HW. Regional immunotherapy of lung cancer with intrapleural BCG. Lancet. 1976 Feb 21;1(7956):377-9. link to original article EuroPMC
# LCSG 801: Feld R, Rubinstein L, Thomas PA; Lung Cancer Study Group. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. J Natl Cancer Inst. 1993 Feb 17;85(4):299-306. link to original article EuroPMC
# JCOG8601: Ohta M, Tsuchiya R, Shimoyama M, Sawamura K, Mori T, Miyazawa N, Suemasu K, Watanabe Y, Tomita M, Terashima M; Japan Clinical Oncology Group. Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer: results of a randomized prospective study. J Thorac Cardiovasc Surg. 1993 Oct;106(4):703-8. link to original article EuroPMC
# LCSG 853: Figlin RA, Piantodosi S. A phase 3 randomized trial of immediate combination chemotherapy vs delayed combination chemotherapy in patients with completely resected stage II and III non-small cell carcinoma of the lung. Chest. 1994 Dec;106(6 Suppl):310S-312S. link to original article EuroPMC
# ALPI: Scagliotti GV, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M; Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61. link to original article EuroPMC
# IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article EuroPMC NCT00002823
## Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article EuroPMC
# JCOG9304: Tada H, Tsuchiya R, Ichinose Y, Koike T, Nishizawa N, Nagai K, Kato H. A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304). Lung Cancer. 2004 Feb;43(2):167-73. link to original article EuroPMC
# 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 EuroPMC
# WJSG4: Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H; West Japan Study Group for Lung Cancer Surgery. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG)--the 4th study. Ann Oncol. 2005 Jan;16(1):75-80. link to original article EuroPMC
# JBR.10: Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article EuroPMC NCT00002583
## Update: Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. link to original article link to PMC article EuroPMC
# ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article EuroPMC NCT00576914
# CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article link to PMC article EuroPMC NCT00002852
# NATCH: Felip E, Rosell R, Maestre JA, Rodríguez-Paniagua JM, Morán T, Astudillo J, Alonso G, Borro JM, González-Larriba JL, Torres A, Camps C, Guijarro R, Isla D, Aguiló R, Alberola V, Padilla J, Sánchez-Palencia A, Sánchez JJ, Hermosilla E, Massuti B; Spanish Lung Cancer Group. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010 Jul 1;28(19):3138-45. Epub 2010 Jun 1. link to original article EuroPMC NCT00913705
#IMpower010: Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, Chen YM, Chella A, Sugawara S, Voong D, Wu F, Yi J, Deng Y, McCleland M, Bennett E, Gitlitz B, Wakelee H; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357. Epub 2021 Sep 20. Erratum in: Lancet. 2021 Sep 23. link to original article EuroPMC NCT02486718
##Update: Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, Chella A, Reck M, Goloborodko O, Huang M, Belleli R, McNally V, Srivastava MK, Bennett E, Gitlitz BJ, Wakelee HA. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023 Oct;34(10):907-919. Epub 2023 Jul 17. link to original article EuroPMC
#ANVIL: NCT02595944
#ECOG-ACRIN E4512: NCT02201992
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Karp et al. 2013 (ECOG E5597) 	2000-10-06 to 2009-11-05	Phase 3 (C)	Selenium 	Did not meet primary endpoint of lung SPT rate
Goss et al. 2013 (NCIC CTG BR.19) 	2002-2011 	Phase 3 (C)	Gefitinib 	Did not meet primary endpoint of OSMedian OS: NYR vs 5.1 years(HR 0.81, 95% CI 0.61-1.06)
Kelly et al. 2015 (RADIANT) 	2007-2010 	Phase 3 (C)	Erlotinib 	Did not meet primary endpoint of DFSMedian DFS: 48.2 vs 50.5 mo(HR 1.11, 95% CI 0.91-1.35)
Seely et al. 2021 (AMPLCaRe) 	2007-10 to 2015-09 	Phase 3 (C)	Melatonin 	Did not meet primary endpoint of DFS24
Vansteenkiste et al. 2016 (MAGRIT) 	2007-10-18 to 2012-07-17	Phase 3 (C)	recMAGE-A3 with AS15 immunostimulant	Did not meet primary endpoint of DFSMedian DFS: 57.9 vs 60.5 mo(HR 0.98, 95% CI 0.85-1.12)
Awaiting publication (NCIC CTG BR.31)	2014-ongoing 	Phase 3 (C)	Durvalumab 	TBD if different primary endpoint of DFS
O'Brien et al. 2022 (PEARLS) 	2016-2020 	Phase 3 (C)	Pembrolizumab 	Shorter DFSMedian DFS: 42 vs 53.6 mo(HR 1.32, 95% CI 1.1-1.59)
Garon et al. 2023 (CANOPY-A) 	2018-04 to 2021-12 	Phase 3 (C)	Canakinumab 	Did not meet primary endpoint of DFS
No active antineoplastic treatment after surgery.
