Non-small cell lung cancer

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Travis Osterman, DO, MS
Vanderbilt University
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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:

114 regimens on this page
210 variants on this page

Contents


Guidelines

ASCO

Older

ASCO/CCO

Current

Former

ESMO

Older

NCCN

Neoadjuvant therapy

Cisplatin & Docetaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Pless et al. 2015 (SAKK 16/00) Phase III (C) Cisplatin & Docetaxel, then RT Did not meet primary endpoint of EFS

This trial included patients with Stage IIIA or N2 NSCLC.

Chemotherapy

Subsequent treatment

References

  1. SAKK 16/00: Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Früh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015 Sep 12;386(9998):1049-56. Epub 2015 Aug 11. Erratum in: Lancet. 2015 Sep 12;386(9998):1040. link to original article PubMed

Cisplatin & Gemcitabine

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Regimen

Study Evidence Comparator Comparative Efficacy
Scagliotti et al. 2011 Phase III (E-esc) 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

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

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

Subsequent treatment

References

  1. Mattson KV, Abratt RP, ten Velde G, Krofta K. Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomised phase III study. Ann Oncol. 2003 Jan;14(1):116-22. link to original article PubMed
  2. MRC LU22/NVALT 2/EORTC 08012: Gilligan D, Nicolson M, Smith I, Groen H, Dalesio O, Goldstraw P, Hatton M, Hopwood P, Manegold C, Schramel F, Smit H, van Meerbeeck J, Nankivell M, Parmar M, Pugh C, Stephens R. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007 Jun 9;369(9577):1929-37. link to original article PubMed
  3. SWOG S9900: Pisters KM, Vallières E, Crowley JJ, Franklin WA, Bunn PA Jr, Ginsberg RJ, Putnam JB Jr, Chansky K, Gandara D. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol. 2010 Apr 10;28(11):1843-9. Epub 2010 Mar 15. link to original article link to PMC article PubMed
  4. 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 Comparative Efficacy
Strauss et al. 2008 (CALGB 9633) Phase III (E-esc) Observation Did not meet primary endpoint of OS

Preceding treatment

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 Comparative Efficacy Comparative Toxicity
Barlesi et al. 2015 Phase III (E-switch-ic) Cisplatin & Gemcitabine Did not meet primary endpoint of QoL
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) 1. Cisplatin, Docetaxel, Bevacizumab
2. Cisplatin, Gemcitabine, Bevacizumab
3. Cisplatin, Pemetrexed, Bevacizumab
4. Cisplatin, Vinorelbine, Bevacizumab
Did not meet primary endpoint of OS

Preceding treatment

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 Comparative Efficacy
Arriagada et al. 2004 (IALT) Phase III (E-esc) Observation Seems to have superior OS

Preceding treatment

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 Comparative Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) 1. Cisplatin, Docetaxel, Bevacizumab
2. Cisplatin, Gemcitabine, Bevacizumab
3. Cisplatin, Pemetrexed, Bevacizumab
4. Cisplatin, Vinorelbine, Bevacizumab
Did not meet primary endpoint of OS

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Variant #2, 75/1250 x 3

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Barlesi et al. 2015 Phase III (E-switch-ic) Cisplatin & Docetaxel Did not meet primary endpoint of QoL

This trial included patients with Stage IB–III NSCLC.

Preceding treatment

Chemotherapy

21-day cycle for 3 cycles

Variant #3, 75/1250 x 4

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

This regimen was intended for patients with squamous histology.

Preceding treatment

Chemotherapy

21-day cycle for 4 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
  3. NVALT-8: Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Jul 24. [Epub ahead of print] link to original article contains verified protocol PubMed

Cisplatin & Pemetrexed

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CPx: Cisplatin & Pemetrexed

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Kreuter et al. 2013 (TREAT) Randomized Phase II (E-switch-ic) Cisplatin & Vinorelbine Did not meet secondary endpoint of OS (*) Superior clinical feasibility rate
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) 1. Cisplatin, Docetaxel, Bevacizumab
2. Cisplatin, Gemcitabine, Bevacizumab
3. Cisplatin, Pemetrexed, Bevacizumab
4. Cisplatin, Vinorelbine, Bevacizumab
Did not meet primary endpoint of OS
Groen et al. 2019 (NVALT-8) Phase III (C) CPx & Nadroparin Did not meet primary endpoint of RFS

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

Preceding treatment

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
  3. NVALT-8: Groen HJM, van der Heijden EHFM, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, Kloosterziel C, Pieterman R, van den Borne B, Smit HJM, Hoekstra O, Schramel FMNH, van der Noort V, van Tinteren H, Smit EF, Dingemans AC; NVALT Study Group. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019 Jul 24. [Epub ahead of print] link to original article contains verified protocol PubMed

Cisplatin & Vinblastine

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Regimen

Study Evidence Comparator Comparative Efficacy
Arriagada et al. 2004 (IALT) Phase III (E-esc) 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

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 Comparative Efficacy
Arriagada et al. 2004 (IALT) Phase III (E-esc) 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

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 Comparative Efficacy Comparative Toxicity
Winton et al. 2005 (JBR.10) Phase III (E-esc) Observation Seems to have superior OS
Kreuter et al. 2013 (TREAT) Randomized Phase II (C) Cisplatin & Pemetrexed Did not meet secondary endpoint of OS (*) Superior clinical feasibility rate

Efficacy for TREAT based on 2016 update.

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

Variant #2, cisplatin 75 mg/m2, q3wk

Study Evidence Comparator Comparative Efficacy
Wakelee et al. 2017 (ECOG-ACRIN E1505) Phase III (C) 1. Cisplatin, Docetaxel, Bevacizumab
2. Cisplatin, Gemcitabine, Bevacizumab
3. Cisplatin, Pemetrexed, Bevacizumab
4. Cisplatin, Vinorelbine, Bevacizumab
Did not meet primary endpoint of OS
Zhong et al. 2017 (ADJUVANT/CTONG1104) Phase III (C) Gefinitib Inferior DFS

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Variant #3, cisplatin 100 mg/m2, q4wk

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

Preceding treatment

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, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed
  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 Comparative Efficacy
McKneally et al. 1976 Phase III (C) Intrapleural BCG Inferior OS
Feld et al. 1993 (LCSG 801) Phase III (C) CAP Did not meet endpoint of OS
Ohta et al. 1993 (JCOG8601) Phase III (C) Cisplatin & Vindesine Did not meet endpoint of OS
Scagliotti et al. 2003 (ALPI) Phase III (C) MVP Did not meet primary endpoint of OS
Arriagada et al. 2004 (IALT) Phase III (C) 1. Cisplatin & Etoposide Seems to have inferior OS
2. Cisplatin & Vinblastine Seems to have inferior OS
3. Cisplatin & Vindesine Seems to have inferior OS
4. Cisplatin & Vinorelbine Seems to have inferior OS
Tada et al. 2004 (JCOG9304) Phase III (C) Cisplatin & Vindesine Did not meet endpoint of OS50%
Kato et al. 2004 Phase III (C) Tegafur & Uracil Seems to have inferior OS
Nakagawa et al. 2005 (WJSG4) Phase III (C) Tegafur & Uracil Did not meet primary endpoint of OS
Winton et al. 2005 (JBR.10) Phase III (C) Cisplatin & Vinorelbine Seems to have inferior OS
Douillard et al. 2006 (ANITA) Phase III (C) Cisplatin & Vinorelbine Seems to have inferior OS
Strauss et al. 2008 (CALGB 9633) Phase III (C) Carboplatin & Paclitaxel Did not meet primary endpoint of OS
Felip et al. 2010 Phase III (C) 1. Carboplatin & Paclitaxel; adjuvant
2. Carboplatin & Paclitaxel; neoadjuvant
Did not meet primary endpoint of DFS

