Non-small cell lung cancer

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Travis Osterman, DO, MS
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!.
There are several related dedicated pages:

90 regimens on this page
154 variants on this page

Contents


Guidelines

ASCO

Current

Former

ASCO/CCO

Current

Former

ESMO

NCCN

Neoadjuvant therapy

Cisplatin & Gemcitabine

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Regimen

Study Evidence Comparator Efficacy
Scagliotti et al. 2011 Phase III (E) Surgery alone Seems to have superior OS

This trial included patients with Stage IB to IIIA NSCLC.

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

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

References

  1. 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

No neoadjuvant therapy

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Regimen

Study Evidence Comparator Efficacy
Gilligan et al. 2007 (MRC LU22/NVALT 2/EORTC 08012) Phase III (C) Platinum doublet Seems not superior
Pisters et al. 2010 (SWOG S9900) Phase III (C) Carboplatin & Paclitaxel Seems not superior
Scagliotti et al. 2011 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

  • Complete resection

References

  1. 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
  2. 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
  3. 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

Carboplatin & Paclitaxel

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Regimen

Study Evidence Comparator Efficacy
Strauss et al. 2008 (CALGB 9633) Phase III (E) Observation Seems not superior

Preceding treatment

  • Lobectomy or pneumonectomy, within 4 to 8 weeks

Chemotherapy

21-day cycle for 4 cycles

References

  1. CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol link to PMC article PubMed

Cisplatin & Docetaxel

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DC: Docetaxel & Cisplatin

Regimen

Study Evidence Comparator Efficacy
Barlesi et al. 2015 Phase III (E) Cisplatin & Gemcitabine Seems not superior
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) Cisplatin, Docetaxel, Bevacizumab
Cisplatin, Gemcitabine, Bevacizumab
Cisplatin, Pemetrexed, Bevacizumab
Cisplatin, Vinorelbine, Bevacizumab
Seems not superior

Preceding treatment

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

Chemotherapy

21-day cycle for 3 cycles (Barlesi et al. 2015) or 4 cycles (ECOG-ACRIN E1505)

References

  1. Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. link to original article contains verified protocol PubMed
  2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed

Cisplatin & Etoposide

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Regimen

Study Evidence Comparator Efficacy
Arriagada et al. 2004 (IALT) Phase III (E) Observation Seems to have superior OS

Preceding treatment

  • Complete surgical resection, within 60 days

Chemotherapy

28-day cycle for 4 cycles

References

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

Cisplatin & Gemcitabine

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GC: Gemcitabine & Cisplatin

Variant #1, 75/1200 x 4

Study Evidence Comparator Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) Cisplatin, Docetaxel, Bevacizumab
Cisplatin, Gemcitabine, Bevacizumab
Cisplatin, Pemetrexed, Bevacizumab
Cisplatin, Vinorelbine, Bevacizumab
Seems not superior

Preceding treatment

  • Complete surgical resection, within 6 to 12 weeks

Chemotherapy

21-day cycle for 4 cycles

Variant #2, 75/1250 x 3

Study Evidence Comparator Efficacy
Barlesi et al. 2015 Phase III (E) Cisplatin & Docetaxel Seems not superior

This trial included patients with Stage IB–III NSCLC.

Preceding treatment

  • Complete R0 resection, within 8 weeks

Chemotherapy

21-day cycle for 3 cycles

References

  1. Barlesi F, Chouaid C, Crequit J, Le Caer H, Pujol JL, Legodec J, Vergnenegre A, Le Treut J, Fabre-Guillevin E, Loundou A, Auquier P, Simeoni MC, Thomas PA. A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective. Interact Cardiovasc Thorac Surg. 2015 Jun;20(6):783-90. Epub 2015 Mar 11. link to original article contains verified protocol PubMed
  2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed

Cisplatin & Pemetrexed

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CPx: Cisplatin & Pemetrexed

Regimen

Study Evidence Comparator Efficacy
Kreuter et al. 2013 (TREAT) Randomized Phase II (E) Cisplatin & Vinorelbine Seems not superior (*)
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) Cisplatin, Docetaxel, Bevacizumab
Cisplatin, Gemcitabine, Bevacizumab
Cisplatin, Pemetrexed, Bevacizumab
Cisplatin, Vinorelbine, Bevacizumab
Seems not superior

In TREAT, intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1. Efficacy reported for TREAT based on 2016 update.

Preceding treatment

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

Chemotherapy

21-day cycle for 4 cycles

References

  1. TREAT: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. link to original article contains verified protocol PubMed
    1. Update: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. link to original article PubMed
  2. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed

Cisplatin & Vinblastine

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Regimen

Study Evidence Comparator Efficacy
Arriagada et al. 2004 (IALT) Phase III (E) Observation Seems to have superior OS

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

Preceding treatment

  • Complete surgical resection, within 60 days

Chemotherapy

12-week course

References

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

Cisplatin & Vindesine

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Regimen

Study Evidence Comparator Efficacy
Arriagada et al. 2004 (IALT) Phase III (E) Observation Seems to have superior OS

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

Preceding treatment

  • Complete surgical resection, within 60 days

Chemotherapy

12-week course

References

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

Cisplatin & Vinorelbine

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CVb: Cisplatin & Vinorelbine

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

Study Evidence Comparator Efficacy
Winton et al. 2005 (JBR.10) Phase III (E) Observation Seems to have superior OS
Kreuter et al. 2013 (TREAT) Randomized Phase II (C) Cisplatin & Pemetrexed Seems not superior (*)

Efficacy for TREAT based on 2016 update.

Preceding treatment

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

Chemotherapy

28-day cycle for 4 cycles

Variant #2, cisplatin 75 mg/m2, q3wk

Study Evidence Comparator Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) Cisplatin, Docetaxel, Bevacizumab
Cisplatin, Gemcitabine, Bevacizumab
Cisplatin, Pemetrexed, Bevacizumab
Cisplatin, Vinorelbine, Bevacizumab
Seems not superior
Zhong et al. 2017 (ADJUVANT/CTONG1104) Phase III (C) Gefinitib Inferior DFS

Patients enrolled in ADJUVANT/CTONG1104 had EGFR-mutated lung cancer.

Preceding treatment

  • Complete surgical resection, within 6 to 12 weeks

Chemotherapy

21-day cycle for 4 cycles

Variant #3, cisplatin 100 mg/m2, q4wk

Study Evidence Comparator Efficacy
Arriagada et al. 2004 (IALT) Phase III (E) Observation Seems to have superior OS
Douillard et al. 2006 (ANITA) Phase III (E) Observation Seems to have superior OS

Preceding treatment

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

Chemotherapy

28-day cycle for 4 cycles

References

  1. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
    1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
  2. JBR.10: Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed
    1. Update: Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. link to original article link to PMC article PubMed
  3. ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, 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
  4. TREAT: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M; TREAT investigators. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol. 2013 Apr;24(4):986-92. Epub 2012 Nov 15. link to original article contains verified protocol PubMed
    1. Update: Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt WE, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Griesinger F, Thomas M; TREAT investigators. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol. 2016 Jan;11(1):85-93. link to original article PubMed
  5. ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed
  6. ADJUVANT/CTONG1104: Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, Wang J, Fei K, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yan HH, Yang XN, Zhou Q, Wu YL; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. Epub 2017 Nov 21. link to original article contains protocol PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Feld et al. 1993 (LCSG 801) Phase III (C) CAP Seems not superior
Scagliotti et al. 2003 (ALPI) Phase III (C) MVP Seems not superior
Arriagada et al. 2004 (IALT) Phase III (C) Cisplatin & Etoposide Seems to have inferior OS
Cisplatin & Vinblastine Seems to have inferior OS
Cisplatin & Vindesine Seems to have inferior OS
Cisplatin & Vinorelbine Seems to have inferior OS
Kato et al. 2004 Phase III (C) Tegafur & Uracil Seems to have inferior OS
Nakagawa et al. 2005 (WJSG4) Phase III (C) Tegafur & Uracil Seems not superior
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 Seems not superior

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

  • Surgery

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, 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
  8. 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

Tegafur & Uracil

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Regimen

Study Evidence Comparator Efficacy
Kato et al. 2004 Phase III (E) Observation Seems to have superior OS

Preceding treatment

  • Surgery

Chemotherapy

2-year course

References

  1. 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

Induction chemotherapy for locally advanced disease

Carboplatin & Paclitaxel

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PC: Paclitaxel & Carboplatin

Variant #1, AUC 6/200

Study Evidence Comparator Efficacy
Belani et al. 2005 (LAMP) Phase II
Vokes et al. 2007 (CALGB 39801) Phase III (E) No induction Seems not superior

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

Variant #2, AUC 6/225

Study Evidence Comparator Efficacy
Hoang et al. 2012 (ECOG 3598) Phase III (C) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

References

  1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol 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
  3. ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains verified protocol PubMed

Cisplatin & Vinblastine

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Regimen

Study Evidence Comparator Efficacy
Dillman et al. 1990 Phase III (E) No induction Superior OS
Curran et al. 2011 (RTOG 9410) Phase III (C) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

5-week course

Subsequent treatment

  • RT x 60 to 63 Gy

References

  1. Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, Carey RW, Frei EF 3rd, Green MR. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4;323(14):940-5. link to original article contains protocol PubMed
  2. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed

No induction

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Regimen

Study Evidence Comparator Efficacy
Vokes et al. 2007 (CALGB 39801) Phase III (C) Carboplatin & Paclitaxel Seems not superior

No treatment given prior to definitive therapy.

Subsequent treatment

References

  1. 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

Definitive therapy for locally advanced disease

Carboplatin, Paclitaxel, RT

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PC & RT: Paclitaxel, Carboplatin, Radiation Therapy

Variant #1, 60 Gy

Study Evidence Comparator Efficacy
Hoang et al. 2012 (ECOG 3598) Phase III (C) See link See link
Bradley et al. 2015 (RTOG 0617) Phase III (C) Carboplatin, Paclitaxel, Cetuximab, concurrent RT Seems not superior
Carboplatin, Paclitaxel, high-dose RT
Carboplatin, Paclitaxel, Cetuximab, high-dose RT
Superior OS
Liang et al. 2017 Phase III (C) EP & RT Might have inferior OS

Preceding treatment

  • ECOG 3598: PC induction x 2

Chemoradiotherapy

  • Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
  • Paclitaxel (Taxol) 45 mg/m2 IV over 1 to 3 hours once per day on days 1, 8, 15, given first
  • Concurrent radiation therapy: 2 Gy fractions x 30 fractions given 5 days per week, over a 6 week course of treatment

21-day cycle for 2 cycles

Subsequent treatment

  • RTOG 0617: PC consolidation x 2

Variant #2, 63 Gy

Study Evidence
Belani et al. 2005 (LAMP) Phase II

Preceding treatment

Chemoradiotherapy

  • Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
  • Paclitaxel (Taxol) 45 mg/m2 IV over 1 to 3 hours once per day on days 1, 8, 15, given first
  • Concurrent radiation therapy: 1.8 Gy fractions x 25 fractions given 5 days per week, then 2 Gy fractions x 9 fractions given 5 days per week, over a 7 week course of treatment

21-day cycle for 2 cycles

Subsequent treatment

  • PC consolidation x 2

Variant #3, 66 Gy

Study Evidence
Vokes et al. 2007 (CALGB 39801) Non-randomized portion of RCT

Preceding treatment

Chemoradiotherapy

One course

References

  1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol 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
  3. ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains verified protocol PubMed
  4. RTOG 0617: Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. contains verified protocol link to PMC article PubMed
  5. Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains verified protocol PubMed

Carboplatin & RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Atagi et al. 2012 (JCOG0301) Phase III (E) RT Seems to have superior OS

Chemoradiotherapy

References

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

Cisplatin & RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Schaake-Koning et al. 1992 Phase III (E) Cisplatin & RT (weekly dosing) Seems not superior
RT Superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 6 mg/m2 IV once per day on days of radiation
  • Concurrent radiation therapy as follows:
    • Weeks 1 & 2: 3 Gy fractions, five fractions per week
    • Weeks 3 to 5: no radiation
    • Weeks 6 & 7: 2.5 Gy fractions, five fractions per week

7-week course

References

  1. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier JP, van Zandwijk N, Bartelink H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30. link to original article contains protocol PubMed

Cisplatin, Docetaxel, RT

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RT: Radiation Therapy

Regimen

Study Evidence
Ahn et al. 2015 (KCSG-LU05-04) Non-randomized portion of RCT

In this trial, no benefit was observed to giving post-definitive consolidation.