====Biomarker eligibility criteria====
*MAGRIT: MAGE-A3-positive
====Preceding treatment====
*Surgery
===References===
# NCIC-CTG BR.19: Goss GD, O'Callaghan C, Lorimer I, Tsao MS, Masters GA, Jett J, Edelman MJ, Lilenbaum R, Choy H, Khuri F, Pisters K, Gandara D, Kernstine K, Butts C, Noble J, Hensing TA, Rowland K, Schiller J, Ding K, Shepherd FA. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013 Sep 20;31(27):3320-6. Epub 2013 Aug 26. link to original article link to PMC article EuroPMC NCT00049543
#ECOG E5597: Karp DD, Lee SJ, Keller SM, Wright GS, Aisner S, Belinsky SA, Johnson DH, Johnston MR, Goodman G, Clamon G, Okawara G, Marks R, Frechette E, McCaskill-Stevens W, Lippman SM, Ruckdeschel J, Khuri FR. Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597. J Clin Oncol. 2013 Nov 20;31(33):4179-87. Epub 2013 Sep 3. link to original article link to PMC article EuroPMC NCT00008385
# RADIANT: Kelly K, Altorki NK, Eberhardt WE, O'Brien ME, Spigel DR, Crinò L, Tsai CM, Kim JH, Cho EK, Hoffman PC, Orlov SV, Serwatowski P, Wang J, Foley MA, Horan JD, Shepherd FA. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol. 2015 Dec 1;33(34):4007-14. Epub 2015 Aug 31. link to original article EuroPMC NCT00373425
#MAGRIT: Vansteenkiste JF, Cho BC, Vanakesa T, De Pas T, Zielinski M, Kim MS, Jassem J, Yoshimura M, Dahabreh J, Nakayama H, Havel L, Kondo H, Mitsudomi T, Zarogoulidis K, Gladkov OA, Udud K, Tada H, Hoffman H, Bugge A, Taylor P, Gonzalez EE, Liao ML, He J, Pujol JL, Louahed J, Debois M, Brichard V, Debruyne C, Therasse P, Altorki N. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Jun;17(6):822-835. Epub 2016 Apr 27. link to original article EuroPMC NCT00480025
#AMPLCaRe: Seely D, Legacy M, Auer RC, Fazekas A, Delic E, Anstee C, Angka L, Kennedy MA, Tai LH, Zhang T, Maziak DE, Shamji FM, Sundaresan RS, Gilbert S, Villeneuve PJ, Ashrafi AS, Inculet R, Yasufuku K, Waddell TK, Finley C, Shargall Y, Plourde M, Fergusson DA, Ramsay T, Seely AJE. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): A randomized placebo controlled clinical trial. EClinicalMedicine. 2021 Feb 27;33:100763. link to original article link to PMC article EuroPMC NCT00668707
# PEARLS: O'Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, Esteban E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee JS, Nakagawa K, Yang J, Samkari A, Keller SM, Mauer M, Jha N, Stahel R, Besse B, Peters S; EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022 Oct;23(10):1274-1286. Epub 2022 Sep 9. link to original article EuroPMC NCT02504372
#CANOPY-A: Garon EB, Lu S, Goto Y, De Marchi P, Paz-Ares L, Spigel DR, Thomas M, Yang JC, Ardizzoni A, Barlesi F, Orlov S, Yoshioka H, Mountzios G, Khanna S, Bossen C, Carbini M, Turri S, Myers A, Cho BC. Canakinumab as Adjuvant Therapy in Patients With Completely Resected Non-Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized Clinical Trial. J Clin Oncol. 2024 Jan 10;42(2):180-191. Epub 2023 Oct 3. link to original article EuroPMC NCT03447769
# NCIC-CTG BR.31: NCT02273375
=Induction chemotherapy for locally advanced disease=
==No induction==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Vokes et al. 2007 (CALGB 39801)	1998-2002 	Phase 3 (C)	Carboplatin & Paclitaxel	Might have lower OS50%Median OS: 12 vs 14 mo(aHR 1.22, 95% CI 0.95-1.56)
No treatment given prior to definitive therapy.