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

Preceding treatment

References

  1. McKneally MF, Maver C, Kausel HW. Regional immunotherapy of lung cancer with intrapleural BCG. Lancet. 1976 Feb 21;1(7956):377-9. link to original article PubMed
  2. LCSG 801: Feld R, Rubinstein L, Thomas PA; The Lung Cancer Study Group. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. J Natl Cancer Inst. 1993 Feb 17;85(4):299-306. link to original article PubMed
  3. JCOG8601: Ohta M, Tsuchiya R, Shimoyama M, Sawamura K, Mori T, Miyazawa N, Suemasu K, Watanabe Y, Tomita M, Terashima M; The Japan Clinical Oncology Group. Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer: results of a randomized prospective study. J Thorac Cardiovasc Surg. 1993 Oct;106(4):703-8. PubMed
  4. ALPI: Scagliotti GV, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M; Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61. link to original article PubMed
  5. IALT: Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22;350(4):351-60. link to original article PubMed
    1. Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
  6. JCOG9304: Tada H, Tsuchiya R, Ichinose Y, Koike T, Nishizawa N, Nagai K, Kato H. A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304). Lung Cancer. 2004 Feb;43(2):167-73. link to original article PubMed
  7. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article contains protocol PubMed
  8. WJSG4: Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H; West Japan Study Group for Lung Cancer Surgery. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG)--the 4th study. Ann Oncol. 2005 Jan;16(1):75-80. link to original article PubMed
  9. JBR.10: Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 2005 Jun 23;352(25):2589-97. link to original article PubMed
    1. Update: Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, Johnson DH, Kesler KA, Green M, Vincent M, Cormier Y, Goss G, Findlay B, Johnston M, Tsao MS, Shepherd FA. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010 Jan 1;28(1):29-34. Epub 2009 Nov 23. link to original article link to PMC article PubMed
  10. ANITA: Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Rodrigues Pereira J, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed
  11. CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol link to PMC article PubMed
  12. Felip E, Rosell R, Maestre JA, Rodríguez-Paniagua JM, Morán T, Astudillo J, Alonso G, Borro JM, González-Larriba JL, Torres A, Camps C, Guijarro R, Isla D, Aguiló R, Alberola V, Padilla J, Sánchez-Palencia A, Sánchez JJ, Hermosilla E, Massuti B; Spanish Lung Cancer Group. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010 Jul 1;28(19):3138-45. Epub 2010 Jun 1. link to original article PubMed

Placebo

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Regimen

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

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

Preceding treatment

References

  1. RADIANT: Kelly K, Altorki NK, Eberhardt WE, O'Brien ME, Spigel DR, Crinò L, Tsai CM, Kim JH, Cho EK, Hoffman PC, Orlov SV, Serwatowski P, Wang J, Foley MA, Horan JD, Shepherd FA. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol. 2015 Dec 1;33(34):4007-14. Epub 2015 Aug 31. link to original article PubMed

Tegafur & Uracil

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Regimen

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

Preceding treatment

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, 6/200

Study Evidence Comparator Comparative Efficacy
Belani et al. 2005 (LAMP) Phase II
Huber et al. 2006 (CTRT99/97) Non-randomized portion of RCT
Vokes et al. 2007 (CALGB 39801) Phase III (E-esc) No induction Did not meet primary endpoint of OS50%

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, 6/225

Study Evidence Comparator Comparative 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. CTRT99/97: Huber RM, Flentje M, Schmidt M, Pöllinger B, Gosse H, Willner J, Ulm K; Bronchial Carcinoma Therapy Group. Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol. 2006 Sep 20;24(27):4397-404. link to original article contains protocol PubMed
  3. 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
  4. 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 Comparative Efficacy
Dillman et al. 1990 (CALGB 8433) Phase III (E-esc) No induction Seems to have superior OS (*)
Sause et al. 1995 (RTOG 88-08) Phase III (E-esc) No induction Seems to have 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. Reported efficacy for CALGB 8433 is based on the 1996 update.

Chemotherapy

5-week course

Subsequent treatment

  • RT x 60 to 63 Gy

References

  1. CALGB 8433: 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
    1. Update: Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5. link to original article PubMed
  2. RTOG 88-08: Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, Dar AR, Cox JD. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995 Feb 1;87(3):198-205. link to original article contains protocol PubMed
    1. Update: Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, Emami B, Curran W Jr, Byhardt R, Dar AR, Turrisi A 3rd. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000 Feb;117(2):358-64. link to original article PubMed
  3. 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 Comparative Efficacy
Vokes et al. 2007 (CALGB 39801) Phase III (C) Carboplatin & Paclitaxel Did not meet primary endpoint of OS50%

No treatment given prior to definitive therapy.

Subsequent treatment

References

  1. Kim TY, Yang SH, Lee SH, Park YS, Im YH, Kang WK, Ha SH, Park CI, Heo DS, Bang YJ, Kim NK. A phase III randomized trial of combined chemoradiotherapy versus radiotherapy alone in locally advanced non-small-cell lung cancer. Am J Clin Oncol. 2002 Jun;25(3):238-43. link to original article PubMed
  2. CALGB 39801: Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson DM, Akerley W, Green MR; Cancer and Leukemia Group B. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007 Apr 2. link to original article contains protocol PubMed

Definitive therapy for locally advanced disease

Carboplatin, Paclitaxel, RT

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PC & RT: Paclitaxel, Carboplatin, Radiation Therapy

Variant #1, 2/40/60

Study Evidence Comparator Comparative Efficacy
Yamamoto et al. 2010 (WJTOG0105) Phase III (E-switch-ic) 1. MVP & RT
2. Carboplatin, Irinotecan, RT
Inconclusive whether non-inferior OS

Chemotherapy

Radiotherapy

6-week course

Variant #2, 2/45/60

Study Evidence Comparator Comparative Efficacy
Lu et al. 2010 (ID99-303) Phase III (C) PC, AE-941, RT Did not meet primary endpoint of OS
Hoang et al. 2012 (ECOG 3598) Phase III (C) See link See link
Bradley et al. 2015 (RTOG 0617) Phase III (C) 1. Carboplatin, Paclitaxel, Cetuximab, concurrent RT Did not meet primary endpoint of OS
2. Carboplatin, Paclitaxel, high-dose RT
3. Carboplatin, Paclitaxel, Cetuximab, high-dose RT
Superior OS
Liang et al. 2017 Phase III (C) EP & RT Might have inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Preceding treatment

  • ECOG 3598: PC induction x 2

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

6-week course

Subsequent treatment

  • RTOG 0617: PC consolidation x 2

Variant #3, 2/45/63

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

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy: 1.8 Gy fractions x 25 fractions, then 2 Gy fractions x 9 fractions

7-week course

Subsequent treatment

  • PC consolidation x 2

Variant #4, 2/50/66

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

Preceding treatment

Chemotherapy

  • Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, given second
  • Paclitaxel (Taxol) 50 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43, given first

Radiotherapy

7-week 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 verified protocol PubMed
  3. ID99-303: Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, Choy H, Desjardins P, Esparaz BT, Truong MT, Saxman S, Kelaghan J, Bleyer A, Fisch MJ. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst. 2010 Jun 16;102(12):859-65. Epub 2010 May 26. link to original article link to PMC article contains protocol PubMed
  4. WJTOG0105: Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010 Aug 10;28(23):3739-45. Epub 2010 Jul 12. link to original article contains protocol PubMed
  5. 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
  6. 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
    1. Dataset: Project Data Sphere
  7. 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, Vinorelbine, RT