Chemoradiotherapy

One course

Subsequent treatment

  • Cisplatin & Docetaxel consolidation versus no further treatment

References

  1. KCSG-LU05-04: Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. Epub 2015 Jul 6. link to original article contains verified protocol PubMed

Cisplatin, Etoposide, RT

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

Variant #1, 45 Gy with response-adapted treatment

Study Evidence
Albain et al. 2002 (SWOG 9019) Phase II
Albain et al. 2009 (RTOG 93-09) Non-randomized portion of RCT

Chemoradiotherapy

  • Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1, 8, 29, 36
  • Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5, 29 to 33
  • Concurrent radiation therapy, 1.80 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of chemotherapy

5-week course

Subsequent treatment

  • SWOG 9019: Patients were re-imaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2.00 Gy per day x 8 fractions for a total of 61 Gy administered overall
  • RTOG 93-09: Additional radiation to 61 Gy, then cisplatin & etoposide consolidation versus surgery, then cisplatin & etoposide consolidation

Variant #2, 60 to 66 Gy

Study Evidence Comparator Efficacy
Kelly et al. 2008 (SWOG S0023) Non-randomized portion of RCT
Hanna et al. 2008 (HOG Lun 01-24) Non-randomized portion of RCT
Senan et al. 2016 (PROCLAIM) Phase III (C) Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation Seems not superior
Liang et al. 2017 Phase III (C) PC & RT Might have superior OS

Chemoradiotherapy

28-day cycle for 2 cycles

Subsequent treatment

Variant #3, 69.6 Gy (hyperfractionated)

Study Evidence Comparator Efficacy
Curran et al. 2011 (RTOG 9410) Phase III (E) Cisplatin, Vinblastine, RT Seems not superior
Cisplatin & Vinblastine, then RT Might have superior OS

Chemoradiotherapy

5-week course

References

  1. SWOG 9019: Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002 Aug 15;20(16):3454-60. link to original article contains protocol PubMed
  2. NPC 95-01: Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, Delhoume JY, Le Treut J, Silvani JA, Dansin E, Bozonnat MC, Daurés JP, Mornex F, Pérol M; Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005 Sep 1;23(25):5910-7. Epub 2005 Aug 8. link to original article PubMed
  3. 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
  4. 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
  5. RTOG 93-09: Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009 Aug 1;374(9687):379-86. Epub 2009 Jul 24. link to original article contains verified protocol link to PMC article PubMed
  6. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed
  7. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
  8. Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains verified protocol PubMed

Cisplatin, Vinblastine, RT

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Regimen

Study Evidence Comparator Efficacy
Curran et al. 2011 (RTOG 9410) Phase III (E) Cisplatin, Etoposide, RT Seems not superior
Cisplatin & Vinblastine, then RT Seems to have superior OS

Chemoradiotherapy

5-week course of chemotherapy

References

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

Radiation therapy

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RT: Radiation Therapy

Variant #1, 45 Gy + 18 Gy boost (63 Gy total)

Study Evidence Comparator Efficacy
Belani et al. 2005 (LAMP) Phase II
Curran et al. 2011 (RTOG 9410) Phase III (C) See link See link

Preceding treatment

Radiotherapy

  • External beam radiotherapy 45 Gy in 1.80 Gy fractions x 25 fractions, given once per day 5 days per week, then 18 Gy boost in 2.00 Gy fractions x 9 fractions, given once per day 5 days per week.

7-week course

Variant #2, 60 Gy

Study Evidence Comparator Efficacy
Atagi et al. 2012 (JCOG0301) Phase III (C) Carboplatin & RT Seems to have inferior OS

Radiotherapy

One course

References

  1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol PubMed
  2. RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed
  3. JCOG0301: Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; Japan Clinical Oncology Group Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. link to original article contains protocol PubMed

Consolidation or maintenance after definitive therapy for inoperable disease

Carboplatin & Paclitaxel

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Regimen

Study Evidence
Belani et al. 2005 (LAMP) Phase II
Bradley et al. 2015 (RTOG 0617) Non-randomized portion of RCT
Senan et al. 2016 (PROCLAIM) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. LAMP: Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1;23(25):5883-91. link to original article contains protocol PubMed
  2. RTOG 0617: Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. Epub 2015 Jan 16. contains verified protocol link to PMC article PubMed
  3. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed

Cisplatin & Etoposide

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Regimen

Study Evidence
Senan et al. 2016 (PROCLAIM) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

28-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed

Cisplatin & Vinorelbine

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Regimen

Study Evidence
Senan et al. 2016 (PROCLAIM) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed

Durvalumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Antonia et al. 2017 (PACIFIC) Phase III (E) Placebo Superior PFS

Preceding treatment

  • "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."

Immunotherapy

Up to 12-month course

References

  1. PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Kelly et al. 2008 (SWOG S0023) Phase III (C) Gefitinib Seems to have superior OS
Butts et al. 2013 (START) Phase III (C) Tecemotide Seems not superior
Antonia et al. 2017 (PACIFIC) Phase III (C) Durvalumab Inferior PFS

Preceding treatment

  • SWOG S0023: Cisplatin, Etoposide, RT, then Docetaxel x 3
  • START: 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."

Treatment

  • Placebo

Up to 12-month course

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, Pereira JR, 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
  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

Observation

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Regimen

Study Evidence Comparator Efficacy
Hanna et al. 2008 (HOG Lun 01-24) Phase III (C) Docetaxel Seems not superior
Gore et al. 2010 (RTOG 0214) Phase III (C) Prophylactic cranial irradiation Seems not superior
Li et al. 2014 Phase III (C) Prophylactic cranial irradiation Seems to have inferior DFS
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

  • HOG Lun 01-24: EP & RT
  • NVALT-11/DLCRG-02: Definitive therapy

References

  1. 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
  2. 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
  3. 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
  4. 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

Advanced or metastatic disease, first-line

ABCP

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ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel

Variant #1, 1200/15/6/175 x 4

Study Evidence Comparator Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E) ACP Not reported
BCP Seems to have superior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #2, 1200/15/6/175 x 6

Study Evidence Comparator Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E) ACP Not reported
BCP Seems to have superior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

Variant #3, 1200/15/6/200 x 4

Study Evidence Comparator Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E) ACP Not reported
BCP Seems to have superior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #4, 1200/15/6/200 x 6

Study Evidence Comparator Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E) ACP Not reported
BCP Seems to have superior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. Patients in SWOG S0819 were EGFR FISH positive.

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Carboplatin & Docetaxel

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DCb: Docetaxel & Carboplatin

Regimen

Study Evidence Comparator Efficacy
Fossella et al. 2003 (TAX 326) Phase III (E) Cisplatin & Docetaxel Not reported
Cisplatin & Vinorelbine Seems not superior
Booton et al. 2006 (BTOG1) Phase III (E) MIC
MVP
Seems not superior
Lynch et al. 2010 (BMS099) Phase III (C) Carboplatin, Docetaxel, Cetuximab Seems not superior
Groen et al. 2011 (NVALT-4) Phase III (C) Carboplatin, Docetaxel, Celecoxib Seems not superior
Rossell et al. 2012 (EURTAC) Phase III (C) Erlotinib Inferior PFS

Note: Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21.

Chemotherapy

21-day cycle for up to 5 cycles (NVALT-4), 6 cycles (BMS099), or indefinitely

References

  1. TAX 326: Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
  2. BTOG1: Booton R, Lorigan P, Anderson H, Baka S, Ashcroft L, Nicolson M, O'Brien M, Dunlop D, O'Byrne K, Laurence V, Snee M, Dark G, Thatcher N. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol. 2006 Jul;17(7):1111-9. Epub 2006 Apr 7. link to original article PubMed
  3. BMS099: Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. link to original article contains protocol PubMed
  4. NVALT-4: Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, Dalesio O, Biesma B, Smit HJ, Termeer A, Hiltermann TJ, van den Borne BE, Schramel FM. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol. 2011 Nov 10;29(32):4320-6. Epub 2011 Oct 11. link to original article PubMed
  5. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed

Carboplatin & Etoposide

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Regimen

Study Evidence Comparator Efficacy
Klastersky et al. 1990 (EORTC 07861) Phase III (E) Cisplatin & Etoposide Might have inferior ORR

Chemotherapy

3- to 4-week cycles

References

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

Carboplatin & Gemcitabine

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GC: Gemcitabine and Carboplatin
GCb: Gemcitabine and Carboplatin

Variant #1, 5/1000 q3wk

Study Evidence Comparator Efficacy
Grønberg et al. 2009 Phase III (C) Carboplatin & Pemetrexed Seems not superior
Zhou et al. 2011 (OPTIMAL) Phase III (C) Erlotinib Inferior PFS
Rossell et al. 2012 (EURTAC) Phase III (C) Erlotinib Inferior PFS

Patients in OPTIMAL were EGFR mutation positive; patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21. It is unclear from the abstract how many cycles of therapy were given in EURTAC.

Chemotherapy

21-day cycle for up to 4 cycles

Variant #2, 5/1000 q4wk

Study Evidence Comparator Efficacy
Danson et al. 2003 Phase III (E) MIC
MVP
Seems not superior

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

Chemotherapy

28-day cycle for 4 cycles

Variant #3, 5/1250 q3wk

Study Evidence Comparator Efficacy Toxicity
Zatloukal et al. 2003 Phase III (E) Cisplatin & Gemcitabine Seems not superior
Sederholm et al. 2005 Phase III (C) Gemcitabine Seems to have superior OS
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL

Note: Zatloukal et al. 2003 used a 1200 mg/m2 dosing, which is quite similar to the 1250 mg/m2 dosing.

Chemotherapy

21-day cycle for 4 to 6 cycles

Variant #4, 5/1250 q4wk

Study Evidence Comparator Efficacy
Wu et al. 2013 (FASTACT-2) Phase III (C) Carboplatin & Gemcitabine/Erlotinib Seems to have inferior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

28-day cycle for 4 cycles

Variant #5, 6/1250 ("GCb6")

Study Evidence Comparator Efficacy Toxicity
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Ferry et al. 2017 (BTOG2) Phase III (E) GC50 Seems to have superior OS
GC80 Non-inferior OS

Chemotherapy

21-day cycle for 4 to 6 cycles

References

  1. Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003 Aug 1;98(3):542-53. link to original article contains protocol PubMed
  2. Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. link to original article contains protocol PubMed
  3. Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, Gawande SR. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005 Nov 20;23(33):8380-8. link to original article contains verified protocol PubMed
  4. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S. Phase III study by the Norwegian Lung Cancer Study Group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains verified protocol PubMed
  5. OPTIMAL: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. Epub 2011 Jul 23. link to original article PubMed
    1. Update: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3. link to original article contains verified protocol PubMed
  6. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed
  7. FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article contains protocol PubMed
  8. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  9. Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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

Variant #1, 5/200

Study Evidence Comparator Efficacy Toxicity
Mok et al. 2009 (IPASS) Phase III (C) Gefitinib Inferior PFS
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Mok et al. 2015 (KEYNOTE-042) Phase III (C) Pembrolizumab Inferior OS

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

Chemotherapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

Variant #2, 6/175

Study Evidence Comparator Efficacy
Stathopoulos et al. 2004 Phase III (C) Paclitaxel & Vinorelbine Seems not superior
Lynch et al. 2012 Randomized Phase II (C) Carboplatin, Paclitaxel, Ipilimumab Seems to have inferior PFS
Zhou et al. 2015 (BEYOND) Phase III (C) Carboplatin, Paclitaxel, Bevacizumab Seems to have inferior OS
Govindan et al. 2017 (CA184-104) Phase III (C) Carboplatin, Paclitaxel, Ipilimumab Seems not superior

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Variant #3, 6/200

Study Evidence Comparator Efficacy Toxicity
Rosell et al. 2002 Phase III (E) Cisplatin & Paclitaxel Seems to have inferior OS
Johnson et al. 2004 Randomized Phase II (C) PacCBev Seems to have inferior TTP
Herbst et al. 2005 (TRIBUTE) Phase III (C) Carboplatin, Erlotinib, Paclitaxel Seems not superior
Ohe et al. 2006 Phase III (E) Cisplatin & Gemcitabine Seems not superior
Cisplatin & Irinotecan Seems not superior
Cisplatin & Vinorelbine Seems not superior
Sandler et al. 2006 (ECOG E4599) Phase III (C) PacCBev, then Maintenance Bev Inferior OS
Mok et al. 2009 (IPASS) Phase III (C) Gefitinib Inferior PFS
Maemondo et al. 2010 (NEJ002) Phase III (C) Gefitinib Inferior PFS
Hirsh et al. 2011 Phase III (C) Agatolimod, Carboplatin, Paclitaxel Seems not superior
Lara et al. 2011 Phase III (C) Carboplatin, Paclitaxel, Vadimezan Seems not superior
Socinski et al. 2012 Phase III (C) Carboplatin & nab-Paclitaxel Inferior ORR
Scagliotti et al. 2012 (MONET1) Phase III (C) Carboplatin, Motesanib, Paclitaxel Seems not superior
Langer et al. 2014 Phase III (C) Carboplatin, Figitumumab, Paclitaxel Might have superior OS
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Ramalingam et al. 2016 Randomized Phase II (C) Carboplatin, Paclitaxel, Veliparib Seems not superior
Kubota et al. 2017 (MONET-A) Phase III (C) Carboplatin, Motesanib, Paclitaxel Might have inferior PFS
Herbst et al. 2017 (SWOG S0819) Phase III (C) Carboplatin, Paclitaxel, Cetuximab Seems not superior
Mok et al. 2015 (KEYNOTE-042) Phase III (C) Pembrolizumab Inferior OS

Note: Patients in TRIBUTE received a maximum of 6 cycles. Patients in SWOG S0819 were EGFR FISH positive. Patients enrolled in this arm of KEYNOTE-042 had squamous histology.