====Subsequent treatment====
*Definitive CP & RT
===References===
# Kim TY, Yang SH, Lee SH, Park YS, Im YH, Kang WK, Ha SH, Park CI, Heo DS, Bang YJ, Kim NK. A phase III randomized trial of combined chemoradiotherapy versus radiotherapy alone in locally advanced non-small-cell lung cancer. Am J Clin Oncol. 2002 Jun;25(3):238-43. link to original article EuroPMC
# CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; CALGB. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article EuroPMC NCT00003387
=Consolidation after definitive therapy for inoperable disease=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pines 1976 	1970-1973 	Randomized (C)	BCG 	Seems to have shorter OS
Carter et al. 2011 	1999-2002 	Phase 3 (C) 	Paclitaxel 	Might have longer OS
Hanna et al. 2008 (HOG Lun 01-24) 	2002-2006 	Phase 3 (C) 	Docetaxel 	Did not meet primary endpoint of OS
Gore et al. 2010 (RTOG 0214) 	2002-2007 	Phase 3 (C) 	Prophylactic cranial irradiation	Did not meet primary endpoint of OS
Li et al. 2014 	2005-2009 	Phase 3 (C) 	Prophylactic cranial irradiation	Seems to have shorter DFS
Flentje et al. 2016 (GILT) 	2005-2009 	Phase 3 (C) 	Cisplatin & Vinorelbine 	Did not meet primary endpoint of PFS
de Ruysscher et al. 2018 (NVALT-11/DLCRG-02)	2009-2015 	Phase 3 (C) 	Prophylactic cranial irradiation	Shorter time to symptomatic CNS metastases
No further treatment.
====Preceding treatment====
*Pines 1976: Definitive RT
*HOG Lun 01-24: Definitive EP & RT
*GILT: Definitive CVb & RT
*NVALT-11/DLCRG-02: Definitive therapy
===References===
# Pines A. A 5-year controlled study of BCG and radiotherapy inoperable lung cancer. Lancet. 1976 Feb 21;1(7956):380-1. link to original article EuroPMC
# HOG Lun 01-24: Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L; Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and US Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. link to original article EuroPMC NCT00216125
## Update: Jalal SI, Riggs HD, Melnyk A, Richards D, Agarwala A, Neubauer M, Ansari R, Govindan R, Bruetman D, Fisher W, Breen T, Johnson CS, Yu M, Einhorn L, Hanna N. Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology. Ann Oncol. 2012 Jul;23(7):1730-8. Epub 2011 Dec 9. link to original article EuroPMC
# RTOG 0214: Gore EM, Bae K, Wong SJ, Sun A, Bonner JA, Schild SE, Gaspar LE, Bogart JA, Werner-Wasik M, Choy H. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol. 2011 Jan 20;29(3):272-8. Epub 2010 Dec 6. Erratum in: J Clin Oncol. 2011 Aug 10;29(23):3204. link to original article link to PMC article EuroPMC NCT00048997
## Update: Sun A, Hu C, Wong SJ, Gore E, Videtic G, Dutta S, Suntharalingam M, Chen Y, Gaspar LE, Choy H. Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: a long-term update of the NRG Oncology/RTOG 0214 phase 3 randomized clinical trial. JAMA Oncol. 2019 Jun 1;5(6):847-855. Epub 2019 Mar 14. link to original article link to PMC article EuroPMC
# Carter DL, Garfield D, Hathorn J, Mundis R, Boehm KA, Ilegbodu D, Asmar L, Reynolds C. A randomized phase III trial of combined paclitaxel, carboplatin, and radiation therapy followed by weekly paclitaxel or observation for patients with locally advanced inoperable non-small-cell lung cancer. Clin Lung Cancer. 2012 May;13(3):205-13. Epub 2011 Dec 3. link to original article EuroPMC
# Li N, Zeng ZF, Wang SY, Ou W, Ye X, Li J, He XH, Zhang BB, Yang H, Sun HB, Fang Q, Wang BX. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann Oncol. 2015 Mar;26(3):504-9. Epub 2014 Dec 15. link to original article EuroPMC
# GILT: Flentje M, Huber RM, Engel-Riedel W, Andreas S, Kollmeier J, Staar S, Dickgreber N, Vaissiere N, De Almeida C, Edlich B, Fietkau R. GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer. Strahlenther Onkol. 2016 Apr;192(4):216-22. Epub 2016 Jan 25. link to original article EuroPMC
# NVALT-11/DLCRG-02: De Ruysscher D, Dingemans AC, Praag J, Belderbos J, Tissing-Tan C, Herder J, Haitjema T, Ubbels F, Lagerwaard F, El Sharouni SY, Stigt JA, Smit E, van Tinteren H, van der Noort V, Groen HJM. Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: a randomized phase III NVALT-11/DLCRG-02 study. J Clin Oncol. 2018 Aug 10;36(23):2366-2377. Epub 2018 May 22. link to original article EuroPMC NCT01282437
=Maintenance after definitive therapy for inoperable disease=
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kelly et al. 2008 (SWOG S0023) 	2001-2005 	Phase 3 (C)	Gefitinib 	Longer OS (primary endpoint)Median OS: 35 vs 23 mo(HR 0.63, 95% CI 0.44-0.91)
Butts et al. 2013 (STARTNSCLC) 	2007-2011 	Phase 3 (C)	Tecemotide 	Did not meet primary endpoint of OS
Antonia et al. 2017 (PACIFIC) 	2014-2016 	Phase 3 (C)	Durvalumab 	Shorter OS1Median OS: 29.1 vs 47.5 mo(HR 1.39, 95% CI 1.12-1.69)
Zhou et al. 2022 (GEMSTONE-301)	2018-2020 	Phase 3 (C)	Sugemalimab	Shorter PFSMedian PFS: 5.8 vs 9 mo(HR 1.56, 95% CI 1.18-2.08)
1Reported efficacy for PACIFIC is based on the 2022 update.