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Regimen

Study Evidence Comparator Comparative Efficacy
Strøm et al. 2013 Phase III (E-esc) Carboplatin & Vinorelbine Superior OS

Chemotherapy

Radiotherapy

References

  1. Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013 Sep 17;109(6):1467-75. Epub 2013 Aug 20. link to original article link to PMC article PubMed

Carboplatin & RT

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Carboplatin & RT: Carboplatin & Radiation Therapy

Regimen

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

Chemotherapy

Radiotherapy

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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Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Schaake-Koning et al. 1992 Phase III (E-esc) 1. Cisplatin & RT (weekly dosing) Did not meet primary endpoint of OS
2. RT Superior OS

Chemotherapy

Radiotherapy

  • 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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DC & RT: Docetaxel, Cisplatin, Radiation Therapy
DP & RT: Docetaxel, Platinol (Cisplatin), Radiation Therapy

Variant #1, 20/20

Study Evidence Comparator Comparative Efficacy
Oh et al. 2013 (KASLC 0401) Phase III (C) 1. TP & RT
2. GP & RT
Did not meet primary endpoint of ORR
Ahn et al. 2015 (KCSG-LU05-04) Non-randomized portion of RCT

In KCSG-LU05-04, no benefit was observed to giving post-definitive consolidation.

Chemotherapy

Radiotherapy

6-week course

Subsequent treatment

  • KCSG-LU05-04: Cisplatin & Docetaxel consolidation versus no further treatment

Variant #2, 40/40

Study Evidence Comparator Comparative Efficacy
Segawa et al. 2010 (OLCSG 0007) Phase III (E-switch-ic) MVP & RT Might have superior OS

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

References

  1. OLCSG 0007: Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, Watanabe Y, Sugimoto K, Shibayama T, Yonei T, Ueoka H, Takemoto M, Kanazawa S, Takata I, Nogami N, Hotta K, Hiraki A, Tabata M, Matsuo K, Tanimoto M. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol. 2010 Jul 10;28(20):3299-306. Epub 2010 Jun 7. link to original article contains protocol PubMed
  2. KASLC 0401: Oh IJ, Kim KS, Kim YC, Ban HJ, Kwon YS, Kim YI, Lim SC, Chung WK, Nam TK, Song JY, Yoon MS, Ahn SJ. A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401. Cancer Chemother Pharmacol. 2013 Dec;72(6):1247-54. Epub 2013 Oct 5. link to original article contains protocol PubMed
  3. 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

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.80 Gy fractions x 25 fractions (total dose: 45 Gy), to start within 24 hours of cycle 1 day 1

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 Comparative 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 Did not meet primary endpoint of OS
Liang et al. 2017 Phase III (C) PC & RT Might have superior OS

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.80 to 2.00 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy)

6- to 6.5-week course

Subsequent treatment

Variant #3, 66 Gy, split cisplatin

Study Evidence Comparator Comparative Efficacy
Fournel et al. 2005 (NPC 95-01) Phase III (E-switch-ic) Cisplatin & Vinorelbine, then RT Did not meet primary endpoint of OS

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

28-day cycle for 2 cycles

Radiotherapy

6.5-week course

Subsequent treatment

Variant #4, 69.6 Gy (hyperfractionated)

Study Evidence Comparator Comparative Efficacy
Curran et al. 2011 (RTOG 9410) Phase III (E-switch-ic) 1. Cisplatin, Vinblastine, RT Did not meet primary endpoint of OS
2. Cisplatin & Vinblastine, then RT Might have superior OS

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

  • Concurrent radiation therapy, 1.20 Gy fractions (total dose: 69.6 Gy), given twice per day for 5 days per week, starting on cycle 1 day 1

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 contains protocol 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
    1. Dataset: Project Data Sphere
  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 Comparative Efficacy
Curran et al. 2011 (RTOG 9410) Phase III (E-switch-ic) 1. Cisplatin, Etoposide, RT Did not meet primary endpoint of OS
2. Cisplatin & Vinblastine, then RT Seems to have superior OS

Chemotherapy

Radiotherapy

5-week course

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, 20 Gy

Study Evidence Comparator Comparative Efficacy
Ball et al. 1997 Phase III (C) 5-FU & RT Seems to have inferior OS

Radiotherapy

5-day course

Variant #2, 45 Gy + 18 Gy boost (63 Gy total)

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

Preceding treatment

Radiotherapy

7-week course

Variant #3, 60 Gy

Study Evidence Comparator Comparative Efficacy
Morton et al. 1991 Phase III (C) MACC & RT Did not meet primary endpoint of OS
Clamon et al. 1999 Phase III (C) Carboplatin & RT Did not meet primary endpoint of OS
Bradley et al. 2002 (RTOG 93-04) Phase III (C) Beta-interferon & RT Did not meet primary endpoint of OS
Groen et al. 2004 Phase III (C) Carboplatin & RT Did not meet primary endpoint of OS24
Atagi et al. 2012 (JCOG0301) Phase III (C) Carboplatin & RT Seems to have inferior OS

Preceding treatment

Radiotherapy

One course

References

  1. Morton RF, Jett JR, McGinnis WL, Earle JD, Therneau TM, Krook JE, Elliott TE, Mailliard JA, Nelimark RA, Maksymiuk AW, Drummond RG, Laurie JA, Kugler JW, Anderson RT. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer: a randomized, phase III trial. Ann Intern Med. 1991 Nov 1;115(9):681-6. link to original article PubMed
  2. Ball D, Smith J, Bishop J, Olver I, Davis S, O'Brien P, Bernshaw D, Ryan G, Millward M. A phase III study of radiotherapy with and without continuous-infusion fluorouracil as palliation for non-small-cell lung cancer. Br J Cancer. 1997;75(5):690-7. link to PMC article PubMed
  3. Clamon G, Herndon J, Cooper R, Chang AY, Rosenman J, Green MR. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999 Jan;17(1):4-11. link to original article PubMed
  4. RTOG 93-04: Bradley JD, Scott CB, Paris KJ, Demas WF, Machtay M, Komaki R, Movsas B, Rubin P, Sause WT. A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1173-9. link to original article contains protocol PubMed
  5. Groen HJ, van der Leest AH, Fokkema E, Timmer PR, Nossent GD, Smit WJ, Nabers J, Hoekstra HJ, Hermans J, Otter R, van Putten JW, de Vries EG, Mulder NH. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol. 2004 Mar;15(3):427-32. link to original article PubMed
  6. 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
  7. 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
  8. 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
    1. Dataset: Project Data Sphere
  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
    1. Dataset: Project Data Sphere

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
    1. Dataset: Project Data Sphere

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
    1. Dataset: Project Data Sphere

Durvalumab monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Antonia et al. 2017 (PACIFIC) Phase III (E-RT-esc) Placebo Superior OS (*)

Note: reported efficacy is based on the 2018 update.

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

14-day cycle for up to 26 cycles (1 year)

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
    1. Update: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. link to original article PubMed

Placebo

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Regimen

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

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

No further antineoplastic treatment.