Chemotherapy

21-day cycle for 3 or more cycles

Subsequent treatment

Variant #4, 6/225

Study Evidence Comparator Efficacy
Schiller et al. 2002 (ECOG E1594) Phase III (E) Cisplatin & Docetaxel Seems not superior
Cisplatin & Gemcitabine Seems not superior
Cisplatin & Paclitaxel Seems not superior
Herbst et al. 2004 (INTACT 2) Phase III (C) Carboplatin, Paclitaxel, Gefitinib Seems not superior
Lilenbaum et al. 2005 (CALGB 9730) Phase III (E) Paclitaxel Superior FFS
Williamson et al. 2005 (SWOG S0003) Phase III (C) Carboplatin, Paclitaxel, Tirapazamine Seems not superior
Kubota et al. 2008 (JMTO LC00-03) Phase III (C) Gemcitabine & Vinorelbine, then Docetaxel Seems not superior
Treat et al. 2009 (ALPHA A1-99002L) Phase III (C) Carboplatin & Gemcitabine
Gemcitabine & Paclitaxel
Seems not superior
Lynch et al. 2010 (BMS099) Phase III (C) TC & Cetuximab Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles or indefinitely (ECOG E1594)

References

  1. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
  2. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. link to original article contains protocol PubMed
  3. INTACT 2: Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004 Mar 1;22(5):785-94. link to original article contains protocol PubMed
  4. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
  5. Stathopoulos GP, Veslemes M, Georgatou N, Antoniou D, Giamboudakis P, Katis K, Tsavdaridis D, Rigatos SK, Dimitroulis I, Bastani S, Loukides S, Vergos K, Marossis K, Grigoratou T, Kalatzi E, Charalambatou M, Paspalli A, Michalopoulou P, Stoka M, Gerogianni A. Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial. Ann Oncol. 2004 Jul;15(7):1048-55. link to original article contains protocol PubMed
  6. CALGB 9730: Lilenbaum RC, Herndon JE 2nd, List MA, Desch C, Watson DM, Miller AA, Graziano SL, Perry MC, Saville W, Chahinian P, Weeks JC, Holland JC, Green MR. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer and Leukemia Group B (study 9730). J Clin Oncol. 2005 Jan 1;23(1):190-6. link to original articlecontains verified protocol PubMed
  7. TRIBUTE: Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25. link to original article contains verified protocol PubMed
  8. SWOG S0003: Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR; Southwest Oncology Group Trial S0003. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005 Dec 20;23(36):9097-104. link to original article contains protocol PubMed
  9. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
  10. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
  11. JMTO LC00-03: Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, Fujita Y, Teramukai S, Fukushima M, Furuse K; Japan Multi-National Trial Organisation. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol. 2008 Dec;9(12):1135-42. Epub 2008 Nov 13. link to original article contains protocol PubMed
  12. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed
    1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
  13. ALPHA A1-99002L: Treat JA, Gonin R, Socinski MA, Edelman MJ, Catalano RB, Marinucci DM, Ansari R, Gillenwater HH, Rowland KM, Comis RL, Obasaju CK, Belani CP; Alpha Oncology Research Network. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010 Mar;21(3):540-7. Epub 2009 Oct 15. link to original article contains protocol PubMed
  14. BMS099: Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20;28(6):911-7. Epub 2010 Jan 25. link to original article contains protocol PubMed
  15. NEJ002: Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-8. link to original article contains verified protocol PubMed
    1. Update: Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013 Jan;24(1):54-9. Epub 2012 Sep 11. link to original article PubMed
  16. Hirsh V, Paz-Ares L, Boyer M, Rosell R, Middleton G, Eberhardt WE, Szczesna A, Reiterer P, Saleh M, Arrieta O, Bajetta E, Webb RT, Raats J, Benner RJ, Fowst C, Meech SJ, Readett D, Schiller JH. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Jul 1;29(19):2667-74. Epub 2011 May 31. link to original article contains verified protocol PubMed
  17. Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A, Scagliotti G. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 1;29(22):2965-71. Epub 2011 Jun 27. link to original article contains verified protocol PubMed
  18. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
  19. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
  20. MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article contains protocol PubMed
  21. Langer CJ, Novello S, Park K, Krzakowski M, Karp DD, Mok T, Benner RJ, Scranton JR, Olszanski AJ, Jassem J. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2014 Jul 1;32(19):2059-66. Epub 2014 Jun 2. link to original article link to PMC article PubMed
  22. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed
  23. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  24. Ramalingam SS, Blais N, Mazieres J, Reck M, Jones CM, Juhasz E, Urban L, Orlov S, Barlesi F, Kio E, Keiholz U, Qin Q, Qian J, Nickner C, Dziubinski J, Xiong H, Ansell P, McKee M, Giranda V, Gorbunova V. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin Cancer Res. 2017 Apr 15;23(8):1937-1944. Epub 2016 Oct 10. link to original article contains protocol PubMed
  25. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed
  26. MONET-A: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. Epub 2017 Sep 13. link to original article contains verified protocol PubMed
  27. SWOG S0819: Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. link to original article contains protocol PubMed
  28. Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract

Carboplatin & nab-Paclitaxel

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Regimen

Study Evidence Comparator Efficacy
Socinski et al. 2012 Phase III (E) Carboplatin & Paclitaxel Superior ORR

Chemotherapy

21-day cycle for 6 cycles; treatment could continue at physician's discretion if there was no progressive disease or unacceptable toxicity

References

  1. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Bevacizumab

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

Variant #1, 6/175/15 x 4

Study Evidence Comparator Efficacy
Socinski et al. 2018 (IMpower150) Phase III (C) ACP Not reported
ABCP Seems to have inferior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #2, 6/175/15 x 6

Study Evidence Comparator Efficacy
Socinski et al. 2018 (IMpower150) Phase III (C) ACP Not reported
ABCP Seems to have inferior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

Variant #3, 6/200/15 x 4

Study Evidence Comparator Efficacy
Patel et al. 2013 (PointBreak) Phase III (C) PemCBev, then PemBev maint. Seems to have inferior PFS
Zinner et al. 2015 (PRONOUNCE) Phase III (C) See link See link
Socinski et al. 2018 (IMpower150) Phase III (C) ACP Not reported
ABCP Seems to have inferior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization.

Chemotherapy

Supportive medications

  • Premedications per paclitaxel label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Subsequent treatment

Variant #4, 6/200/15 x 6

Study Evidence Comparator Efficacy
Johnson et al. 2004 Randomized Phase II (E) Carboplatin & Paclitaxel Seems to have superior TTP
Sandler et al. 2006 (ECOG E4599) Phase III (E) See link See link
Zhou et al. 2015 (BEYOND) Phase III (E) Carboplatin & Paclitaxel Seems to have superior OS
Herbst et al. 2017 (SWOG S0819) Phase III (C) Carboplatin, Paclitaxel, Bevacizumab, Cetuximab Seems not superior
Socinski et al. 2018 (IMpower150) Phase III (C) ACP Not reported
ABCP Seems to have inferior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. Patients in SWOG S0819 were EGFR FISH positive.

Chemotherapy

  • Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
  • Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
  • Bevacizumab (Avastin) 15 mg/kg IV on day 1, given third, starting 60 minutes after the completion of carboplatin
    • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004 Jun 1;22(11):2184-91. link to original article PubMed
  2. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
  3. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
  4. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
  5. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed
  6. SWOG S0819: Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. Epub 2017 Nov 20. link to original article contains protocol PubMed
  7. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Ipilimumab

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Regimen

Study Evidence Comparator Efficacy
Lynch et al. 2012 Randomized Phase II (E) Carboplatin & Paclitaxel Seems to have superior PFS
Govindan et al. 2017 (CA184-104) Phase III (E) Carboplatin & Paclitaxel Seems not superior

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

Chemoimmunotherapy

Supportive medications

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
  2. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Carboplatin & Pemetrexed

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

Example orders

Variant #1, 5/500 x 4

Study Evidence Comparator Efficacy
Langer et al. 2016 (KEYNOTE-021) Randomized Phase II (C) See link See link
Soria et al. 2017 (ASCEND-4) Phase III (C) Ceritinib Inferior PFS
Gandhi et al. 2018 (KEYNOTE-189) Phase III (C) See link See link

Patients enrolled in ASCEND-4 had ALK-rearranged NSCLC.

Chemotherapy

Supportive medications

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

21-day cycle for up to 4 cycles

Subsequent treatment

Variant #2, 5/500 x 6

Study Evidence Comparator Efficacy Toxicity
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Mok et al. 2015 (KEYNOTE-042) Phase III (C) Pembrolizumab Inferior OS

Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.

Chemotherapy

Supportive medications

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

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #3, 6/500 x 4

Study Evidence Comparator Efficacy
Grønberg et al. 2009 Phase III (E) Carboplatin & Gemcitabine Seems not superior
Zinner et al. 2015 (PRONOUNCE) Phase III (E) See link See link
Soria et al. 2017 (ASCEND-4) Phase III (C) Ceritinib Inferior PFS

Patients enrolled in ASCEND-4 had ALK-rearranged NSCLC.