No further antineoplastic treatment. Note that there is another trial named START in gastric cancer.
====Preceding treatment====
*SWOG S0023: Definitive EP & RT, then Docetaxel consolidation x 3
*STARTNSCLC: Definitive Chemoradiotherapy (type not specified in protocol)
*PACIFIC: "Two or more cycles (defined according to local practice) of platinum-based chemoradiotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 6600 cGy), in which the mean dose to the lung was less than 2000 cGy, the V20 (the volume of lung parenchyma that received 2000 cGy or more) was less than 35%, or both."
*GEMSTONE-301: Concurrent or sequential definitive chemoradiotherapy
===References===
# SWOG S0023: Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. link to original article EuroPMC NCT00020709
# START: Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Rodrigues Pereira J, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. Epub 2013 Dec 9. link to original article EuroPMC NCT00409188
## Update: Mitchell P, Thatcher N, Socinski MA, Wasilewska-Tesluk E, Horwood K, Szczesna A, Martín C, Ragulin Y, Zukin M, Helwig C, Falk M, Butts C, Shepherd FA. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol. 2015 Jun;26(6):1134-42. Epub 2015 Feb 26. link to original article EuroPMC
## Dataset: Project Data Sphere
#PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article EuroPMC NCT02125461
##Update: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. link to original article EuroPMC
##PRO analysis: Hui R, Özgüroğlu M, Villegas A, Daniel D, Vicente D, Murakami S, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Gray JE, Rydén A, Viviers L, Poole L, Zhang Y, Dennis PA, Antonia SJ. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol. 2019 Dec;20(12):1670-1680. Epub 2019 Oct 7. link to original article EuroPMC
##Update: Gray JE, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, Cho BC, Planchard D, Paz-Ares L, Faivre-Finn C, Vansteenkiste JF, Spigel DR, Wadsworth C, Taboada M, Dennis PA, Özgüroğlu M, Antonia SJ. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC. J Thorac Oncol. 2020 Feb;15(2):288-293. Epub 2019 Oct 14. link to original article link to PMC article EuroPMC
##Update: Faivre-Finn C, Vicente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste JF, Spigel DR, Garassino MC, Reck M, Senan S, Naidoo J, Rimner A, Wu YL, Gray JE, Özgüroğlu M, Lee KH, Cho BC, Kato T, de Wit M, Newton M, Wang L, Thiyagarajah P, Antonia SJ. Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial. J Thorac Oncol. 2021 May;16(5):860-867. Epub 2021 Jan 19. link to original article EuroPMC
##Update: Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, Vansteenkiste JF, Garassino MC, Hui R, Quantin X, Rimner A, Wu YL, Özgüroğlu M, Lee KH, Kato T, de Wit M, Kurata T, Reck M, Cho BC, Senan S, Naidoo J, Mann H, Newton M, Thiyagarajah P, Antonia SJ. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022 Apr 20;40(12):1301-1311. Epub 2022 Feb 2. link to original article link to PMC article EuroPMC
#GEMSTONE-301: Zhou Q, Chen M, Jiang O, Pan Y, Hu D, Lin Q, Wu G, Cui J, Chang J, Cheng Y, Huang C, Liu A, Yang N, Gong Y, Zhu C, Ma Z, Fang J, Chen G, Zhao J, Shi A, Lin Y, Li G, Liu Y, Wang D, Wu R, Xu X, Shi J, Liu Z, Cui N, Wang J, Wang Q, Zhang R, Yang J, Wu YL. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):209-219. Epub 2022 Jan 14. link to original article EuroPMC NCT03728556
#PACIFIC-5: NCT03706690
#TQB2450-III-05: NCT04325763
=Advanced or metastatic disease, first-line=
==Best supportive care==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Durrant et al. 1971 	1960-1965 	Phase 3 (C)	1. RT2. Mechlorethamine 3. Mechlorethamine & RT 	Did not meet endpoint of OS
Laing et al. 1975 	1970-1973 	Phase 3 (C)	1. Procarbazine2. MVPP 	Seems to have longer OS
Rapp et al. 1988 	1983-1986 	Phase 3 (C)	Cisplatin & Vindesine 	Shorter OS
Cartei et al. 1993 	1984 to not reported	Phase 3 (C)	Cisplatin, Cyclophosphamide, Mitomycin 	Shorter OS
Cullen et al. 1999 (MIC2) 	1988-1996 	Phase 3 (C)	MIC 	Seems to have shorter OS
De Marinis et al. 1999 	1990-01 to 1992-09 	Phase 3 (C)	1. Lonidamine2. Lonidamine & Vindesine 3. Vindesine	Did not meet efficacy endpoint
Ranson et al. 2000 	1995-1997 	Phase 3 (C)	Paclitaxel 	Seems to have shorter OSMedian OS: 4.8 vs 6.8 mo(HR 1.47, 95% CI 1.00-2.04)
Gridelli et al. 1999 (ELVIS)	1996-04 to 1997-11 	Phase 3 (C)	Vinorelbine 	Seems to have shorter OS
No active antineoplastic treatment.