Preceding treatment

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

References

  1. SWOG S0023: Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. link to original article contains verified protocol PubMed
  2. START: Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Rodrigues Pereira J, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. Epub 2013 Dec 9. link to original article PubMed
    1. Update: Mitchell P, Thatcher N, Socinski MA, Wasilewska-Tesluk E, Horwood K, Szczesna A, Martín C, Ragulin Y, Zukin M, Helwig C, Falk M, Butts C, Shepherd FA. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol. 2015 Jun;26(6):1134-42. Epub 2015 Feb 26. link to original article PubMed
    2. Dataset: Project Data Sphere
  3. PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains verified protocol PubMed
    1. Update: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. Epub 2018 Sep 25. link to original article PubMed

Observation

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Regimen

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

No further treatment.

Preceding treatment

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

References

  1. Pines A. A 5-year controlled study of BCG and radiotherapy inoperable lung cancer. Lancet. 1976 Feb 21;1(7956):380-1. link to original article PubMed
  2. HOG Lun 01-24: Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L; Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10. link to original article contains protocol PubMed
    1. Update: Jalal SI, Riggs HD, Melnyk A, Richards D, Agarwala A, Neubauer M, Ansari R, Govindan R, Bruetman D, Fisher W, Breen T, Johnson CS, Yu M, Einhorn L, Hanna N. Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology. Ann Oncol. 2012 Jul;23(7):1730-8. Epub 2011 Dec 9. link to original article PubMed
  3. RTOG 0214: Gore EM, Bae K, Wong SJ, Sun A, Bonner JA, Schild SE, Gaspar LE, Bogart JA, Werner-Wasik M, Choy H. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol. 2011 Jan 20;29(3):272-8. Epub 2010 Dec 6. Erratum in: J Clin Oncol. 2011 Aug 10;29(23):3204. link to original article link to PMC article PubMed
    1. Update: Sun A, Hu C, Wong SJ, Gore E, Videtic G, Dutta S, Suntharalingam M, Chen Y, Gaspar LE, Choy H. Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: a long-term update of the NRG Oncology/RTOG 0214 phase 3 randomized clinical trial. JAMA Oncol. 2019 Mar 14. [Epub ahead of print] link to original article link to PMC article PubMed
  4. Carter DL, Garfield D, Hathorn J, Mundis R, Boehm KA, Ilegbodu D, Asmar L, Reynolds C. A randomized phase III trial of combined paclitaxel, carboplatin, and radiation therapy followed by weekly paclitaxel or observation for patients with locally advanced inoperable non-small-cell lung cancer. Clin Lung Cancer. 2012 May;13(3):205-13. Epub 2011 Dec 3. link to original article PubMed
  5. Li N, Zeng ZF, Wang SY, Ou W, Ye X, Li J, He XH, Zhang BB, Yang H, Sun HB, Fang Q, Wang BX. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann Oncol. 2015 Mar;26(3):504-9. Epub 2014 Dec 15. link to original article PubMed
  6. GILT: Flentje M, Huber RM, Engel-Riedel W, Andreas S, Kollmeier J, Staar S, Dickgreber N, Vaissiere N, De Almeida C, Edlich B, Fietkau R. GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer. Strahlenther Onkol. 2016 Apr;192(4):216-22. Epub 2016 Jan 25. link to original article PubMed
  7. NVALT-11/DLCRG-02: De Ruysscher D, Dingemans AC, Praag J, Belderbos J, Tissing-Tan C, Herder J, Haitjema T, Ubbels F, Lagerwaard F, El Sharouni SY, Stigt JA, Smit E, van Tinteren H, van der Noort V, Groen HJM. Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: a randomized phase III NVALT-11/DLCRG-02 study. J Clin Oncol. 2018 Aug 10;36(23):2366-2377. Epub 2018 May 22. link to original article PubMed

Advanced or metastatic disease, first-line

Carboplatin & Docetaxel

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DCb: Docetaxel & Carboplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Fossella et al. 2003 (TAX 326) Phase III (E-RT-switch-ic) 1. Cisplatin & Docetaxel Not reported
2. Cisplatin & Vinorelbine Did not meet primary endpoint of OS
Booton et al. 2006 (BTOG1) Phase III (E-switch-ic) 1. MIC
2. MVP
Did not meet primary endpoint of OS
Lynch et al. 2010 (BMS099) Phase III (C) Carboplatin, Docetaxel, Cetuximab Did not meet primary endpoint of PFS
Groen et al. 2011 (NVALT-4) Phase III (C) Carboplatin, Docetaxel, Celecoxib Did not meet primary endpoint of OS
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, Rodrigues Pereira J, 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 Comparative Efficacy
Klastersky et al. 1990 (EORTC 07861) Phase III (E-switch-ic) 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 & Carboplatin
GCa: Gemcitabine & Carboplatin
GCb: Gemcitabine & Carboplatin

Variant #1, 4/1000

Study Evidence Comparator Comparative Efficacy
Helbekkmo et al. 2007 Phase III (E-switch-ic) VC Did not meet primary endpoint of OS

Note: AUC was calculated using the Chatelut formula.

Chemotherapy

21-day cycle for 3 cycles

Variant #2, 5/1000 q3wk

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Grønberg et al. 2009 Phase III (C) Carboplatin & Pemetrexed Did not meet primary endpoint of HRQoL
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 #3, 5/1000 q4wk

Study Evidence Comparator Comparative Efficacy
Danson et al. 2003 Phase III (E-switch-ic) 1. MIC
2. MVP
Did not meet primary endpoint of OS

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 #4, 5/1200

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Zatloukal et al. 2003 Phase III (E-switch-ic) Cisplatin & Gemcitabine Did not meet primary endpoint of grade 3/4 toxicity
Rudd et al. 2005 Phase III (E-switch-ic) MIC Superior OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #5, 5/1250 q3wk

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Sederholm et al. 2005 Phase III (C) Gemcitabine Seems to have superior OS
Bepler et al. 2013 (MCC-15005) Phase III (C) ERCC1 and RRM1 expression-based chemotherapy Did not meet primary endpoint of PFS6
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL

Chemotherapy

21-day cycle for 4 to 6 cycles

Variant #6, 5/1250 q4wk

Study Evidence Comparator Comparative 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 #7, 6/1000

Study Evidence Comparator Comparative Efficacy
Kosmidis et al. 2007 Phase III (C) Gemcitabine & Paclitaxel Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

Variant #8, 6/1250 ("GCb6")

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Ferry et al. 2017 (BTOG2) Phase III (E-switch-ic) 1. GC50 Seems to have superior OS
2. GC80 Non-inferior OS

Chemotherapy

21-day cycle for 4 to 6 cycles

Variant #9, 300/1000

Study Evidence Comparator Comparative Efficacy
Grigorescu et al. 2002 Phase III (E-switch-ic) Cisplatin & Vinblastine Superior OS

Chemotherapy

21-day cycles

References

  1. Grigorescu AC, Draghici IN, Nitipir C, Gutulescu N, Corlan E. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer. 2002 Jul;37(1):9-14. link to original article contains protocol PubMed
  2. 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
  3. 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
  4. Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG, Littler JA, Hatton M, Johnson PW, Martin WM, Rankin EM, James LE, Gregory WM, Qian W, Lee SM. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol. 2005 Jan 1;23(1):142-53. link to original article contains protocol PubMed
  5. 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
  6. Helbekkmo N, Sundstrøm SH, Aasebø U, Brunsvig PF, von Plessen C, Hjelde HH, Garpestad OK, Bailey A, Bremnes RM; Norwegian Lung Cancer Study Group. Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer. 2007 Aug 6;97(3):283-9. Epub 2007 Jun 26. link to original article link to PMC article contains verified protocol PubMed
  7. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains protocol PubMed
  8. 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
  9. 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
  10. 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
  11. 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
  12. MCC-15005: Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, Gadgeel S, Zhao X, Schreiber F, Brahmer J, Chiappori A, Tanvetyanon T, Pinder-Schenck M, Gray J, Haura E, Antonia S, Fischer JR. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013 Jul 1;31(19):2404-12. Epub 2013 May 20. link to original article link to PMC article contains verified protocol PubMed
  13. 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
  14. 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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
  15. 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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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
TC: Taxol (Paclitaxel) & Carboplatin