Chemotherapy

Supportive medications

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

21-day cycle for up to 4 cycles

Subsequent treatment

Variant #4, 6/500 x 6

Study Evidence Comparator Efficacy Toxicity
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Mok et al. 2015 (KEYNOTE-042) Phase III (C) Pembrolizumab Inferior OS

Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. Epub 2009 May 11. link to original article contains protocol PubMed
  2. PROFILE 1014: Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. link to original article does not contain specific protocol PubMed
    1. Subgroup analysis: Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, Mok TS. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65. Epub 2016 Mar 28. link to original article PubMed
    2. Update: Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, Mok TS. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018 Aug 1;36(22):2251-2258. Epub 2018 May 16. link to original article PubMed
  3. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
  4. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  5. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed
  6. ASCEND-4: Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. Epub 2017 Jan 24. link to original article contains protocol PubMed
  7. Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract
  8. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Carboplatin, Pemetrexed, Bevacizumab

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PemCBev: Pemetrexed, Carboplatin, Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Patel et al. 2013 (PointBreak) Phase III (E) PacCBev, then Maintenance Bev Seems to have superior PFS

Chemotherapy

Supportive medications

  • Premedications, folic acid, and vitamin supplementation per pemetrexed label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Subsequent treatment

References

  1. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed

Carboplatin, Pemetrexed, Pembrolizumab

Source: Carboplatin, Pemetrexed, Pembrolizumab in advanced or metastatic non-small cell lung cancer

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Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Langer et al. 2016 (KEYNOTE-021) Randomized Phase II (E) See link See link
Gandhi et al. 2018 (KEYNOTE-189) Phase III (E) See link See link

Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemoimmunotherapy

Supportive medications

21-day cycle for 4 cycles

Subsequent treatment

References

  1. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary appendixPubMed
  2. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Carboplatin & Vinorelbine

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VC: Vinorelbine & Carboplatin

Variant #1, IV vinorelbine

Study Evidence Comparator Efficacy
Tan et al. 2005 (GLOB 2) Phase III (C) Gemcitabine & Vinorelbine Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles

Variant #2, PO vinorelbine

Study Evidence Comparator Efficacy
Fløtten et al. 2012 Phase III (C) Gemcitabine & Vinorelbine Seems not superior

Chemotherapy

21-day cycle for 3 cycles

References

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

Cisplatin & Docetaxel

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

Variant #1, 50/75

Study Evidence Comparator Efficacy
Berghmans et al. 2013 (ELCWP-01041) Phase III (C) GIP
IG
Seems not superior

Chemotherapy

21-day cycles

Variant #2, 70/60

Study Evidence Comparator Efficacy
Park et al. 2017 Phase III (C) Cisplatin & Pemetrexed Inconclusive whether non-inferior

Chemotherapy

21-day cycle for up to 4 cycles

Variant #3, 75/75

Study Evidence Comparator Efficacy
Schiller et al. 2002 (ECOG E1594) Phase III (E) Carboplatin & Paclitaxel Seems not superior
Cisplatin & Gemcitabine Seems not superior
Cisplatin & Paclitaxel Seems not superior
Fossella et al. 2003 (TAX 326) Phase III (E) Carboplatin & Docetaxel Not reported
Cisplatin & Vinorelbine Seems to have superior OS
Tan et al. 2009 (GLOB3) Phase III (C) Cisplatin & Vinorelbine Seems not superior
Rossell et al. 2012 (EURTAC) Phase III (C) Erlotinib Inferior PFS

Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation.

Chemotherapy

21-day cycle for up to 4 cycles (EURTAC), 6 cycles (GLOB3), or indefinitely (E1594, TAX326)

Variant #4, 80/60

Study Evidence Comparator Efficacy
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Seems not superior
Mitsudomi et al. 2016 (WJTOG3405) Phase III (C) Gefitinib Inferior PFS

Patients in WJTOG3405 had EGFR exon 19 deletion or p.L858R mutation.

Chemotherapy

21-day cycle for 3 to 6 cycles

Variant #5, 80/100

Study Evidence Comparator Efficacy
Georgoulias et al. 2001 Phase III (C) Docetaxel & Gemcitabine Seems not superior
Georgoulias et al. 2004 Phase III (C) Docetaxel Seems not superior

Chemotherapy

21-day cycles

References

  1. Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, Palamidas P, Vlachonikolis I; Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001 May 12;357(9267):1478-84. link to original article PubMed
  2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
  3. TAX 326: Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
  4. Georgoulias V, Ardavanis A, Agelidou A, Agelidou M, Chandrinos V, Tsaroucha E, Toumbis M, Kouroussis C, Syrigos K, Polyzos A, Samaras N, Papakotoulas P, Christofilakis C, Ziras N, Alegakis A. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol. 2004 Jul 1;22(13):2602-9. link to original article contains protocol PubMed
  5. GLOB3: Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R. Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and iv vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2009 Jul;20(7):1249-56. Epub 2009 Mar 10. link to original article contains protocol PubMed
  6. WJTOG3405: Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121-8. Epub 2009 Dec 18. link to original article contains verified protocol PubMed
  7. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed
  8. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed
  9. ELCWP-01041: Berghmans T, Lafitte JJ, Scherpereel A, Paesmans M, Lecomte J, Marco VG, Meert AP, Leclercq N, Sculier JP; European Lung Cancer Working Party. An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC. Anticancer Res. 2013 Dec;33(12):5477-82. link to original article contains verified protocol PubMed
  10. Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains protocol PubMed

Cisplatin & Etoposide

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EC: Etoposide & Cisplatin

Variant #1, 60/360

Study Evidence Comparator Efficacy
Ruckdeschel et al. 1986 (ECOG E1581) Phase III (E) CAMP
Cisplatin & Vindesine
MVP
Seems not superior

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

Chemotherapy

21-day cycles

Variant #2, 75/300

Study Evidence Comparator Efficacy
Bonomi et al. 2000 (ECOG E5592) Phase III (C) Cisplatin & Paclitaxel Seems to have inferior OS

Chemotherapy

21-day cycles

Variant #3, 100/300

Study Evidence Comparator Efficacy
Cardenal et al. 1999 Phase III (C) Cisplatin & Gemcitabine Inferior TTP

Chemotherapy

21-day cycles

Variant #4, 120/300

Study Evidence Comparator Efficacy
Klastersky et al. 1990 (EORTC 07861) Phase III (C) Carboplatin & Etoposide Might have superior ORR

Chemotherapy

3- to 4-week cycles

References

  1. ECOG E1581: Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986 Jan;4(1):14-22. link to original article contains verified protocol PubMed
  2. EORTC 07861: Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, Cordier R, Finet C, Berchier MC, Sergysels R, Mommen P, Paesmans M. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol. 1990 Sep;8(9):1556-62. link to original article contains verified protocol PubMed
  3. Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. link to original article contains protocol PubMed
  4. ECOG E5592: Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. link to original article contains verified protocol PubMed

Cisplatin & Gemcitabine

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

Variant #1, 75/1000

Study Evidence Comparator Efficacy
Wu et al. 2014 (LUX-Lung 6) Phase III (C) Afatinib Inferior PFS

Tumor specimen was required to be EGFR mutation-positive.

Chemotherapy

21-day cycle for up to 6 cycles

Variant #2, 75/1250 q3wk

Study Evidence Comparator Efficacy Toxicity
Rossell et al. 2012 (EURTAC) Phase III (C) Erlotinib Inferior PFS
Paz-Ares et al. 2012 (NExUS) Phase III (C) Cisplatin, Gemcitabine, Sorafenib Seems not superior
Thatcher et al. 2015 (SQUIRE) Phase III (C) Cisplatin, Gemcitabine, Necitumumab Seems to have inferior OS
Wu et al. 2015 (ENSURE) Phase III (C) Erlotinib Inferior PFS
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL

Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21.

Chemotherapy

21-day cycles

Patients in ENSURE received up to 4 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles.

Variant #3, 75/1250 q4wk

Study Evidence Comparator Efficacy
Wu et al. 2013 (FASTACT-2) Phase III (C) Cisplatin & Gemcitabine/Erlotinib Seems to have superior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

28-day cycle for 4 cycles

Variant #4, 80/1000

Study Evidence Comparator Efficacy
Ohe et al. 2006 Phase III (E) Carboplatin & Paclitaxel Seems not superior
Cisplatin & Irinotecan Seems not superior
Cisplatin & Vinorelbine Seems not superior
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Seems not superior

Chemotherapy

21-day cycle for 6 cycles (WJTOG0203) or indefinitely (Ohe et al. 2006)

Variant #5, 80/1125

Study Evidence Comparator Efficacy
Wachters et al. 2003 Phase III (C) Epirubicin & Gemcitabine Seems not superior

Chemotherapy

21-day cycle for up to 5 cycles

Variant #6, 80/1250 x 4

Study Evidence Comparator Efficacy
Pérol et al. 2012 Non-randomized portion of RCT
Ferry et al. 2017 (BTOG2) Phase III (E) GC50 Seems to have superior OS
GCb6 Non-inferior OS

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #7, 80/1250 x 6

Study Evidence Comparator Efficacy
Giaccone et al. 2004 (INTACT 1) Phase III (C) Cisplatin, Gefitinib, Gemcitabine Seems not superior
Gatzemeier et al. 2007 (TALENT) Phase III (C) Cisplatin, Erlotinib, Gemcitabine Seems not superior
Reck et al. 2009 (AVAil) Phase III (C) Cisplatin, Gemcitabine, low-dose Bevacizumab Inferior PFS
Cisplatin, Gemcitabine, standard-dose Bevacizumab Seems to have inferior PFS
Boni et al. 2012 (FAST) Phase III (C) GIN
GN
Seems to have superior OS
GIP Seems not superior
Gridelli et al. 2012 (TORCH) Phase III (C) Erlotinib Superior OS

Note: TORCH used a gemcitabine dose of 1200 mg/m2, which is essentially identical to the more common 1250 mg/m2 dosing.

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #8, 80/1250 x 9

Study Evidence Comparator Efficacy
Han et al. 2012 (First-SIGNAL) Phase III (C) Gefitinib Seems not superior

Chemotherapy

21-day cycle for up to 9 cycles

Variant #9, 100/1000

Study Evidence Comparator Efficacy
Schiller et al. 2002 (ECOG E1594) Phase III (E) Carboplatin & Paclitaxel Seems not superior
Cisplatin & Docetaxel Seems not superior
Cisplatin & Paclitaxel Superior PFS
Scagliotti et al. 2008 (JMDB) Phase III (C) Cisplatin & Pemetrexed Seems non-inferior

Chemotherapy

28-day cycles

Variant #10, 100/1250

Study Evidence Comparator Efficacy
Cardenal et al. 1999 Phase III (E) Cisplatin & Etoposide Superior TTP
Alberola et al. 2003 Phase III (C) CGV
GV-VI
Seems not superior

Chemotherapy

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

References

  1. Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, García M, Lianes P, Montalar J, Vadell C, González-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8. link to original article contains protocol PubMed
  2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains protocol PubMed
  3. Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jiménez U, González-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Peñas R, Felip E, López-Vivanco G; Spanish Lung Cancer Group. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003 Sep 1;21(17):3207-13. link to original article contains protocol PubMed
  4. Zatloukal P, Petruzelka L, Zemanová M, Kolek V, Skricková J, Pesek M, Fojtů H, Grygárková I, Sixtová D, Roubec J, Horenková E, Havel L, Průsa P, Nováková L, Skácel T, Kůta M. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003 Sep;41(3):321-31. link to original article contains protocol PubMed
  5. Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Br J Cancer. 2003 Oct 6;89(7):1192-9. link to original article link to PMC article contains protocol PubMed
  6. INTACT 1: Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. link to original article contains protocol PubMed
  7. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
  8. TALENT: Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007 Apr 20;25(12):1545-52. link to original article contains protocol PubMed
  9. JMDB: Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed
  10. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains protocol PubMed
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
  11. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed
  12. FAST: Boni C, Tiseo M, Boni L, Baldini E, Recchia F, Barone C, Grossi F, Germano D, Matano E, Marini G, Labianca R, Di Costanzo F, Bagnulo A, Pennucci C, Caroti C, Mencoboni M, Zanelli F, Prochilo T, Cafferata MA, Ardizzoni A; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). Br J Cancer. 2012 Feb 14;106(4):658-65. Epub 2012 Jan 12. link to original article link to PMC article contains verified protocol PubMed
  13. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed
  14. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed
  15. TORCH: Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, Maione P, Morgillo F, Genestreti G, Favaretto A, Leighl N, Wierzbicki R, Cinieri S, Alam Y, Siena S, Tortora G, Felletti R, Riccardi F, Mancuso G, Rossi A, Cantile F, Tsao MS, Saieg M, da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A, Perrone F. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012 Aug 20;30(24):3002-11. Epub 2012 Jul 9. link to original article contains protocol PubMed
  16. NExUS: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non–small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. Epub 2012 Jul 30. link to original article contains protocol PubMed
  17. 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
  18. FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article contains protocol PubMed
  19. LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article contains verified protocol PubMed
    1. Update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    2. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  20. SQUIRE: Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. Epub 2015 Jun 1. link to original article contains protocol PubMed
  21. ENSURE: Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, Huang C, Qin S, Zhu Y, Pan H, Liang H, Li E, Jiang G, How SH, Fernando MC, Zhang Y, Xia F, Zuo Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015 Sep;26(9):1883-9. Epub 2015 Jun 23. link to original article contains verified protocol PubMed
  22. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  23. BTOG2: Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, O'Byrne K. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer. 2017 Sep;83:302-312. Epub 2017 Aug 4. link to original article contains verified protocol PubMed

Cisplatin, Gemcitabine, Bevacizumab

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Variant #1, low-dose bev

Study Evidence Comparator Efficacy
Reck et al. 2009 (AVAil) Phase III (E) Cisplatin & Gemcitabine Superior PFS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #2, standard-dose bev