===References===
# Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet. 1971 Apr 10;1(7702):715-9. link to original article EuroPMC
# Laing AH, Berry RJ, Newman CR, Peto J. Treatment of inoperable carcinoma of bronchus. Lancet. 1975 Dec 13;2(7946):1161-4. link to original article EuroPMC
# Rapp E, Pater JL, Willan A, Cormier Y, Murray N, Evans WK, Hodson DI, Clark DA, Feld R, Arnold AM, Ayoub JI, Wilson KS, Latreille J, Wierzbicki RF, Hill DP. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin Oncol. 1988 Apr;6(4):633-41. link to original article EuroPMC
# Cartei G, Cartei F, Cantone A, Causarano D, Genco G, Tobaldin A, Interlandi G, Giraldi T. Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer. J Natl Cancer Inst. 1993 May 19;85(10):794-800. link to original article EuroPMC
# ELVIS: Gridelli C, Perrone F, Gallo C; Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article EuroPMC
# De Marinis F, Rinaldi M, Ardizzoni A, Bruzzi P, Pennucci MC, Portalone L, D'Aprile M, Ripanti P, Romano F, Belli M, Altavilla G, Migliorino MR, Rosso R, Salvati F; Italian Lung Cancer Task Force. The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Tumori. 1999 May-Jun;85(3):177-82. link to original article EuroPMC
# Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, Ferry DR, Rudd RM, Spiro SG, Cook JE, Trask C, Bessell E, Connolly CK, Tobias J, Souhami RL. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol. 1999 Oct;17(10):3188-94. link to original article EuroPMC
# Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, Anderson H, Gustafson N, Jeynes A, Gallant G, Washington T, Thatcher N. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2000 Jul 5;92(13):1074-80. link to original article EuroPMC
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cormier et al. 1982 	Not reported 	Phase 3 (C)	MACC 	Shorter OS
Lee et al. 2012 (TOPICAL)	2005-2009 	Phase 3 (C)	Erlotinib 	Did not meet primary endpoint of OSMedian OS: 3.6 vs 3.7 mo(HR 1.06, 95% CI 0.91-1.23)
No active antineoplastic treatment.
===References===
# Cormier Y, Bergeron D, La Forge J, Lavandier M, Fournier M, Chenard J, Desmeules M. Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma. Cancer. 1982 Sep 1;50(5):845-9. link to original article EuroPMC
# TOPICAL: Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, Marshall E, Woll PJ, Hatton M, Lal R, Jones R, Toy E, Chao D, Middleton G, Bulley S, Ngai Y, Rudd R, Hackshaw A, Boshoff C. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1161-70. Epub 2012 Oct 16. link to original article link to PMC article EuroPMC NCT00275132
=Maintenance after first-line therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pérol et al. 2012 (IFCT-GFPC 0502)	2006-2009 	Phase 3 (C)	1. Erlotinib 	Shorter PFS
Pérol et al. 2012 (IFCT-GFPC 0502)	2006-2009 	Phase 3 (C)	2. Gemcitabine 	Shorter PFS
Rodriguez et al. 2016 	2006-2012 	Phase 3 (C)	CIMAvax-EGF 	Might have shorter OS
Zhang et al. 2021 (TFINE) 	2009-2011 	Phase 3 (C)	Docetaxel 	Shorter PFSMedian PFS: 3 vs 5.8 mo(HR 1.75, 95% CI 1.25-2.50)
Quoix et al. 2020 (MODEL) 	2013-2016 	Phase 3 (C)	1. Gemcitabine2. Pemetrexed	Did not meet primary endpoint of OS
No further treatment after first-line therapy.