Variant #1, 5/200

Study Evidence Comparator Comparative Efficacy Comparative 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

Chemotherapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

Variant #2, 6/175

Study Evidence Comparator Comparative Efficacy
Stathopoulos et al. 2004 Phase III (C) Paclitaxel & Vinorelbine Did not meet primary endpoints of ORR/OS
Lynch et al. 2012 Randomized Phase II (C) CP & Ipilimumab Seems to have inferior PFS
Govindan et al. 2017 (CA184-104) Phase III (C) CP & Ipilimumab Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Variant #3, 6/200

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Socinski et al. 2002 Phase III (E-de-esc) CP; indefinite Did not meet primary endpoint of OS Did not meet primary endpoint of QoL
Kosmidis et al. 2002 Phase III (E-switch-ic) Gemcitabine & Paclitaxel Did not meet primary endpoint of OS
Rosell et al. 2002 Phase III (E-switch-ic) Cisplatin & Paclitaxel Seems to have inferior OS
Johnson et al. 2004 Randomized Phase II (C) PacCBev Seems to have inferior TTP
Leighl et al. 2005 (NCIC CTG BR.18) Phase III (C) CP & BMS-275291 Did not meet primary endpoint of OS Less toxic
Herbst et al. 2005 (TRIBUTE) Phase III (C) CP & Erlotinib Did not meet primary endpoint of OS
Schuette et al. 2006 Phase III (C) CP; weekly Seems to have non-inferior ORR Mixed toxicity
Ohe et al. 2006 Phase III (E-switch-ic) 1. Cisplatin & Gemcitabine Inconclusive whether non-inferior OS
2. Cisplatin & Irinotecan Inconclusive whether non-inferior OS
3. Cisplatin & Vinorelbine Inconclusive whether non-inferior OS
Blumenschein et al. 2008 (SPIRIT II) Phase III (C) CP & Bexarotene Did not meet primary endpoint of OS
Scagliotti et al. 2010 (ESCAPE) Phase III (C) CP & Sorafenib Did not meet primary endpoint of OS
Maemondo et al. 2010 (NEJ002) Phase III (C) Gefitinib Inferior PFS
Okamoto et al. 2010 (LETS) Phase III (C) Carboplatin & S-1 Non-inferior OS
Hirsh et al. 2011 Phase III (C) CP & Agatolimod Did not meet primary endpoint of OS
Lara et al. 2011 Phase III (C) CP & Vadimezan Did not meet primary endpoint of OS
Socinski et al. 2012 (CA031) Phase III (C) Carboplatin & nab-Paclitaxel Inferior ORR
Laurie et al. 2013 (NCIC CTG BR.29) Phase III (C) CP & Cediranib Did not meet primary endpoint of OS Less toxic
Langer et al. 2014 Phase III (C) CP & Figitumumab Might have superior OS
Reck et al. 2016 (KEYNOTE-024) Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Ramalingam et al. 2016 (M10-898) Randomized Phase II (C) CP & Veliparib Did not meet primary endpoint of PFS
Herbst et al. 2017 (SWOG S0819) Phase III (C) CP & Cetuximab Did not meet primary endpoints of PFS/OS

Note: Patients in TRIBUTE received a maximum of 6 cycles. Patients in SWOG S0819 were EGFR FISH positive.

Chemotherapy

21-day cycle for 3 or more cycles

Subsequent treatment

  • Socinski et al. 2002, upon progression: Paclitaxel
  • KEYNOTE-024: Patients with nonsquamous histology could optionally proceed, after 4 to 6 cycles, to pemetrexed switch maintenance

Variant #4, 6/225

Study Evidence Comparator Comparative Efficacy
Kelly et al. 2001 (SWOG 9509) Phase III (E-switch-ic) Cisplatin & Vinorelbine Did not meet primary endpoint of OS
Schiller et al. 2002 (ECOG E1594) Phase III (E-switch-ic) 1. Cisplatin & Docetaxel Did not meet primary endpoint of OS
2. Cisplatin & Gemcitabine Did not meet primary endpoint of OS
3. Cisplatin & Paclitaxel Did not meet primary endpoint of OS
Herbst et al. 2004 (INTACT 2) Phase III (C) CP & Gefitinib Did not meet primary endpoint of OS
Lilenbaum et al. 2005 (CALGB 9730) Phase III (E-esc) Paclitaxel Superior FFS
Williamson et al. 2005 (SWOG S0003) Phase III (C) CP & Tirapazamine Did not meet primary endpoint of OS
Belani et al. 2008 Phase III (C) CP; weekly paclitaxel Did not meet primary endpoint of OS
Kubota et al. 2008 (JMTO LC00-03) Phase III (C) Gemcitabine & Vinorelbine, then Docetaxel Did not meet primary endpoint of OS
Treat et al. 2009 (ALPHA A1-99002L) Phase III (C) 1. Carboplatin & Gemcitabine
2. Gemcitabine & Paclitaxel
Did not meet primary endpoint of OS
Lynch et al. 2010 (BMS099) Phase III (C) CP & Cetuximab Did not meet primary endpoint of PFS
Weissman et al. 2011 Phase III (C) GEMOX Did not meet primary endpoint of PFS

Chemotherapy

21-day cycle for up to 4 cycles (Belani et al. 2008), 6 cycles (Weissman et al. 2011), 10 cycles (SWOG 9509), or indefinitely (ECOG E1594)

Subsequent treatment

  • Belani et al. 2008: Paclitaxel maintenance

References

  1. SWOG 9509: Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. link to original article contains verified 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. Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, Unger P, Lee J, Lee JH, Tynan M, Moore M, Kies MS. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002 Mar 1;20(5):1335-43. link to original article contains protocol PubMed
  4. Kosmidis P, Mylonakis N, Nicolaides C, Kalophonos C, Samantas E, Boukovinas J, Fountzilas G, Skarlos D, Economopoulos T, Tsavdaridis D, Papakostas P, Bacoyiannis C, Dimopoulos M. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2002 Sep 1;20(17):3578-85. link to original article contains protocol PubMed
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. NCIC CTG BR.18: Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Depierre A, Santoro A, Betticher DC, Gatzemeier U, Jassem J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA. Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR18. J Clin Oncol. 2005 Apr 20;23(12):2831-9. link to original article contains protocol PubMed
  11. 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
  12. 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
  13. Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N, Appel T, Ukena D. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer. 2006 Mar;7(5):338-43. link to original article contains protocol PubMed
  14. 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
  15. Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol. 2008 Jan 20;26(3):468-73. link to original article contains protocol PubMed
  16. SPIRIT II: Blumenschein GR Jr, Khuri FR, von Pawel J, Gatzemeier U, Miller WH Jr, Jotte RM, Le Treut J, Sun SL, Zhang JK, Dziewanowska ZE, Negro-Vilar A. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008 Apr 10;26(11):1879-85. link to original article contains verified protocol PubMed
  17. 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
  18. 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
  19. 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
  20. ESCAPE: Scagliotti G, Novello S, von Pawel J, Reck M, Rodrigues Pereira J, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010 Apr 10;28(11):1835-42. Epub 2010 Mar 8. link to original article contains protocol PubMed
    1. Dataset: Project Data Sphere
  21. 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. HRQoL analysis: Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, Isobe H, Harada M, Kinoshita I, Okinaga S, Kato T, Harada T, Gemma A, Saijo Y, Yokomizo Y, Morita S, Hagiwara K, Nukiwa T. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Oncologist. 2012;17(6):863-70. Epub 2012 May 11. link to original article link to PMC article PubMed
    2. 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
  22. LETS: Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata T, Fukuoka M, Nakagawa K. Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study. J Clin Oncol. 2010 Dec 20;28(36):5240-6. Epub 2010 Nov 15. link to original article contains verified protocol PubMed
  23. Weissman CH, Reynolds CH, Neubauer MA, Pritchard S, Kobina S, Asmar L. A phase III randomized trial of gemcitabine-oxaliplatin versus carboplatin-paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011 Feb;6(2):358-64. link to original article contains protocol PubMed
  24. 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
  25. 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
  26. 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
  27. CA031: 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
    1. Dataset: Project Data Sphere
  28. NCIC CTG BR.29: Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, Boyer MJ, Arnold AM, Clingan P, Laberge F, Fenton D, Hirsh V, Zukin M, Stockler MR, Lee CW, Chen EX, Montenegro A, Ding K, Bradbury PA. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer. 2014 Mar;50(4):706-12. Epub 2013 Dec 17. link to original article contains protocol PubMed
  29. 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
  30. 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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
  31. M10-898: 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
  32. 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