Study Evidence Comparator Efficacy
Reck et al. 2009 (AVAil) Phase III (E) Cisplatin & Gemcitabine Seems to have superior PFS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed

Cisplatin, Gemcitabine, Necitumumab

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Regimen

Study Evidence Comparator Efficacy
Thatcher et al. 2015 (SQUIRE) Phase III (E) Cisplatin & Gemcitabine Seems to have superior OS

Patients had stage IV squamous non-small-cell lung cancer

Chemotherapy

Supportive medications

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

21-day cycle for 6 cycles

Subsequent treatment

References

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

Cisplatin & Irinotecan

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IP: Irinotecan & Platinol (Cisplatin)

Regimen

Study Evidence Comparator Efficacy
Negoro et al. 2003 Phase III (E) Cisplatin & Vindesine Seems not superior
Ohe et al. 2006 Phase III (C) Carboplatin & Paclitaxel Seems not superior
Cisplatin & Gemcitabine Seems not superior
Cisplatin & Vinorelbine Seems not superior
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Seems not superior

Chemotherapy

28-day cycle for up to 6 cycles (WJTOG0203) or indefinitely (Ohe et al. 2006)

References

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

Cisplatin & Paclitaxel

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PC: Paclitaxel & Cisplatin

Variant #1, 75/135

Study Evidence Comparator Efficacy
Bonomi et al. 2000 (ECOG E5592) Phase III (E) Cisplatin & Etoposide Might have superior OS
Schiller et al. 2002 (ECOG E1594) Phase III (C) Carboplatin & Paclitaxel Seems not superior
Cisplatin & Docetaxel Seems not superior
Cisplatin & Gemcitabine Inferior PFS

Chemotherapy

21-day cycles

Variant #2, 80/175

Study Evidence Comparator Efficacy
Smit et al. 2003 (EORTC 08975) Phase III (C) Cisplatin & Gemcitabine
Gemcitabine & Paclitaxel
Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles

Variant #3, 80/200

Study Evidence Comparator Efficacy
Rosell et al. 2002 Phase III (E) Carboplatin & Paclitaxel Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. ECOG E5592: Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18(3):623-31. link to original article contains protocol PubMed
  2. ECOG E1594: Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. link to original article contains verified protocol PubMed
  3. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002 Oct;13(10):1539-49. link to original article contains protocol PubMed
  4. EORTC 08975: Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C, Neymark N, Giaccone G; European Organization for Research and Treatment of Cancer Lung Cancer Group. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol. 2003 Nov 1;21(21):3909-17. link to original article contains protocol PubMed

Cisplatin & Pemetrexed

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Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed

Variant #1, 70/500

Study Evidence Comparator Efficacy
Park et al. 2017 Phase III (E) Cisplatin & Docetaxel Inconclusive whether non-inferior

Chemotherapy

21-day cycle for up to 4 cycles

Variant #2, 75/500

FDA-recommended dose
Study Evidence Comparator Efficacy Toxicity
Scagliotti et al. 2008 (JMDB) Phase III (E) Cisplatin & Gemcitabine Seems non-inferior
Paz-Ares et al. 2012 (PARAMOUNT) Non-randomized portion of RCT
Sequist et al. 2013 (LUX-Lung 3) Phase III (C) Afatinib Inferior PFS
Solomon et al. 2014 (PROFILE 1014) Phase III (C) Crizotinib Inferior PFS
Paz-Ares et al. 2015 (INSPIRE) Phase III (C) Cisplatin, Pemetrexed, Necitumumab Seems not superior
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Soria et al. 2017 (ASCEND-4) Phase III (C) Ceritinib Inferior PFS
Shi et al. 2017 (CONVINCE) Phase III (C) See link See link
Gandhi et al. 2018 (KEYNOTE-189) Phase III (C) See link See link

Note: although the FDA does not specify the cisplatin dose to be given with pemetrexed, the JMDB trial is cited in the package insert. Patients in LUX-Lung 3 had activating mutations in EGFR. Patients in CONVINCE had stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Patients in PROFILE 1014 & ASCEND-4 had ALK-rearranged NSCLC. Selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. JMDB: Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 27. link to original article contains protocol PubMed
  2. 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. 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
  3. LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
    2. Update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    3. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  4. PROFILE 1014: Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. link to original article contains verified protocol PubMed
    1. Supgroup analysis: Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, Nakagawa K, Wu YL, Mekhail T, Paolini J, Tursi J, Usari T, Wilner KD, Selaru P, Mok TS. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65. Epub 2016 Mar 28. link to original article PubMed
    2. Update: Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Tang Y, Wilner KD, Blackhall F, Mok TS. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018 Aug 1;36(22):2251-2258. Epub 2018 May 16. link to original article PubMed
  5. INSPIRE: Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA; INSPIRE investigators. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015 Mar;16(3):328-37. Epub 2015 Feb 18. link to original article PubMed
  6. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  7. Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains protocol PubMed
  8. ASCEND-4: Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. Epub 2017 Jan 24. link to original article contains protocol PubMed
  9. CONVINCE: Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. link to original article contains verified protocol PubMed
  10. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Cisplatin, Pemetrexed, Bevacizumab

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Regimen

Study Evidence
Barlesi et al. 2013 (AVAPERL) Non-randomized portion of RCT

Chemotherapy

  • Cisplatin (Platinol) 75 mg/m2 IV over 2 hours once on day 1
  • Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
  • Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1; administered over 90 minutes for the first dose, and if well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes

Supportive medications

21-day cycle for 4 cycles

Subsequent treatment

References

  1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed

Cisplatin, Pemetrexed, Pembrolizumab

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Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Gandhi et al. 2018 (KEYNOTE-189) Phase III (E) See link See link

Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemoimmunotherapy

Supportive medications

21-day cycle for 4 cycles

Subsequent treatment

References

  1. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Cisplatin & Vinorelbine

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

Variant #1, 80/25

Study Evidence Comparator Efficacy
Ohe et al. 2006 Phase III (E) Carboplatin & Paclitaxel Seems not superior
Cisplatin & Gemcitabine Seems not superior
Cisplatin & Irinotecan Seems not superior
Pirker et al. 2009 (FLEX) Phase III (C) Cisplatin, Vinorelbine, Cetuximab Seems to have inferior OS
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles (FLEX; WJTOG0203) or indefinitely (Ohe et al. 2006)

Variant #2, 80/30, 2 out of 3 weeks vinorelbine

Study Evidence Comparator Efficacy
Georgoulias et al. 2005 Phase III (C) Docetaxel & Gemcitabine Seems not superior

Chemotherapy

21-day cycle for up to 9 cycles

Variant #3, 80/30, weekly vinorelbine

Study Evidence Comparator Efficacy
Depierre et al. 1994 Phase III (E) Vinorelbine Superior TTP

Chemotherapy

21-day cycles

Variant #4, 100/25

Study Evidence Comparator Efficacy
Fossella et al. 2003 (TAX 326) Phase III (C) Carboplatin & Docetaxel Seems not superior
Cisplatin & Docetaxel Seems to have inferior OS

Chemotherapy

28-day cycles

Variant #5, 100/30

Study Evidence Comparator Efficacy
Pujol et al. 2005 Phase III (C) Docetaxel & Gemcitabine Seems not superior

Chemotherapy

28-day cycle for 6 cycles

Variant #6, 120/30

Study Evidence Comparator Efficacy
Le Chevalier et al. 1994 Phase III (E) Cisplatin & Vindesine Seems to have superior OS
Vinorelbine Superior OS
Comella et al. 2000 Phase III (C) Cisplatin & Gemcitabine Not reported
PGV Inferior OS

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

Chemotherapy

Continued indefinitely (see note)

References

  1. Depierre A, Chastang C, Quoix E, Lebeau B, Blanchon F, Paillot N, Lemarie E, Milleron B, Moro D, Clavier J, Herman D, Tuchais E, Jacoulet P, Brechot JM, Cordier JF, Solal-Celigny P, Badri N, Besenval M. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol. 1994 Jan;5(1):37-42. link to original article contains protocol PubMed
  2. Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S, Gottfried M, Ruffle P, Panizo A, Gaspard MH, Ravaioli A, Besenval M, Besson F, Martinez A, Berthaud P, Tursz T. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994 Feb;12(2):360-7. link to original article contains protocol PubMed
  3. Comella P, Frasci G, Panza N, Manzione L, De Cataldis G, Cioffi R, Maiorino L, Micillo E, Lorusso V, Di Rienzo G, Filippelli G, Lamberti A, Natale M, Bilancia D, Nicolella G, Di Nota A, Comella G. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 2000 Apr;18(7):1451-7. link to original article contains verified protocol PubMed
  4. TAX 326: Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
  5. Georgoulias V, Ardavanis A, Tsiafaki X, Agelidou A, Mixalopoulou P, Anagnostopoulou O, Ziotopoulos P, Toubis M, Syrigos K, Samaras N, Polyzos A, Christou A, Kakolyris S, Kouroussis C, Androulakis N, Samonis G, Chatzidaki D. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2005 May 1;23(13):2937-45. Epub 2005 Feb 22. link to original article contains verified protocol PubMed
  6. Pujol JL, Breton JL, Gervais R, Rebattu P, Depierre A, Morère JF, Milleron B, Debieuvre D, Castéra D, Souquet PJ, Moro-Sibilot D, Lemarié E, Kessler R, Janicot H, Braun D, Spaeth D, Quantin X, Clary C. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol. 2005 Apr;16(4):602-10. Epub 2005 Mar 1. link to original article contains verified protocol PubMed
  7. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007 Feb;18(2):317-23. Epub 2006 Nov 1. link to original article contains verified protocol PubMed
  8. FLEX: Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains verified protocol PubMed
  9. WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed

Cisplatin, Vinorelbine, Cetuximab

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Regimen

Study Evidence Comparator Efficacy
Pirker et al. 2009 (FLEX) Phase III (E) Cisplatin & Vinorelbine Seems to have superior OS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

  • Cetuximab maintenance

References

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

Gefitinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Mok et al. 2009 (IPASS) Phase III (E) Carboplatin & Paclitaxel Superior PFS
Han et al. 2012 (First-SIGNAL) Phase III (E) Cisplatin & Gemcitabine Seems not superior

Chemotherapy

Continued indefinitely

References

  1. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed
    1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
  2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed

Gemcitabine & Vinorelbine

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VG: Vinorelbine & Gemcitabine

Regimen

Study Evidence Comparator Efficacy
Laack et al. 2004 Phase III (E) GVP Seems not superior
Tan et al. 2005 (GLOB 2) Phase III (E) Carboplatin & Vinorelbine Seems not superior

Chemotherapy

Supportive medications

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

21-day cycles

References

  1. Laack E, Dickgreber N, Müller T, Knuth A, Benk J, Lorenz C, Gieseler F, Dürk H, Engel-Riedel W, Dalhoff K, Kortsik C, Graeven U, Burk M, Dierlamm T, Welte T, Burkholder I, Edler L, Hossfeld DK; German and Swiss Lung Cancer Study Group. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004 Jun 15;22(12):2348-56. link to original article contains protocol PubMed
  2. GLOB 2: Tan EH, Szczesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Pawel JV, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R; GLOB 2 group. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2005 Aug;49(2):233-40. link to original article contains protocol PubMed
  3. Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. link to original article link to PMC article contains protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Efficacy Comparator Efficacy
Carbone et al. 2017 (CheckMate 026) Phase III (E) 26% (95% CI 20 - 33) Platinum doublet Seems not superior

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

Immunotherapy

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

14-day cycles

References

  1. CheckMate 026: Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. link to original articlecontains verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence Comparator Efficacy Toxicity
Reck et al. 2016 (KEYNOTE-024) Phase III (E) Carboplatin & Gemcitabine
Carboplatin & Paclitaxel
Carboplatin & Pemetrexed
Cisplatin & Gemcitabine
Cisplatin & Pemetrexed
Superior OS Superior HRQoL
Mok et al. 2015 (KEYNOTE-042) Phase III (E) Carboplatin & Paclitaxel
Carboplatin & Pemetrexed
Superior OS

KEYNOTE-024 required PD-L1 to be expressed on at least 50% of tumor cells, no EGFR/ALK mutations. Treatment choice for patients in the comparator arm was up to the investigators; most with nonsquamous histology received carboplatin & pemetrexed, whereas most with squamous histology received carboplatin & gemcitabine. Patients could receive a maximum of 35 cycles. ORR was 45% (95% CI: 37-53).
KEYNOTE-042 required PD-L1 to be expressed on at least 1% of tumor cells. Treatment choice for patients in the comparator arm was carboplatin & paclitaxel for patients with squamous histology, and carboplatin & pemetrexed for patients with nonsquamous histology.