====Preceding treatment====
*IFCT-GFPC 0502: First-line Cisplatin & Gemcitabine x 4
*Rodriguez et al. 2016: First-line platinum-based chemotherapy x 4 to 6
*TFINE: First-line DC; DC60 x 4 versus DC; DC75 x 4
*MODEL: First-line CP x 4
===References===
#Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 May;52(2):155-63. Epub 2006 Mar 29. link to original article EuroPMC
# IFCT-GFPC 0502: Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B; IFCT. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original articleEuroPMC NCT00300586
# Rodriguez PC, Popa X, Martínez O, Mendoza S, Santiesteban E, Crespo T, Amador RM, Fleytas R, Acosta SC, Otero Y, Romero GN, de la Torre A, Cala M, Arzuaga L, Vello L, Reyes D, Futiel N, Sabates T, Catala M, Flores YI, Garcia B, Viada C, Lorenzo-Luaces P, Marrero MA, Alonso L, Parra J, Aguilera N, Pomares Y, Sierra P, Rodríguez G, Mazorra Z, Lage A, Crombet T, Neninger E. A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non-Small Cell Lung Cancer Patients. Clin Cancer Res. 2016 Aug 1;22(15):3782-90. Epub 2016 Feb 29. link to original article EuroPMC RPCEC00000161
# MODEL: Quoix E, Audigier-Valette C, Lavolé A, Molinier O, Westeel V, Barlesi F, Le Treut J, Pichon E, Dauba J, Otto J, Moreau L, Madelaine J, Dumont P, Margery J, Debieuvre D, Renault PA, Pujol JL, Langlais A, Morin F, Moro-Sibilot D, Souquet PJ; IFCT. Switch maintenance chemotherapy versus observation after carboplatin and weekly paclitaxel doublet chemotherapy in elderly patients with advanced non-small cell lung cancer: IFCT-1201 MODEL trial. Eur J Cancer. 2020 Oct;138:193-201. Epub 2020 Sep 6. link to original article EuroPMC NCT01850303
# TFINE: Zhang L, Lu S, Cheng Y, Hu Z, Wu YL, Chen Z, Chen G, Liu X, Yang J, Zhang L, Chen J, Huang M, Tao M, Cheng G, Huang C, Zhou C, Zhang W, Zhao H, Sun Y. Docetaxel maintenance therapy versus best supportive care after first-line chemotherapy with different dose docetaxel plus cisplatin for advanced non-small cell lung cancer (TFINE study, CTONG-0904): an open-label, randomized, phase III trial. Ann Transl Med. 2021 Feb;9(4):338. link to original article link to PMC article EuroPMC NCT01038661
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Johnson et al. 2008 (NCCTG 97-24-51)	1999-2004 	Phase 3 (C)	CAI 	Did not meet primary endpoint of OS
Lee et al. 2009 	2003-2005 	Phase 3 (C)	Thalidomide 	Did not meet primary endpoint of OS
Koch et al. 2011 (CYCLUS) 	2003-2006 	Phase 3 (C)	Celecoxib 	Did not meet primary endpoint of OS
Gaafar et al. 2011 (EORTC 08021) 	2004-2009 	Phase 3 (C)	Gefitinib 	Did not meet primary endpoint of OSMedian OS: 9.4 vs 10.9 mo(HR 1.20, 95% CI 0.87-1.67)
Ciuleanu et al. 2009 (JMEN) 	2005-2007 	Phase 3 (C)	Pemetrexed 	Shorter PFS (primary endpoint)Median PFS: 2.6 vs 4.3 mo(HR 2.00, 95% CI 1.64-2.38)Shorter OS (secondary endpoint)Median OS: 10.6 vs 13.4 mo(HR 1.27, 95% CI 1.05-1.54)
Cappuzzo et al. 2010 (SATURN) 	2005-2008 	Phase 3 (C)	Erlotinib 	Shorter PFSMedian PFS: 11.1 vs 12.3 weeks(HR 1.41, 95% CI 1.22-1.61)
Zhang et al. 2012 (INFORM) 	2008-09-28 to 2009-08-11	Phase 3 (C)	Gefitinib 	Shorter PFSMedian PFS: 2.6 vs 4.8 mo(HR 2.38, 95% CI 1.82-3.03)
Paz-Ares et al. 2012 (PARAMOUNT) 	2008-2010 	Phase 3 (C)	Pemetrexed 	Shorter PFSMedian PFS: 2.8 vs 4.1 mo(HR 1.61, 95% CI 1.27-2.04)
Giaccone et al. 2015 (STOP) 	2008-2012 	Phase 3 (C)	Belagenpumatucel-L	Did not meet primary endpoint of OS
Baggstrom et al. 2017 (CALGB 30607) 	2008-2013 	Phase 3 (C)	Sunitinib 	Shorter PFSMedian PFS: 2.6 vs 4.3 mo(HR 1.61, 95% CI 1.22-2.13)
O'Brien et al. 2015 (EORTC 08092) 	2011-2013 	Phase 3 (C)	Pazopanib 	Did not meet primary endpoint of OS
Cicènas et al. 2016 (IUNO) 	2011-2014 	Phase 3 (C)	See link 	See link
No further antineoplastic treatment after first-line therapy. Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks.