Carboplatin & nab-Paclitaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Socinski et al. 2012 (CA031) Phase III (E-RT-switch-ic) 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. CA031: 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
    1. Dataset: Project Data Sphere

Carboplatin, Paclitaxel, Bevacizumab

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

Regimen

Study Evidence Comparator Comparative Efficacy
Johnson et al. 2004 Randomized Phase II (E-esc) Carboplatin & Paclitaxel Seems to have superior TTP
Herbst et al. 2017 (SWOG S0819) Phase III (C) Carboplatin, Paclitaxel, Bevacizumab, Cetuximab Did not meet primary endpoints of PFS/OS

Note: 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 once on day 1, given third, starting 60 minutes after the completion of carboplatin
    • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles

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. 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

Carboplatin, Paclitaxel, Ipilimumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Lynch et al. 2012 Randomized Phase II (E-esc) Carboplatin & Paclitaxel Seems to have superior PFS

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

Chemotherapy

Immunotherapy

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

Carboplatin & Pemetrexed

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

Example orders

Variant #1, 5/500 x 6

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

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #2, 6/500 x 4

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Grønberg et al. 2009 Phase III (E-switch-ic) Carboplatin & Gemcitabine Did not meet primary endpoint of HRQoL

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Variant #3, 6/500 x 6

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

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. 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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article 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 Comparative 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.

Chemotherapy

Immunotherapy

  • Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy

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 Comparative Efficacy
Tan et al. 2005 (GLOB 2) Phase III (C) Gemcitabine & Vinorelbine Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for up to 6 cycles

Variant #2, PO vinorelbine

Study Evidence Comparator Comparative Efficacy
Fløtten et al. 2012 Phase III (C) Gemcitabine & Vinorelbine Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

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 Comparative Efficacy
Berghmans et al. 2013 (ELCWP-01041) Phase III (C) 1. GIP
2. IG
Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

Variant #2, 75/75

Study Evidence Comparator Comparative Efficacy
Schiller et al. 2002 (ECOG E1594) Phase III (E-switch-ic) 1. Carboplatin & Paclitaxel Did not meet primary endpoint of OS
2. Cisplatin & Gemcitabine Did not meet primary endpoint of OS
3. Cisplatin & Paclitaxel Did not meet primary endpoint of OS
Fossella et al. 2003 (TAX 326) Phase III (E-RT-switch-ic) 1. Carboplatin & Docetaxel Not reported
2. Cisplatin & Vinorelbine Seems to have superior OS
Cobo et al. 2007 Phase III (C) ERCC1 mRNA-guided therapy Seems to have inferior ORR
Tan et al. 2009 (GLOB3) Phase III (C) Cisplatin & Vinorelbine Did not meet primary endpoint of TTF
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 #3, 80/60

Study Evidence Comparator Comparative Efficacy
Kubota et al. 2004 Phase III (E-switch-ic) Cisplatin & Vindesine Seems to have superior OS
Mitsudomi et al. 2009 (WJTOG3405) Phase III (C) Gefitinib Inferior PFS
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Did not meet primary endpoint of OS
Kubota et al. 2015 (TCOG0701 CATS) Phase III (C) Cisplatin & S-1 Non-inferior OS

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

Chemotherapy

21-day cycle for 3 to 6 cycles

Variant #4, 80/100

Study Evidence Comparator Comparative Efficacy
Georgoulias et al. 2001 Phase III (C) Docetaxel & Gemcitabine Did not meet primary endpoints of ORR/TTP
Georgoulias et al. 2003 Phase III (C) Docetaxel Did not meet primary endpoint of OS

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. Georgoulias V, Pallis AG, Kourousis C, Alexopoulos A, Ardavanis A, Agelidou A, Agelidou M, Toumbis M, Tzannes S, Pavlakou G, Ziotopoulos P, Tzelepatiotis E, Samaras N. Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study. Clin Lung Cancer. 2003 Mar;4(5):288-93. link to original article PubMed
    1. Update: 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
  4. TAX 326: Fossella F, Rodrigues Pereira J, 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. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004 Jan 15;22(2):254-61. link to original article contains protocol PubMed
  6. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 2007 Jul 1;25(19):2747-54. link to original article contains verified protocol PubMed
  7. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains verified protocol PubMed
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. TCOG0701 CATS: Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S; Tokyo Cooperative Oncology Group. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol. 2015 Jul;26(7):1401-8. Epub 2015 Apr 23. link to original article link to PMC article contains protocol PubMed

Cisplatin & Etoposide

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PE: Platinol (Cisplatin) & Etoposide
EC: Etoposide & Cisplatin

Variant #1, 60/360

Study Evidence Comparator Comparative Efficacy
Ruckdeschel et al. 1986 (ECOG E1581) Phase III (E-switch-ic) 1. CAMP
2. Cisplatin & Vindesine
3. MVP
Did not meet primary endpoint

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 Comparative Efficacy
Bonomi et al. 2000 (ECOG E5592) Phase III (C) Cisplatin & Paclitaxel Seems to have inferior OS
Belani et al. 2005 Phase III (C) Carboplatin & Paclitaxel Might have superior OS

Chemotherapy

21-day cycles

Variant #3, 100/300

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

Chemotherapy

21-day cycles

Variant #4, 105/600

Study Evidence Comparator Comparative Efficacy
Font et al. 1999 Phase III (C) PE; dose-dense Did not meet primary endpoint of ORR

Chemotherapy

28-day cycles

Variant #5, 120/300

Study Evidence Comparator Comparative Efficacy
Klastersky et al. 1990 (EORTC 07861) Phase III (C) Carboplatin & Etoposide Might have superior ORR
Comella et al. 1996 Phase III (C) Carboplatin, Cisplatin, Etoposide, Vinorelbine Did not meet primary endpoint of 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. Comella P, Frasci G, De Cataldis G, Panza N, Cioffi R, Curcio C, Belli M, Bianco A, Ianniello G, Maiorino L, Della Vittoria M, Perchard J, Comella G; Gruppo Oncologico Campano. Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Br J Cancer. 1996 Dec;74(11):1805-11. link to original article contains protocol PubMed
  4. 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
  5. Font A, Moyano AJ, Puerto JM, Tres A, Garcia-Giron C, Barneto I, Anton A, Sanchez JJ, Salvador A, Rosell R. Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. Cancer. 1999 Feb 15;85(4):855-63. link to original article PubMed
  6. 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
  7. Belani CP, Lee JS, Socinski MA, Robert F, Waterhouse D, Rowland K, Ansari R, Lilenbaum R, Natale RB. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol. 2005 Jul;16(7):1069-75. Epub 2005 Apr 28. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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