Immunotherapy

21-day cycles

References

  1. Phase 1: Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. link to original article PubMed
  2. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  3. Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract

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

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
Gridelli et al. 1999 (Elderly Lung Cancer Vinorelbine Italian Study Group) Phase III (C) Vinorelbine Seems to have inferior OS

No active antineoplastic treatment.

References

  1. 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

Carboplatin & Paclitaxel

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TC: Taxol (Paclitaxel) and Carboplatin

Variant #1, 6/200

Study Evidence Comparator Efficacy
Lilenbaum et al. 2008 Phase III (C) Erlotinib Seems to have superior OS

Chemotherapy

21-day cycle for up to 4 cycles

Variant #2, paclitaxel 3 out of 4 weeks

Study Evidence Comparator Efficacy
Quoix et al. 2011 (IFCT-0501) Phase III (E) Gemcitabine Superior OS
Vinorelbine Superior OS

Study involved only patients 70 to 89 years old

Chemotherapy

Supportive medications

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

28-day cycle for up to 4 cycles

References

  1. Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D. Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol. 2008 Feb 20;26(6):863-9. link to original article contains protocol PubMed
  2. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed

Carboplatin & Pemetrexed

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Example orders

Regimen

Study Evidence Comparator Efficacy
Zukin et al. 2013 (INCA-Lung001) Phase III (E) Pemetrexed Superior OS

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

References

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

Carboplatin, Pemetrexed, Bevacizumab

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Regimen

Study Evidence Comparator Efficacy
Spigel et al. 2018 Randomized Phase II (E) Pemetrexed
Pemetrexed & Bevacizumab
PFS: 4.8 mo

Chemotherapy

Supportive medications

  • Premedications, folic acid, and vitamin supplementation per standard guidelines
  • Antiemetics per standard guidelines

21-day cycle for 4 cycles

Subsequent treatment

References

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

Docetaxel monotherapy

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Example orders

Variant #1, 3 out of 4 weeks

Study Evidence Comparator Efficacy
Hainsworth et al. 2007 Phase III (C) Docetaxel & Gemcitabine Seems not superior

Chemotherapy

28-day cycles

Variant #2, q3wk

Study Evidence Comparator Efficacy
Kudoh et al. 2006 (WJTOG 9904) Phase III (E) Vinorelbine Seems not superior
Abe et al. 2015 (JCOG0803/WJOG4307L) Phase III (C) Cisplatin & Docetaxel Seems not superior

This is the PMDA-approved dose.

Chemotherapy

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

References

  1. WJTOG 9904: Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. link to original article contains protocol PubMed
  2. Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, Houston GA, Greco FA. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007 Nov 1;110(9):2027-34. link to original article contains protocol PubMed
  3. JCOG0803/WJOG4307L: Abe T, Takeda K, Ohe Y, Kudoh S, Ichinose Y, Okamoto H, Yamamoto N, Yoshioka H, Minato K, Sawa T, Iwamoto Y, Saka H, Mizusawa J, Shibata T, Nakamura S, Ando M, Yokoyama A, Nakagawa K, Saijo N, Tamura T. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015 Feb 20;33(6):575-81. Epub 2015 Jan 12. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Variant #1, 1150 mg/m2

Study Evidence Comparator Efficacy
Quoix et al. 2011 (IFCT-0501) Phase III (C) Carboplatin & Paclitaxel Inferior OS

Study involved only patients 70 to 89 years old

Chemotherapy

Supportive medications

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

21-day cycle for up to 5 cycles

Variant #2, 1200 mg/m2

Study Evidence Comparator Efficacy
Gridelli et al. 2003 (MILES) Phase III (E) Gemcitabine & Vinorelbine Seems not superior
Vinorelbine Seems not superior
Gridelli et al. 2018 (MILES-3/MILES-4) Phase III (C) Cisplatin & Gemcitabine Seems not superior

Studies involved only patients at least 70 years old

Chemotherapy

Supportive medications

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

21-day cycle for up to 6 cycles

References

  1. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
  2. SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains protocol PubMed
  3. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed
  4. MILES-3/MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed

Gemcitabine & Paclitaxel

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GT: Gemcitabine & Taxol (Paclitaxel)

Regimen

Study Evidence Comparator Efficacy
Comella et al. 2004 (SICOG 9909) Phase III (E) Gemcitabine Seems not superior
GV Seems not superior
Paclitaxel Seems to have superior OS

Chemotherapy

21-day cycle for up to 6 cycles

References

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

Gemcitabine & Vinorelbine

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GV: Gemcitabine & Vinorelbine
VG: Vinorelbine & Gemcitabine

Variant #1, 1000/25

Study Evidence Comparator Efficacy
Gridelli et al. 2003 (MILES) Phase III (E) Gemcitabine Seems not superior
Vinorelbine Seems not superior

This study involved only patients at least 70 years old

Chemotherapy

Supportive medications

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

21-day cycle for up to 6 cycles

Variant #2, 1200/30

Study Evidence Comparator Efficacy
Frasci et al. 2000 Phase III (E) Vinorelbine Superior OS

This study involved only patients at least 70 years old

Chemotherapy

21-day cycle for up to 6 cycles

References

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

Pemetrexed monotherapy

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Example orders

Regimen

Study Evidence Comparator Efficacy
Zukin et al. 2013 (INCA-Lung001) Phase III (C) Carboplatin & Pemetrexed Inferior OS
Gridelli et al. 2018 (MILES-4) Phase III (C) Cisplatin & Gemcitabine
Cisplatin & Pemetrexed
Seems not superior

Chemotherapy

21-day cycle for up to 4 cycles (INCA-Lung001) or 6 cycles (MILES-4)

References

  1. INCA-Lung001: Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III Trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. link to original article contains verified protocol PubMed
  2. Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed
  3. MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed

Pemetrexed & Bevacizumab

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Regimen

Study Evidence Comparator Efficacy
Spigel et al. 2018 Randomized Phase II (E) Pemetrexed
Carboplatin, Pemetrexed, Bevacizumab
PFS: 4.0 mo

Chemotherapy

Supportive medications

  • Premedications, folic acid, and vitamin supplementation per standard guidelines
  • Antiemetics per standard guidelines

21-day cycles

References

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

Placebo

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Regimen

Study Evidence Comparator Efficacy
Lee et al. 2012 (TOPICAL) Phase III (C) Erlotinib Seems not superior

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

Vinorelbine monotherapy

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Variant #1, 25 mg/m2

Study Evidence Comparator Efficacy
Kudoh et al. 2006 (WJTOG 9904) Phase III (C) Docetaxel Seems not superior
Quoix et al. 2011 (IFCT-0501) Phase III (C) Carboplatin & Paclitaxel Inferior OS

IFCT-0501 involved only patients 70 to 89 years old

Chemotherapy

Supportive medications

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

21-day cycle for up to 4 cycles (WJTOG 9904) or 5 cycles (IFCT-0501)

Variant #2, 30 mg/m2

Study Evidence Comparator Efficacy
Gridelli et al. 1999 (Elderly Lung Cancer Vinorelbine Italian Study Group) Phase III (E) Best supportive care Seems to have superior OS
Gridelli et al. 2003 (MILES) Phase III (C) Gemcitabine Seems not superior
Gemcitabine & Vinorelbine Seems not superior

Study involved only patients at least 70 years old

Chemotherapy

Supportive medications

  • (varies depending on reference):
  • Elderly Lung Cancer Vinorelbine Italian Study Group, 1999: Metoclopramide (Reglan) 20 mg IV bolus prior to Vinorelbine (Navelbine)
  • Gridelli et al. 2003: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for up to 6 cycles

References

  1. 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. MILES: Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, Barbera S, Ferraù F, Piazza E, Rosetti F, Clerici M, Bertetto O, Robbiati SF, Frontini L, Sacco C, Castiglione F, Favaretto A, Novello S, Migliorino MR, Gasparini G, Galetta D, Iaffaioli RV, Gebbia V; MILES Investigators. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003 Mar 5;95(5):362-72. link to original article contains verified protocol PubMed
  3. WJTOG 9904: Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, Shinkai T, Sawa T, Goto I, Semba H, Seto T, Ando M, Satoh T, Yoshimura N, Negoro S, Fukuoka M. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1;24(22):3657-63. link to original article contains protocol PubMed
  4. IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed

Maintenance after first-line therapy

Atezolizumab & Bevacizumab

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Regimen

Study Evidence
Socinski et al. 2018 (IMpower150) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycles

References

  1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Bevacizumab monotherapy

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Variant #1, 7.5 mg/kg

Study Evidence Comparator Efficacy
Reck et al. 2009 (AVAil) Non-randomized portion of RCT
Barlesi et al. 2013 (AVAPERL) Phase III (C) Bevacizumab & Pemetrexed maintenance Inferior PFS

Preceding treatment

Chemotherapy

21-day cycles

Variant #2, 15 mg/kg

Study Evidence Comparator Efficacy Toxicity
Sandler et al. 2006 (ECOG E4599) Phase III (E) See link See link
Reck et al. 2009 (AVAil) Non-randomized portion of RCT
Johnson et al. 2013 (ATLAS) Phase III (C) Erlotinib & Bevacizumab maintenance Inferior PFS (*) Less toxic
Patel et al. 2013 (PointBreak) Non-randomized portion of RCT
Zinner et al. 2015 (PRONOUNCE) Phase III (C) See link See link
Socinski et al. 2018 (IMpower150) Non-randomized portion of RCT

Note that while this arm was inferior in ATLAS, the authors note that, due to toxicity, the "two-drug maintenance regimen will not lead to a new postchemotherapy standard of care."

Preceding treatment

Chemotherapy

21-day cycles

References

  1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
  2. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
  3. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  4. ATLAS: Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, Lin CY, Marsland T, Patel T, Polikoff J, Rubin M, White L, Yang JC, Bowden C, Miller V. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013 Nov 1;31(31):3926-34. Epub 2013 Oct 7. link to original article contains verified protocol in supplement PubMed
  5. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
  6. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
  7. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed

Erlotinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Cappuzzo et al. 2010 (SATURN) Phase III (E) Placebo Superior PFS
Pérol et al. 2012 Phase III (E) Gemcitabine Not reported
Observation Superior PFS
Cicènas et al. 2016 (IUNO) Phase III (E) See link See link

Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks.

Preceding treatment

Chemotherapy

Continued indefinitely

References

  1. 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
  2. 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 article contains verified protocol PubMed
  3. 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

Gemcitabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Pérol et al. 2012 Phase III (E) Erlotinib Not reported
Observation Superior PFS

Preceding treatment

Chemotherapy

21-day cycles

References

  1. 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

Ipilimumab monotherapy

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Regimen

Study Evidence
Lynch et al. 2012 Non-randomized portion of RCT
Govindan et al. 2017 (CA184-104) Non-randomized portion of RCT

Preceding treatment

Immunotherapy

12-week cycles

References

  1. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
  2. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Necitumumab monotherapy

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Regimen

Study Evidence
Thatcher et al. 2015 (SQUIRE) Non-randomized portion of RCT

Patients had stage IV squamous non-small-cell lung cancer.

Preceding treatment

Chemotherapy

21-day cycles

References

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

Observation

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Regimen

Study Evidence Comparator Efficacy
Pérol et al. 2012 Phase III (C) Erlotinib Inferior PFS
Gemcitabine Inferior PFS

No further treatment after first-line therapy.