====Preceding treatment====
*JMEN, SATURN, EORTC 08021, INFORM, IUNO: First-line platinum-doublet therapy x 4
*Lee et al. 2009: First-line GCb x 4
*PARAMOUNT: First-line Cisplatin & Pemetrexed x 4
*STOP: First-line platinum-based chemotherapy
*CALGB 30607: First-line platinum-doublet therapy x 4, with or without bevacizumab
====Subsequent treatment====
*IUNO: Second-line erlotinib, after PD or intolerance
===References===
# NCCTG 97-24-51: Johnson EA, Marks RS, Mandrekar SJ, Hillman SL, Hauge MD, Bauman MD, Wos EJ, Moore DF, Kugler JW, Windschitl HE, Graham DL, Bernath AM Jr, Fitch TR, Soori GS, Jett JR, Adjei AA, Perez EA. Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Lung Cancer. 2008 May;60(2):200-7. Epub 2007 Nov 28. link to original article EuroPMC NCT00003869
# JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. link to original article EuroPMC NCT00102804
##HRQoL analysis: Belani CP, Brodowicz T, Ciuleanu TE, Krzakowski M, Yang SH, Franke F, Cucevic B, Madhavan J, Santoro A, Ramlau R, Liepa AM, Visseren-Grul C, Peterson P, John WJ, Zielinski CC. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol. 2012 Mar;13(3):292-9. Epub 2012 Feb 14. link to original article EuroPMC
# Lee SM, Rudd R, Woll PJ, Ottensmeier C, Gilligan D, Price A, Spiro S, Gower N, Jitlal M, Hackshaw A. Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Nov 1;27(31):5248-54. Epub 2009 Sep 21. link to original article EuroPMC
# SATURN: Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010 Jun;11(6):521-9. Epub 2010 May 20. link to original article EuroPMC NCT00556712
# CYCLUS: Koch A, Bergman B, Holmberg E, Sederholm C, Ek L, Kosieradzki J, Lamberg K, Thaning L, Ydreborg SO, Sörenson S; Swedish Lung Cancer Study Group. Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: a double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group. Eur J Cancer. 2011 Jul;47(10):1546-55. Epub 2011 May 10. link to original article EuroPMC NCT00300729
# EORTC 08021: Gaafar RM, Surmont VF, Scagliotti GV, Van Klaveren RJ, Papamichael D, Welch JJ, Hasan B, Torri V, van Meerbeeck JP; EORTC Lung Cancer Group; Italian Lung Cancer Project. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer. 2011 Oct;47(15):2331-40. Epub 2011 Jul 28. link to original article EuroPMC NCT00091156
# 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 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 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
# INFORM: Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, Yang S, Liu X, Liu Y, Lu S, Wang J, Zhang S, Zhou C, Zhang X, Hayashi N, Wang M; INFORM investigators. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. Lancet Oncol. 2012 May;13(5):466-75. Epub 2012 Apr 17. link to original article EuroPMC NCT00770588
## Update: Zhao H, Fan Y, Ma S, Song X, Han B, Cheng Y, Huang C, Yang S, Liu X, Liu Y, Lu S, Wang J, Zhang S, Zhou C, Wang M, Zhang L; INFORM investigators. Final overall survival results from a phase III, randomized, placebo-controlled, parallel-group study of gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804). J Thorac Oncol. 2015 Apr;10(4):655-64. link to original article EuroPMC
# EORTC 08092: O'Brien ME, Gaafar R, Hasan B, Menis J, Cufer T, Popat S, Woll PJ, Surmont V, Georgoulias V, Montes A, Blackhall F, Hennig I, Schmid-Bindert G, Baas P; EORTC-LCG. Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: a double blind randomised phase III study of the lung cancer group, EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064). Eur J Cancer. 2015 Aug;51(12):1511-28. Epub 2015 Jun 11. link to original article EuroPMC NCT01208064
# STOP: Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhász E, Ramlau R, van den Heuvel MM, Lal R, Kloecker GH, Eaton KD, Chu Q, Dunlop DJ, Jain M, Garon EB, Davis CS, Carrier E, Moses SC, Shawler DL, Fakhrai H. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer. 2015 Nov;51(16):2321-9. Epub 2015 Aug 14. link to original article EuroPMC NCT00676507
# IUNO: Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. link to original article EuroPMC NCT01328951
# CALGB 30607: Baggstrom MQ, Socinski MA, Wang XF, Gu L, Stinchcombe TE, Edelman MJ, Baker S Jr, Feliciano J, Novotny P, Hahn O, Crawford JA, Vokes EE. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study-CALGB 30607 (Alliance). J Thorac Oncol. 2017 May;12(5):843-849. Epub 2017 Feb 1. link to original article link to PMC article EuroPMC NCT00693992
=Advanced or metastatic disease, third-line=
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Han et al. 2018 (ALTER 0303)	2015-03-01 to 2016-08-31	Phase 3 (C)	Anlotinib 	Shorter OSMedian OS: 6.3 vs 9.6 mo(HR 1.47, 95% CI 1.15-1.85)
Lu et al. 2020 (FALUCA) 	2015-2018 	Phase 3 (C)	Fruquintinib	Did not meet primary endpoint of OS
No active antineoplastic treatment.