Variant #1, 70/1000

Study Evidence Comparator Comparative Efficacy
Park et al. 2007 Phase III (E-de-esc) GC; 6 cycles Non-inferior OS

Chemotherapy

21-day cycle for 4 cycles

Variant #2, 75/1250 q3wk

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Bissett et al. 2005 Phase III (C) GC & Prinomastat Did not meet primary endpoint of OS
Novello et al. 2007 Phase III (C) GC x 2, then gemcitabine x 3 Inconclusive whether non-inferior OS
Manegold et al. 2011 Phase III (C) GC & PF-3512676 Did not meet primary endpoint of OS
Rossell et al. 2012 (EURTAC) Phase III (C) Erlotinib Inferior PFS
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

Note: Patients in Novello et al. 2007 received 5 cycles. Patients in ENSURE received up to 4 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles. Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21.

Chemotherapy

21-day cycle for up to 6 cycles (see note)

Variant #3, 75/1250 q4wk

Study Evidence Comparator Comparative Efficacy
Wu et al. 2013 (FASTACT-2) Phase III (C) GC/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 Comparative Efficacy
Ohe et al. 2006 Phase III (E-switch-ic) 1. Carboplatin & Paclitaxel Inconclusive whether non-inferior OS
2. Cisplatin & Irinotecan Inconclusive whether non-inferior OS
3. Cisplatin & Vinorelbine Inconclusive whether non-inferior OS
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Did not meet primary endpoint of OS

Chemotherapy

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

Variant #5, 80/1125

Study Evidence Comparator Comparative Efficacy
Wachters et al. 2003 Phase III (C) Epirubicin & Gemcitabine Did not meet primary endpoint of PFS

Chemotherapy

21-day cycle for up to 5 cycles

Variant #6, 80/1200 x 6

Study Evidence Comparator Comparative Efficacy
Gridelli et al. 2003 Phase III (C) Gemcitabine & Vinorelbine Might have superior OS
Gridelli et al. 2007 (GECO) Phase III (C) 1. GC & Rofecoxib
2. Cisplatin & PCI Gemcitabine
3. Cisplatin, PCI Gemcitabine, Rofecoxib
Did not meet primary endpoint of OS
Gridelli et al. 2012 (TORCH) Phase III (C) Erlotinib Superior OS

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #7, 80/1250 x 4

Study Evidence Comparator Comparative Efficacy
Pérol et al. 2012 Non-randomized portion of RCT
Ferry et al. 2017 (BTOG2) Phase III (E-esc) 1. GC; GC50 Seems to have superior OS
2. GCb6 Non-inferior OS

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #8, 80/1250 x 6

Study Evidence Comparator Comparative Efficacy
Giaccone et al. 2004 (INTACT 1) Phase III (C) GC & Gefitinib Did not meet primary endpoint of OS
Paz-Ares et al. 2006 Phase III (C) GC & Aprinocarsen Did not meet primary endpoint of OS
Gatzemeier et al. 2007 (TALENT) Phase III (C) GC & Erlotinib Did not meet primary endpoint of OS
Boni et al. 2012 (FAST) Phase III (C) 1. GIN
2. GN
Seems to have superior OS
3. GIP Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #9, 100/1000 q3wk

Study Evidence Comparator Comparative Efficacy
Ridolfi et al. 2011 Phase III (C) GC & LD IL-2 Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #10, 100/1000 q4wk

Study Evidence Comparator Comparative Efficacy
Crinò et al. 1999 Phase III (E-switch-ic) MIC Seems to have superior ORR
Sandler et al. 2000 Phase III (E-RT-esc) Cisplatin Superior OS
Schiller et al. 2002 (ECOG E1594) Phase III (E-switch-ic) 1. Carboplatin & Paclitaxel Did not meet primary endpoint of OS
2. Cisplatin & Docetaxel Did not meet primary endpoint of OS
3. Cisplatin & Paclitaxel Superior PFS
Scagliotti et al. 2008 (JMDB) Phase III (C) Cisplatin & Pemetrexed Seems to have non-inferior OS

Chemotherapy

28-day cycles

Variant #11, 100/1250

Study Evidence Comparator Comparative Efficacy
Cardenal et al. 1999 Phase III (E-RT-switch-ic) Cisplatin & Etoposide Superior TTP
Alberola et al. 2003 Phase III (C) 1. CGV
2. GV-VI
Did not meet primary endpoint of OS

Chemotherapy

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

Variant #12, 100/1400

Study Evidence Comparator Comparative Efficacy
Gebbia et al. 2003 Phase III (E-switch-ic) Cisplatin & Vinorelbine Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

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. Crinò L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999 Nov;17(11):3522-30. link to original article contains protocol PubMed
  3. Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000 Jan;18(1):122-30. link to original article contains protocol PubMed
  4. 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
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  14. Novello S, Bruzzi P, Barone C, Buosi R, Masotti A, Michetti G, Fioretti M, Barbera S, Spatafora M, Garetto L, Mazzanti P, Dongiovanni V, Selvaggi G, Crinò L, Scagliotti GV. Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Ann Oncol. 2007 May;18(5):903-8. Epub 2007 Mar 9. link to original article contains protocol PubMed
  15. 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
  16. GECO: Gridelli C, Gallo C, Ceribelli A, Gebbia V, Gamucci T, Ciardiello F, Carozza F, Favaretto A, Daniele B, Galetta D, Barbera S, Rosetti F, Rossi A, Maione P, Cognetti F, Testa A, Di Maio M, Morabito A, Perrone F; GECO investigators. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol. 2007 Jun;8(6):500-12. link to original article contains protocol PubMed
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  18. 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
  19. 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
  20. Manegold C, van Zandwijk N, Szczesna A, Zatloukal P, Au JS, Blasinska-Morawiec M, Serwatowski P, Krzakowski M, Jassem J, Tan EH, Benner RJ, Ingrosso A, Meech SJ, Readett D, Thatcher N. A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2012 Jan;23(1):72-7. Epub 2011 Apr 4. link to original article contains protocol PubMed
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  22. 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
  23. 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
  24. 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
    1. HRQoL analysis: Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, Maione P, Gebbia V, Morgillo F, Wierzbicki R, Favaretto A, Alam Y, Cinieri S, Siena S, Bianco R, Riccardi F, Spatafora M, Ravaioli A, Felletti R, Fregoni V, Genestreti G, Rossi A, Mancuso G, Fasano M, Morabito A, Tsao MS, Signoriello S, Perrone F, Gridelli C. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advancednon-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1830-1844. link to original article PubMed
  25. 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
  26. 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
  27. 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
  28. 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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
  29. 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 & Irinotecan

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IP: Irinotecan & Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Negoro et al. 2003 Phase III (E-switch-ic) Cisplatin & Vindesine Did not meet primary endpoint of OS
Irinotecan Not reported
Ohe et al. 2006 Phase III (C) 1. Carboplatin & Paclitaxel Inconclusive whether non-inferior OS
2. Cisplatin & Gemcitabine Inconclusive whether non-inferior OS
3. Cisplatin & Vinorelbine Inconclusive whether non-inferior OS
Takeda et al. 2009 (WJTOG0203) Phase III (C) Platinum doublet x 3, then Gefitinib Did not meet primary endpoint of OS