Preceding treatment

References

  1. 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

Pemetrexed monotherapy

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Example orders

Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Ciuleanu et al. 2009 (JMEN) Phase III (E) Placebo Seems to have superior OS
Paz-Ares et al. 2012 (PARAMOUNT) Phase III (E) Placebo Superior PFS
Zinner et al. 2015 (PRONOUNCE) Phase III (E) See link See link
Reck et al. 2016 (KEYNOTE-024) Non-randomized portion of RCT
Langer et al. 2016 (KEYNOTE-021) Non-randomized portion of RCT
Mok et al. 2015 (KEYNOTE-042) Non-randomized portion of RCT
Shi et al. 2017 (CONVINCE) Phase III (C) See link See link
Gandhi et al. 2018 (KEYNOTE-189) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Supportive medications

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

21-day cycles

References

  1. JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, 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
  2. 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. 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
  3. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
  4. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
  5. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed
  6. Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract
  7. CONVINCE: Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. link to original article contains verified protocol PubMed
  8. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Pemetrexed & Bevacizumab

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Variant #1, 500/7.5

Study Evidence Comparator Efficacy
Barlesi et al. 2013 (AVAPERL) Phase III (E) Bevacizumab maintenance Superior PFS

Preceding treatment

Chemotherapy

Supportive medications

21-day cycles

Variant #2, 500/15

Study Evidence
Patel et al. 2013 (PointBreak) Non-randomized portion of RCT
Spigel et al. 2018 Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Supportive medications

  • Premedications, folic acid, and vitamin supplementation per pemetrexed label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycles

References

  1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  2. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
  3. Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed

Pemetrexed & Pembrolizumab

Source: Pembrolizumab & Pemetrexed maintenance therapy for advanced or metastatic non-small cell lung cancer

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Regimen

Study Evidence Comparator Efficacy
Langer et al. 2016 (KEYNOTE-021) Randomized Phase II (E) See link See link
Gandhi et al. 2018 (KEYNOTE-189) Phase III (E) See link See link

Note: the pemetrexed portion of the protocol was optional in KEYNOTE-021.

Preceding treatment

Chemotherapy

Supportive medications

21-day cycle for up to 2 years (35 cycles total, including induction)

Subsequent treatment

References

  1. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary appendixPubMed
  2. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Ciuleanu et al. 2009 (JMEN) Phase III (E) Pemetrexed Seems to have inferior OS
Cappuzzo et al. 2010 (SATURN) Phase III (C) Erlotinib Inferior PFS
Koch et al. 2011 (CYCLUS) Phase III (C) Celecoxib Seems not superior
Paz-Ares et al. 2012 (PARAMOUNT) Phase III (C) Pemetrexed Inferior PFS
Giaccone et al. 2015 Phase III (C) Belagenpumatucel-L Seems not superior
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

  • JMEN, SATURN, IUNO: 4 cycles of platinum-doublet therapy
  • PARAMOUNT: Cisplatin & Pemetrexed x 4
  • Giaccone et al. 2015: Platinum-based chemotherapy

Subsequent treatment

References

  1. JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, 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
  2. 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
  3. 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
  4. 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. 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
  5. 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
  6. 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
  7. 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, subsequent lines of therapy

Afatinib monotherapy

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Variant #1, 30 mg/d

FDA-recommended dose

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

Chemotherapy

Given indefinitely

Variant #2, 40 mg/d

FDA-recommended dose
Study Evidence Comparator Efficacy
Soria et al. 2015 (LUX-Lung 8) Phase III (E) Erlotinib Superior OS

Chemotherapy

Given indefinitely

Variant #3, 50 mg/d

Study Evidence Comparator Efficacy
Miller et al. 2012 (LUX-Lung 1) Phase III (E) Placebo Superior PFS
Katakami et al. 2013 (LUX-Lung 4) Phase II ORR: 8% (95% CI: 3-18)

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

Chemotherapy

Given indefinitely

References

  1. LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
  2. LUX-Lung 4: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: A phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
  3. LUX-Lung 8: Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains protocol PubMed

Amrubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Yoshioka et al. 2017 Phase III (E) Docetaxel Seems not superior

Chemotherapy

21-day cycles

References

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

Atezolizumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Fehrenbacher et al. 2016 (POPLAR) Randomized Phase II (E) Docetaxel Seems to have superior OS
Rittmeyer et al. 2017 (OAK) Phase III (E) Docetaxel Superior OS

Immunotherapy

21-day cycles

References

  1. POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains protocol PubMed
  2. OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. link to original article PubMed

Cabozantinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512) Randomized Phase II (E) Cabozantinib & Erlotinib Not reported
Erlotinib Superior PFS

Chemotherapy

Continued indefinitely

References

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

Cabozantinib & Erlotinib

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Regimen

Study Evidence Comparator Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512) Randomized Phase II (E) Cabozantinib Not reported
Erlotinib Superior PFS

Chemotherapy

Continued indefinitely

References

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

Carboplatin & Pemetrexed

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Example orders

Regimen

Study Evidence Comparator Efficacy
Ardizzoni et al. 2012 (GOIRC 02-2006) Randomized Phase II (E) Pemetrexed Seems not superior
Mok et al. 2016 (AURA3) Phase III (C) Osimertinib Inferior PFS

Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.

Chemotherapy

Supportive medications

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

21-day cycle for 4 to 6 cycles, or until progressive disease, unacceptable toxicity, or patient refusal

Subsequent treatment

References

  1. Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. link to original article contains verified protocol PubMed
  2. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains verified protocol PubMed

Cisplatin & Pemetrexed

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Regimen

Study Evidence Comparator Efficacy
Soria et al. 2015 (IMPRESS) Phase III (C) Cisplatin, Pemetrexed, Gefitinib Seems not superior
Mok et al. 2016 (AURA3) Phase III (C) Osimertinib Inferior PFS

Patients enrolled in IMPRESS were EGFR mutation positive and had progression after first-line gefitinib. Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. IMPRESS: Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):990-8. Epub 2015 Jul 6. link to original article contains verified protocol PubMed
  2. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains verified protocol PubMed

Docetaxel monotherapy

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Example orders

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

Study Evidence Comparator Efficacy
Chen et al. 2006 Phase III (E) Docetaxel 40 mg/m2, 2 out of 3 wks Seems not superior
Docetaxel 75 mg/m2, every 3 wks Seems not superior
Garassino et al. 2013 (TAILOR) Phase III (C) Erlotinib Seems to have superior OS

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel

28-day cycles

Variant #2, 60 mg/m2 q3wk, limited duration

Study Evidence Comparator Efficacy
Herbst et al. 2010 (ZODIAC) Phase III (C) Docetaxel & Vandetanib Inferior PFS

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

Chemotherapy

21-day cycle for up to 6 cycles

Variant #3, 60 mg/m2 q3wk, indefinite

Study Evidence Comparator Efficacy
Kawaguchi et al. 2014 (DELTA) Phase III (C) Erlotinib Might have superior PFS
Garon et al. 2014 (REVEL) Phase III (C) Docetaxel & Ramucirumab Seems to have inferior OS
Yoshioka et al. 2017 Phase III (C) Amrubicin Seems not superior
Nokihara et al. 2017 Phase III (C) S-1 Non-inferior OS

This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in Nokihara et al. 2017.

Chemotherapy

21-day cycles

Variant #4, 75 mg/m2 q3wk, limited duration

Study Evidence Comparator Efficacy
Herbst et al. 2010 (ZODIAC) Phase III (C) Docetaxel & Vandetanib Inferior PFS

While statistically inferior, the median PFS difference was only 0.8 months.

Chemotherapy

21-day cycle for up to 6 cycles

Variant #5, 75 mg/m2 q3wk, indefinite

Study Evidence Comparator Efficacy
Shepherd et al. 2000 Phase III (E) Best supportive care Seems to have superior OS
Fossella et al. 2000 (TAX 320) Phase III (E) Docetaxel 100 mg/m2 Seems not superior
Ifosfamide
Vinorelbine
Seems not superior
Hanna et al. 2004 (JMEI) Phase III (C) Pemetrexed Inconclusive whether non-inferior
Chen et al. 2006 Phase III (C) Docetaxel 35 mg/m2, 3 out of 4 wks Seems not superior
Docetaxel 40 mg/m2, 2 out of 3 wks Seems not superior
Kim et al. 2008 (INTEREST) Phase III (C) Gefitinib Seems non-inferior
Fidias et al. 2008 Phase III (C) Docetaxel consolidation Might have inferior OS
Ramlau et al. 2012 Phase III (C) Docetaxel & ziv-Aflibercept Seems not superior
Shaw et al. 2013 (PROFILE 1007) Phase III (C) Crizotinib Inferior PFS
Garassino et al. 2013 (TAILOR) Phase III (C) Erlotinib Seems to have superior OS
Reck et al. 2014 (LUME-Lung 1) Phase III (C) Docetaxel & Nintedanib Inferior PFS
Garon et al. 2014 (REVEL) Phase III (C) Docetaxel & Ramucirumab Seems to have inferior OS
Blumenschein et al. 2015 Randomized Phase II (C) Trametinib Seems not superior
Brahmer et al. 2015 (CheckMate 017) Phase III (C) Nivolumab Inferior OS
Borghaei et al. 2015 (CheckMate 057) Phase III (C) Nivolumab Inferior OS
Herbst et al. 2015 (KEYNOTE-010) Phase II/III (C) Pembrolizumab Inferior OS
Fehrenbacher et al. 2016 (POPLAR) Randomized Phase II (C) Atezolizumab Seems to have inferior OS
Rittmeyer et al. 2016 (OAK) Phase III (C) Atezolizumab Inferior OS
Jänne et al. 2017 (SELECT-1) Phase III (C) Docetaxel & Selumetinib Seems not superior
Shaw et al. 2017 (ASCEND-5) Phase III (C) Ceritinib Inferior PFS
Katakami et al. 2017 (E7389-G000-302) Phase III (C) Eribulin Seems not superior
Nokihara et al. 2017 Phase III (C) S-1 Non-inferior OS

Patients in Blumenschein et al. 2015 and SELECT-1 had KRAS-mutated NSCLC. Patients in ASCEND-5 had ALK-rearranged NSCLC progressed after crizotinib.

Chemotherapy

Supportive medications

  • Per JMEI: Dexamethasone (Decadron) 8 mg PO BID the day before, the day of, and the day after docetaxel
  • Per Chem et al. 2006: Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel

21-day cycles

References

  1. Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, Murphy WK, Lippman S, Benner S, Glisson B, Chasen M, Hong WK, Raber M. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol. 1995 Mar;13(3):645-51. link to original article PubMed
  2. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. link to original article contains protocol PubMed
  3. TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; The TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains verified protocol PubMed
  4. JMEI: Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains verified protocol PubMed
  5. Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. link to original article contains verified protocol PubMed
  6. INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains protocol PubMed
  7. Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, Hristova-Kazmierski M, Treat J, Obasaju CK, Marciniak M, Gill J, Schiller JH. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1;27(4):591-8. Epub 2008 Dec 15. link to original articlecontains verified protocol PubMed
  8. ZODIAC: Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010 Jul;11(7):619-26. link to original article link to PMC article contains verified protocol PubMed
  9. Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Le-Guennec S, Rey A, Miller V, Thatcher N, Scagliotti G. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10;30(29):3640-7. Epub 2012 Sep 10. link to original article contains protocol PubMed
  10. PROFILE 1007: Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed
  11. TAILOR: Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. link to original article contains verified protocol PubMed
  12. LUME-Lung 1: Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. link to original article PubMed
  13. DELTA: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains verified protocol PubMed
  14. REVEL: Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. Epub 2014 Jun 2.link to original article contains verified protocol PubMed
  15. Blumenschein GR Jr, Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn MJ, Hanna NH, Kim JH, Mazieres J, Kim SW, Baas P, Rappold E, Redhu S, Puski A, Wu FS, Jänne PA. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. Ann Oncol. 2015 May;26(5):894-901. Epub 2015 Feb 26. link to original article link to PMC article contains verified protocol PubMed
  16. CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article PubMed
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
  17. CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
  18. KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains protocol PubMed
  19. POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains protocol PubMed
  20. OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. link to original article contains protocol PubMed
  21. Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains verified protocol PubMed
  22. SELECT-1: Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, Orlov S, Blackhall F, Wolf J, Garrido P, Poltoratskiy A, Mariani G, Ghiorghiu D, Kilgour E, Smith P, Kohlmann A, Carlile DJ, Lawrence D, Bowen K, Vansteenkiste J. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: The SELECT-1 randomized clinical trial. JAMA. 2017 May 9;317(18):1844-1853. link to original article contains verified protocol PubMed
  23. ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original articlecontains protocolPubMed
  24. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed
  25. Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article contains verified protocol PubMed

Docetaxel & Ramucirumab

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Variant #1, 60 mg/m2 docetaxel

FDA-recommended dose
Study Evidence Comparator Efficacy
Garon et al. 2014 (REVEL) Phase III (E) Docetaxel Seems to have superior OS

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

Chemotherapy

Supportive medications

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

21-day cycles

Variant #2, 75 mg/m2 docetaxel

FDA-recommended dose
Study Evidence Comparator Efficacy
Garon et al. 2014 (REVEL) Phase III (E) Docetaxel Seems to have superior OS

Note: The FDA only provides recommendations for ramucirumab dosing.