===References===
# ALTER 0303: Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, Yu H, Zhao Y, Chen W, Luo Y, Wu L, Wang X, Pirker R, Nan K, Jin F, Dong J, Li B, Sun Y. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol. 2018 Nov 1;4(11):1569-1575. link to original article link to PMC article EuroPMC NCT02388919
## HRQoL analysis: Si X, Zhang L, Wang H, Zhang X, Wang M, Han B, Li K, Wang Q, Shi J, Wang Z, Cheng Y, He J, Shi Y, Chen W, Wang X, Luo Y, Nan K, Jin F, Li B, Chen Y, Zhou J, Wang D. Quality of life results from a randomized, double-blinded, placebo-controlled, multi-center phase III trial of anlotinib in patients with advanced non-small cell lung cancer. Lung Cancer. 2018 Aug;122:32-37. Epub 2018 May 18. link to original article EuroPMC
# FALUCA: Lu S, Chen G, Sun Y, Sun S, Chang J, Yao Y, Chen Z, Ye F, Lu J, Shi J, He J, Liu X, Zhang Y, Liu Z, Fang J, Cheng Y, Hu C, Mao W, Hu Y, Gong Y, Shan L, Yang Z, Song Y, Li W, Bai C, Wang B, Ma R, Zheng Z, Liu M, Jie Z, Cao L, Liao W, Pan H, Huang D, Chen Y, Yang J, Qin S, Ma S, Liang L, Liu Z, Zhou J, Tao M, Huang Y, Qiu F, Huang Y, Guan S, Peng M, Su W. A Phase III, randomized, double-blind, placebo-controlled, multicenter study of fruquintinib in Chinese patients with advanced nonsquamous non-small-cell lung cancer - The FALUCA study. Lung Cancer. 2020 Aug;146:252-262. Epub 2020 Jun 20. link to original article EuroPMC NCT02691299
=Advanced or metastatic disease, subsequent lines of therapy=
==Best supportive care==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shepherd et al. 2000 (TAX 317)	1994-1998 	Phase 3 (C)	Docetaxel 	Seems to have shorter OSMedian OS: 4.6 vs 7 mo(HR 2.07)
No active antineoplastic treatment.
===References===
# TAX 317: Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. link to original article EuroPMC
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Shepherd et al. 2005 (NCIC-CTG BR.21)	2001-2003 	Phase 3 (C)	Erlotinib 	Shorter OS
Thatcher et al. 2005 (ISEL) 	Not reported 	Phase 3 (C)	Gefitinib 	Might have shorter OSMedian OS: 5.1 vs 5.6 mo(HR 1.12, 95% CI 0.98-1.30)
Lee et al. 2012 (ZEPHYR) 	2006-2008 	Phase 3 (C)	Vandetanib 	Did not meet primary endpoint of OSMedian OS: 7.8 vs 8.5 mo(HR 1.05, 95% CI 0.90-1.23)
Miller et al. 2012 (LUX-Lung 1) 	2008-05-26 to 2009-09-21	Phase 3 (C)	Afatinib 	Did not meet primary endpoint of OSMedian OS: 12 vs 10.8 mo(HR 0.93, 95% CI 0.74-1.16)
Ellis et al. 2014 (NCIC-CTG BR.26) 	2009-2013 	Phase 3 (C)	Dacomitinib	Did not meet primary endpoint of OSMedian OS: 6.3 vs 6.8 mo(HR 1.00, 95% CI 0.83-1.20)
Paz-Ares et al. 2015 (MISSION) 	2009 to not reported 	Phase 3 (C)	Sorafenib 	Did not meet primary endpoint of OSMedian OS: 8.3 vs 8.2 mo(HR 1.01, 95% CI 0.85-1.19)
No active antineoplastic treatment.
===References===
# NCIC-CTG BR.21: Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article EuroPMC NCT00036647
# ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article EuroPMC NCT00242801
# ZEPHYR: Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng RP, Chen YM, Emerson L, Langmuir P, Manegold C. Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012 Apr 1;30(10):1114-21. Epub 2012 Feb 27. link to original article EuroPMC NCT00404924
# LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article EuroPMC NCT00656136
## HRQoL analysis: Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. link to original article EuroPMC 
# NCIC-CTG BR.26: Ellis PM, Shepherd FA, Millward M, Perrone F, Seymour L, Liu G, Sun S, Cho BC, Morabito A, Leighl NB, Stockler MR, Lee CW, Wierzbicki R, Cohen V, Blais N, Sangha RS, Favaretto AG, Kang JH, Tsao MS, Wilson CF, Goldberg Z, Ding K, Goss GD, Bradbury PA; NCIC-CTG; Australasian Lung Cancer Trials Group; NCI Naples Clinical Trials Unit. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC-CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1379-88. Epub 2014 Oct 15. link to original article EuroPMC NCT01000025
# 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 EuroPMC NCT00863746
Category:Non-small cell lung cancer regimens
Category:Null regimens
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Category:Lung cancers