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. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main NSCLC page for current regimens.


Neoadjuvant therapy

No neoadjuvant therapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Mattson et al. 2003 Phase III (C) Docetaxel Did not meet primary endpoint of OS
Gilligan et al. 2007 (MRC LU22/NVALT 2/EORTC 08012) Phase III (C) Platinum doublet Did not meet primary endpoint of OS
Pisters et al. 2010 (SWOG S9900) Phase III (C) Carboplatin & Paclitaxel Did not meet primary endpoint of OS
Scagliotti et al. 2011 (CHEST) Phase III (C) Cisplatin & Gemcitabine Seems to have inferior OS

These trials included patients with Stage IB to IIIA NSCLC. No preoperative therapy is given.

Subsequent treatment

References

  1. 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 PubMed
  2. MRC LU22/NVALT 2/EORTC 08012: 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 PubMed
  3. 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 PubMed
  4. CHEST: Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. link to original article contains verified protocol PubMed

Adjuvant therapy

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
McKneally et al. 1976 Phase III (C) Intrapleural BCG Inferior OS
Feld et al. 1993 (LCSG 801) Phase III (C) CAP Did not meet endpoint of OS
Ohta et al. 1993 (JCOG8601) Phase III (C) Cisplatin & Vindesine Did not meet endpoint of OS
Scagliotti et al. 2003 (ALPI) Phase III (C) MVP Did not meet primary endpoint of OS
Arriagada et al. 2004 (IALT) Phase III (C) 1. Cisplatin & Etoposide Seems to have inferior OS
2. Cisplatin & Vinblastine Seems to have inferior OS
3. Cisplatin & Vindesine Seems to have inferior OS
4. Cisplatin & Vinorelbine Seems to have inferior OS
Tada et al. 2004 (JCOG9304) Phase III (C) Cisplatin & Vindesine Did not meet endpoint of OS50%
Kato et al. 2004 Phase III (C) Tegafur & Uracil Seems to have inferior OS
Nakagawa et al. 2005 (WJSG4) Phase III (C) Tegafur & Uracil Did not meet primary endpoint of OS
Winton et al. 2005 (JBR.10) Phase III (C) Cisplatin & Vinorelbine Seems to have inferior OS
Douillard et al. 2006 (ANITA) Phase III (C) Cisplatin & Vinorelbine Seems to have inferior OS
Strauss et al. 2008 (CALGB 9633) Phase III (C) Carboplatin & Paclitaxel Did not meet primary endpoint of OS
Felip et al. 2010 Phase III (C) 1. Carboplatin & Paclitaxel; adjuvant
2. Carboplatin & Paclitaxel; neoadjuvant 		Did not meet primary endpoint of DFS

No systemic treatment after surgery. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.

Preceding treatment

References

  1. 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 PubMed
  2. LCSG 801: Feld R, Rubinstein L, Thomas PA; The 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 PubMed
  3. JCOG8601: Ohta M, Tsuchiya R, Shimoyama M, Sawamura K, Mori T, Miyazawa N, Suemasu K, Watanabe Y, Tomita M, Terashima M; The 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. PubMed
  4. 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 PubMed
  5. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
    1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
  6. 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 PubMed
  7. 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 contains protocol PubMed
  8. 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 PubMed
  9. JBR.10: Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed
    1. Update: Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. link to original article link to PMC article PubMed
  10. ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed
  11. CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol link to PMC article PubMed
  12. 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 PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Kelly et al. 2015 (RADIANT) Phase III (C) Erlotinib Did not meet primary endpoint of DFS

No active antineoplastic treatment after surgery. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.

Preceding treatment

References

  1. 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 PubMed

Induction chemotherapy for locally advanced disease

No induction

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Regimen

Study Evidence Comparator Comparative Efficacy
Vokes et al. 2007 (CALGB 39801) Phase III (C) Carboplatin & Paclitaxel Did not meet primary endpoint of OS50%

No treatment given prior to definitive therapy.

Subsequent treatment

References

  1. 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 PubMed
  2. CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; Cancer and Leukemia Group B. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article contains protocol PubMed

Consolidation or maintenance after definitive therapy for inoperable disease

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Pines 1976 Randomized (C) BCG Seems to have inferior OS
Hanna et al. 2008 (HOG Lun 01-24) Phase III (C) Docetaxel Did not meet primary endpoint of OS
Gore et al. 2010 (RTOG 0214) Phase III (C) Prophylactic cranial irradiation Did not meet primary endpoint of OS
Carter et al. 2011 Phase III (C) Paclitaxel Might have superior OS
Li et al. 2014 Phase III (C) Prophylactic cranial irradiation Seems to have inferior DFS
Flentje et al. 2016 (GILT) Phase III (C) Cisplatin & Vinorelbine Did not meet primary endpoint of PFS
de Ruysscher et al. 2018 (NVALT-11/DLCRG-02) Phase III (C) Prophylactic cranial irradiation Inferior time to symptomatic CNS metastases

No further treatment.

Preceding treatment

  • Pines 1976: RT
  • HOG Lun 01-24: EP & RT
  • GILT: Cisplatin, Vinorelbine, RT
  • NVALT-11/DLCRG-02: Definitive therapy

References

  1. 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 PubMed
  2. 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 U.S. Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. link to original article contains protocol PubMed
    1. 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 PubMed
  3. 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 PubMed
    1. 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 Mar 14. [Epub ahead of print] link to original article link to PMC article PubMed
  4. 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 PubMed
  5. 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 PubMed
  6. 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 PubMed
  7. 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 PubMed

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kelly et al. 2008 (SWOG S0023) Phase III (C) Gefitinib Seems to have superior OS
Butts et al. 2013 (STARTNSCLC) Phase III (C) Tecemotide Did not meet primary endpoint of OS
Antonia et al. 2017 (PACIFIC) 2014-2016 Phase III (C) Durvalumab Inferior OS (*)

Note: reported efficacy for PACIFIC is based on the 2018 update. There is another trial named START in gastric cancer.