Chemotherapy

Supportive medications

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

21-day cycles

References

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

Docetaxel & Vandetanib

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Variant #1, 60 mg/m2 docetaxel

Study Evidence Comparator Efficacy
Herbst et al. 2010 (ZODIAC) Phase III (E) Docetaxel Superior PFS

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

Chemotherapy

21-day cycle for up to 6 cycles (*)

Variant #2, 75 mg/m2 docetaxel

Study Evidence Comparator Efficacy
Herbst et al. 2010 (ZODIAC) Phase III (E) Docetaxel Superior PFS

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

Chemotherapy

21-day cycle for up to 6 cycles (*)

References

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

Erlotinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Shepherd et al. 2005 (NCIC CTG BR.21) Phase III (E) Placebo Superior OS
Natale et al. 2011 (ZEST) Phase III (C) Vandetanib Seems not superior
Herbst et al. 2011 (BeTa) Phase III (C) Erlotinib & Bevacizumab Seems not superior
Scagliotti et al. 2012 (SUN 1087) Phase III (C) Erlotinib & Sunitinib Seems not superior
Ramalingam et al. 2012 (A7471028) Randomized Phase II (C) Dacomitinib Seems to have inferior PFS
Garassino et al. 2013 (TAILOR) Phase III (E) Docetaxel Seems to have inferior OS
Kawaguchi et al. 2014 (DELTA) Phase III (E) Docetaxel Might have inferior PFS
Ramalingam et al. 2014 (ARCHER 1009) Phase III (C) Dacomitinib Seems not superior
Scagliotti et al. 2015 (ADVIGO 1018) Phase III (C) Erlotinib & Figitumumab Seems not superior
Soria et al. 2015 (LUX-Lung 8) Phase III (C) Afatinib Inferior OS
Scagliotti et al. 2015 (ARQ197-A-U302) Phase III (C) Erlotinib & Tivantinib Seems not superior
Urata et al. 2016 (WJOG 5108L) Phase III (C) Gefitinib Inconclusive whether non-inferior
Smit et al. 2016 (CurrentS) Phase III (C) High-dose Erlotinib Seems not superior
Cicènas et al. 2016 (IUNO) Phase III (C) See link See link
Neal et al. 2016 (ECOG-ACRIN 1512) Randomized Phase II (C) Cabozantinib Inferior PFS
Cabozantinib & Erlotinib Inferior PFS
Spigel et al. 2016 (METLung) Phase III (C) Erlotinib & Onartuzumab Might have superior OS

Preceding treatment

Chemotherapy

Continued indefinitely

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. ZEST: Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, Ferry D, Mulatero C, Whorf R, Thompson J, Barlesi F, Langmuir P, Gogov S, Rowbottom JA, Goss GD. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011 Mar 10;29(8):1059-66. Epub 2011 Jan 31. link to original article contains protocol PubMed
  3. BeTa: Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh CH, O'Connor P, Hainsworth J. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011 May 28;377(9780):1846-54. link to original article link to PMC article contains protocol PubMed
  4. SUN 1087: Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, Wierzbicki RF, Albert I, Thomas M, Miziara JE, Papai ZS, Karaseva N, Thongprasert S, Portulas ED, von Pawel J, Zhang K, Selaru P, Tye L, Chao RC, Govindan R. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2070-8. Epub 2012 May 7. link to original article contains protocol PubMed
  5. A7471028: Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012 Sep 20;30(27):3337-44. link to original article link to PMC article PubMed
  6. TAILOR: Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. Epub 2013 Jul 22. link to original article contains verified protocol PubMed
  7. DELTA: Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8. Epub 2014 May 19. link to original article contains verified protocol PubMed
  8. ARCHER 1009: Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15.link to original article PubMed
  9. ADVIGO 1018: Scagliotti GV, Bondarenko I, Blackhall F, Barlesi F, Hsia TC, Jassem J, Milanowski J, Popat S, Sanchez-Torres JM, Novello S, Benner RJ, Green S, Molpus K, Soria JC, Shepherd FA. Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer. Ann Oncol. 2015 Mar;26(3):497-504. Epub 2014 Nov 13. link to original article PubMed
  10. LUX-Lung 8: Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains protocol PubMed
  11. ARQ197-A-U302: Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, Akerley W, Orlov S, Santoro A, Spigel D, Hirsh V, Shepherd FA, Sequist LV, Sandler A, Ross JS, Wang Q, von Roemeling R, Shuster D, Schwartz B. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Aug 20;33(24):2667-74. Epub 2015 Jul 13. link to original article contains protocol PubMed
  12. WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article contains verified protocol PubMed
  13. CurrentS: Smit EF, Wu YL, Gervais R, Zhou C, Felip E, Feng J, Guclu SZ, Hoiczyk M, Dorokhova E, Freudensprung U, Grange S, Perez-Moreno PD, Mitchell L, Reck M. A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS). Lung Cancer. 2016 Sep;99:94-101. Epub 2016 Jun 27. link to original article PubMed
  14. 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
  15. ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN 1512 Investigators. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed
  16. METLung: Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol. 2017 Feb;35(4):412-420. Epub 2016 Dec 12. link to original article contains verified protocol PubMed

Gefitinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kris et al. 2003 (IDEAL2) Randomized Phase II (E) Gefitinib 500 mg/day Seems not superior
Thatcher et al. 2005 (ISEL) Phase III (E) Placebo Might have superior OS
Kim et al. 2008 (INTEREST) Phase III (E) Docetaxel Seems non-inferior
Han et al. 2011 Randomized Phase II (C) Gefitinib & Simvastatin Seems not superior
Shi et al. 2013 (ICOGEN) Phase III (C) Icotinib Seems non-inferior
Urata et al. 2016 (WJOG 5108L) Phase III (C) Erlotinib Inconclusive whether non-inferior

Chemotherapy

Continued indefinitely

References

  1. IDEAL2: Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22;290(16):2149-58. link to original article PubMed
  2. ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article PubMed
  3. INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains verified protocol PubMed
  4. Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. link to orinigal article contains protocol PubMed
  5. ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article PubMed
  6. WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Variant #1, 1000 mg/m2

Study Evidence Comparator Efficacy
Crinò et al. 1999 Phase II
Katakami et al. 2017 (E7389-G000-302) Phase III (C) Eribulin Seems not superior

Chemotherapy

28-day cycles

Variant #2, 1250 mg/m2

Study Evidence Comparator Efficacy
Katakami et al. 2017 (E7389-G000-302) Phase III (C) Eribulin Seems not superior

Chemotherapy

21-day cycles

References

  1. Crinò L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1999 Jul;17(7):2081-5. link to original article contains protocol PubMed
  2. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed

Icotinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Shi et al. 2013 (ICOGEN) Phase III (E) Gefitinib Seems non-inferior

Note: this drug is only approved in China.

Chemotherapy

Continued indefinitely

References

  1. ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article contains protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Efficacy Comparator Efficacy
Rizvi et al. 2015 (CheckMate 063) Phase II 14% (95% CI 9 - 22)
Brahmer et al. 2015 (CheckMate 017) Phase III (E) 20% (95% CI 14 - 28) Docetaxel Superior OS
Borghaei et al. 2015 (CheckMate 057) Phase III (E) 19% (95% CI 15 - 24) Docetaxel Superior OS

Patients in CheckMate 017 had squamous histology. Patients in CheckMate 057 had non-squamous histology.

Immunotherapy

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

14-day cycles

References

  1. CheckMate 063: Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Feb 19. link to original article contains verified protocol PubMed
  2. CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article PubMed
  3. CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence Efficacy Comparator Efficacy Pt Population
Herbst et al. 2015 (KEYNOTE-010) Phase II/III (E) 2 mg/kg: 18% (95% CI 14 - 23)

10 mg/kg: 19% (95% CI 15 - 23)

Docetaxel Superior OS Chemo exposed

Immunotherapy

21-day cycles

References

  1. Phase 1: Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. Epub 2015 Apr 19. link to original article PubMed
  2. KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains protocol PubMed

Pemetrexed monotherapy

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Example orders

Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Hanna et al. 2004 (JMEI) Phase III (E) Docetaxel Inconclusive whether non-inferior
de Boer et al. 2011 (ZEAL) Phase III (C) Pemetrexed & Vandetanib Seems not superior
Ardizzoni et al. 2012 (GOIRC 02-2006) Randomized Phase II (C) Carboplatin & Pemetrexed Seems not superior
Shaw et al. 2013 Phase III (C) Crizotinib Inferior PFS
Kim et al. 2013 Phase III (C) Pemetrexed & Cetuximab Seems not superior
Hanna et al. 2016 (LUME-Lung 2) Phase III (C) Nintedanib & Pemetrexed Seems to have inferior PFS
Shaw et al. 2017 (ASCEND-5) Phase III (C) Ceritinib Inferior PFS
Katakami et al. 2017 (E7389-G000-302) Phase III (C) Eribulin Seems not superior

Note: Kim et al. 2013 also evaluated docetaxel versus docetaxel & cetuximab, but did not report the efficacy of this comparison; see paper for details. Patients in ASCEND-5 had ALK-rearranged NSCLC that had progressed on crizotinib.

Chemotherapy

Supportive medications

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

21-day cycles

Ardizzoni et al. 2012 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.

References

  1. JMEI: Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains protocol PubMed
  2. ZEAL: de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. Epub 2011 Jan 31. link to original article contains protocol PubMed
  3. GOIRC 02-2006: Ardizzoni A, Tiseo M, Boni L, Vincent AD, Passalacqua R, Buti S, Amoroso D, Camerini A, Labianca R, Genestreti G, Boni C, Ciuffreda L, Di Costanzo F, de Marinis F, Crinò L, Santo A, Pazzola A, Barbieri F, Zilembo N, Colantonio I, Tibaldi C, Mattioli R, Cafferata MA, Camisa R, Smit EF. Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. J Clin Oncol. 2012 Dec 20;30(36):4501-7. Epub 2012 Oct 29. link to original article contains verified protocol PubMed
  4. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed
  5. Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. Epub 2013 Nov 12. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article contains protocol PubMed
  6. LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed
  7. ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original articlecontains protocolPubMed
  8. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
Shepherd et al. 2005 (NCIC CTG BR.21) 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 Seems not superior
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 Seems not superior
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
  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

S-1 monotherapy

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Regimen

Study Evidence Comparator Efficacy
Nokihara et al. 2017 Phase III (E) Docetaxel Non-inferior OS

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA less than 1.25 m2: 40 mg PO BID on days 1 to 28
    • BSA at least 1.25 m2 and less than 1.5 m2: 50 mg PO BID on days 1 to 28
    • BSA 1.5 m2 or more: 60 mg PO BID on days 1 to 28

42-day cycles

References

  1. Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article PubMed

Sorafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Paz-Ares et al. 2015 (MISSION) Phase III (E) Placebo Superior PFS

Note: although the primary endpoint (OS) was negative overall, the authors note that the subgroup of patients with known EGFR mutations treated with sorafenib had significantly superior survival (p=0.002).

Chemotherapy

Continued indefinitely

References

  1. 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

Vinorelbine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Fossella et al. 2000 (TAX 320) Phase III (C) Docetaxel 100 mg/m2 Seems not superior
Docetaxel 75 mg/m2 Seems not superior
Katakami et al. 2017 (E7389-G000-302) Phase III (C) Eribulin Seems not superior

Chemotherapy

Supportive medications

  • Per TAX 320:
  • Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive G-CSF (dose/schedule/duration not specified)
  • Metoclopramide (Reglan) (dose/schedule/route not specified) used first for nausea
  • Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as Ondansetron (Zofran) or Granisetron (dose/schedule/route not specified) prn nausea

Continued indefinitely

References

  1. TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; The TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains verified protocol PubMed
  2. E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed

Investigational agents

Drugs with some degree of promising activity in clinical trials.