No further antineoplastic treatment.

Preceding treatment

  • SWOG S0023: Cisplatin, Etoposide, RT, then Docetaxel x 3
  • STARTNSCLC: Chemoradiotherapy (type not specified in protocol)
  • PACIFIC: "Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."

References

  1. SWOG S0023: Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. link to original article contains verified protocol PubMed
  2. 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 PubMed
    1. 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 PubMed
    2. Dataset: Project Data Sphere
  3. PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains verified protocol PubMed
    1. Update: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. link to original article PubMed

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

Best supportive care

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Regimen

Study Evidence Comparator Comparative Efficacy
Gridelli et al. 1999 (ELVIS) Phase III (C) Vinorelbine Seems to have inferior OS
De Marinis et al. 1999 Phase III (C) 1. Lonidamine
2. Lonidamine & Vindesine
3. Vindesine 		Did not meet efficacy endpoint

No active antineoplastic treatment.

References

  1. ELVIS: Gridelli C, Perrone F, Gallo C; The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
  2. 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 PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Lee et al. 2012 (TOPICAL) Phase III (C) Erlotinib Did not meet primary endpoint of OS

No active antineoplastic treatment. Placed here because one or more randomized clinical trials included a placebo arm in this disease context.

References

  1. 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 PubMed

Maintenance after first-line therapy

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Pérol et al. 2012 (IFCT-GFPC 0502) Phase III (C) 1. Erlotinib Inferior PFS
2. Gemcitabine Inferior PFS

No further treatment after first-line therapy.

Preceding treatment

References

  1. IFCT-GFPC 0502: Pérol M, Chouaid C, Pérol D, Barlési F, Gervais R, Westeel V, Crequit J, Léna H, Vergnenègre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Ségura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012 Oct 1;30(28):3516-24. Epub 2012 Sep 4. link to original articlecontains verified protocol PubMed

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Johnson et al. 2008 (NCCTG 97-24-51) Phase III (C) CAI Did not meet primary endpoint of OS
Ciuleanu et al. 2009 (JMEN) 2005-2007 Phase III (C) Pemetrexed Seems to have inferior OS
Lee et al. 2009 Phase III (C) Thalidomide Did not meet primary endpoint of OS
Cappuzzo et al. 2010 (SATURN) 2005-2008 Phase III (C) Erlotinib Inferior PFS
Koch et al. 2011 (CYCLUS) Phase III (C) Celecoxib Did not meet primary endpoint of OS
Gaafar et al. 2011 (EORTC 08021) Phase III (C) Gefitinib Did not meet primary endpoint of OS
Paz-Ares et al. 2012 (PARAMOUNT) 2008-2010 Phase III (C) Pemetrexed Inferior PFS
Zhang et al. 2012 (INFORM) Phase III (C) Gefitinib Inferior PFS
O'Brien et al. 2015 (EORTC 08092) Phase III (C) Pazopanib Did not meet primary endpoint of OS
Giaccone et al. 2015 (STOP) Phase III (C) Belagenpumatucel-L Did not meet primary endpoint of OS
Cicènas et al. 2016 (IUNO) Phase III (C) See link See link
Baggstrom et al. 2017 (CALGB 30607) Phase III (C) Sunitinib Inferior PFS

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

Subsequent treatment

References

  1. 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 PubMed
  2. JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. link to original article contains protocol PubMed
  3. 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 PubMed
  4. 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 contains protocol PubMed
  5. 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 PubMed
  6. 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 and the 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 PubMed
  7. 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 contains verified protocol PubMed
    1. 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 PubMed
    2. 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 contains verified protocol PubMed
  8. 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 PubMed
    1. 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 PubMed
  9. 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 PubMed
  10. 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 PubMed
  11. 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 contains verified protocol PubMed
  12. 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 PubMed

Advanced or metastatic disease, third-line

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Han et al. 2018 (ALTER 0303) Phase III (C) Anlotinib Inferior OS

No active antineoplastic treatment. Placed here because one or more randomized clinical trials included a placebo arm in this disease context.

References

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

Advanced or metastatic disease, subsequent lines of therapy

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shepherd et al. 2005 (NCIC CTG BR.21) 2001-2003 Phase III (C) Erlotinib Inferior OS
Thatcher et al. 2005 (ISEL) Phase III (C) Gefitinib Might have inferior OS
Lee et al. 2012 (ZEPHYR) Phase III (C) Vandetanib Did not meet primary endpoint of OS
Miller et al. 2012 (LUX-Lung 1) Phase III (C) Afatinib Inferior PFS
Ellis et al. 2014 (NCIC CTG BR.26) Phase III (C) Dacomitinib Did not meet primary endpoint of OS
Paz-Ares et al. 2015 (MISSION) Phase III (C) Sorafenib Inferior PFS

No active antineoplastic treatment. Placed here because one or more randomized clinical trials included a placebo arm in this disease context.

References

  1. 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 contains protocol PubMed
  2. ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article PubMed
  3. 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 PubMed
  4. LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. link to original article PubMed
  5. 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 PubMed
  6. 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 contains verified protocol PubMed
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