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, 70/175 x 4

Study Evidence Comparator Comparative Efficacy
Park et al. 2007 Phase III (E-de-esc) Cisplatin & Paclitaxel x 6 Non-inferior OS

Chemotherapy

21-day cycle for 4 cycles

Variant #2, 75/135, q2wk

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Stathopoulos et al. 2010a Phase III (C) Liposomal Cisplatin & Paclitaxel Did not meet secondary endpoints More toxic

Chemotherapy

14-day cycle for up to 9 cycles

Variant #3, 75/135, q3wk

Study Evidence Comparator Comparative Efficacy
Bonomi et al. 2000 (ECOG E5592) Phase III (E-RT-switch-ic) Cisplatin & Etoposide Seems to have superior OS
Schiller et al. 2002 (ECOG E1594) Phase III (C) 1. Carboplatin & Paclitaxel Did not meet primary endpoint of OS
2. Cisplatin & Docetaxel Did not meet primary endpoint of OS
3. Cisplatin & Gemcitabine Inferior PFS

Chemotherapy

21-day cycles

Variant #4, 80/175

Study Evidence Comparator Comparative Efficacy
Gatzemeier et al. 2000 Phase III (E-esc) Cisplatin Seems to have superior TTP
Smit et al. 2003 (EORTC 08975) Phase III (C) 1. Cisplatin & Gemcitabine
2. Gemcitabine & Paclitaxel
Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #5, 80/200

Study Evidence Comparator Comparative Efficacy
Rosell et al. 2002 Phase III (E-switch-ic) 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. Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, de Marinis F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallant G. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000 Oct 1;18(19):3390-9. link to original article contains protocol PubMed
  3. 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
  4. 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
  5. 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
  6. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. link to original article contains verified protocol PubMed
  7. Stathopoulos GP, Antoniou D, Dimitroulis J, Michalopoulou P, Bastas A, Marosis K, Stathopoulos J, Provata A, Yiamboudakis P, Veldekis D, Lolis N, Georgatou N, Toubis M, Pappas Ch, Tsoukalas G. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010 Nov;21(11):2227-32. Epub 2010 May 3. link to original article link to PMC article contains verified protocol PubMed

Cisplatin & Vinorelbine

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

Variant #1, 75/25

Study Evidence Comparator Comparative Efficacy
Martoni et al. 2005 Phase III (E-switch-ic) Cisplatin & Gemcitabine Did not meet primary endpoint of ORR

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

  • Vinorelbine maintenance

Variant #2, 80/25

Study Evidence Comparator Comparative Efficacy
Ohe et al. 2006 Phase III (E-switch-ic) 1. Carboplatin & Paclitaxel Inconclusive whether non-inferior OS
2. Cisplatin & Gemcitabine Inconclusive whether non-inferior OS
3. Cisplatin & Irinotecan Inconclusive whether non-inferior OS
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 Did not meet primary endpoint of OS

Chemotherapy

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

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

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Gridelli et al. 2003 Phase III (C) Gemcitabine & Vinorelbine Might have superior OS
Georgoulias et al. 2005 Phase III (C) Docetaxel & Gemcitabine Did not meet primary endpoint of OS
Gebbia et al. 2008 Phase III (C) Cisplatin & Vinorelbine; 3 out of 4 weeks Did not meet primary endpoint of OS Less toxic

Chemotherapy

21-day cycle for 6 cycles (Gridelli et al. 2003) or up to 9 cycles (Georgoulias et al. 2005)

Variant #4, 80/30, weekly vinorelbine

Study Evidence Comparator Comparative Efficacy
Depierre et al. 1994 Phase III (E-esc) Vinorelbine Superior TTP
Souquet et al. 2002 (GLOB-1) Phase III (C) NIP Did not meet primary endpoint of OS1

Chemotherapy

21-day cycles

Variant #5, 100/25

Study Evidence Comparator Comparative Efficacy
Wozniak et al. 1998 Phase III (E-RT-esc) Cisplatin Superior OS
Kelly et al. 2001 (SWOG 9509) Phase III (C) Carboplatin & Paclitaxel Did not meet primary endpoint of OS
Scagliotti et al. 2002 Phase III (C) 1. Carboplatin & Paclitaxel
2. Cisplatin & Gemcitabine
Did not meet primary endpoint of ORR
Fossella et al. 2003 (TAX 326) Phase III (C) 1. Carboplatin & Docetaxel Did not meet primary endpoint of OS
2. Cisplatin & Docetaxel Seems to have inferior OS
Ramlau et al. 2008 (SPIRIT I) Phase III (C) CV & Bexarotene Did not meet primary endpoint of OS

Chemotherapy

28-day cycle for up to 10 cycles (SWOG 9509) or indefinitely (TAX 326, SPIRIT I)

Variant #6, 100/30

Study Evidence Comparator Comparative Efficacy
Robinet et al. 2001 (GFPC 95-1) Phase III (C) CV & concurrent WBRT Did not meet primary endpoint of
Pujol et al. 2005 Phase III (C) Docetaxel & Gemcitabine Did not meet primary endpoint of OS

Note: patients in GFPC 95-1 had intracranial metastases.

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

  • GFPC 95-1: WBRT

Variant #7, 120/30

Study Evidence Comparator Comparative Efficacy
Le Chevalier et al. 1994 Phase III (E-RT-esc) 1. Cisplatin & Vindesine Seems to have superior OS
2. Vinorelbine Superior OS
Comella et al. 2000 Phase III (C) 1. Cisplatin & Gemcitabine Not reported
2. PGV Inferior OS

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

Chemotherapy

28-day cycle for 1 cycle, then 42-day cycles (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. Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, Albain KS, Kelly K, Taylor SA, Gandara DR, Livingston RB. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998 Jul;16(7):2459-65. link to original article PubMed
  4. 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
  5. GFPC 95-1: Robinet G, Thomas P, Breton JL, Léna H, Gouva S, Dabouis G, Bennouna J, Souquet PJ, Balmes P, Thiberville L, Fournel P, Quoix E, Riou R, Rebattu P, Pérol M, Paillotin D, Mornex F. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59-67. link to original article contains protocol PubMed
  6. SWOG 9509: Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001 Jul 1;19(13):3210-8. link to original article contains verified protocol PubMed
  7. Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini L, Tonato M; Italian Lung Cancer Project. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002 Nov 1;20(21):4285-91. link to original article PubMed
  8. GLOB-1: Souquet PJ, Tan EH, Rodrigues Pereira J, Van Klaveren R, Price A, Gatzemeier U, Jaworski M, Burillon JP, Aubert D. GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients. Ann Oncol. 2002 Dec;13(12):1853-61. Erratum in: Ann Oncol. 2003 Feb;14(2):347. link to original article contains protocol PubMed
  9. TAX 326: Fossella F, Rodrigues Pereira J, 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
  10. Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains verified protocol PubMed
  11. Martoni A, Marino A, Sperandi F, Giaquinta S, Di Fabio F, Melotti B, Guaraldi M, Palomba G, Preti P, Petralia A, Artioli F, Picece V, Farris A, Mantovani L. Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer. 2005 Jan;41(1):81-92. link to original article contains protocol PubMed
  12. 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
  13. 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
  14. 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
  15. Gebbia V, Galetta D, Lorusso V, Caruso M, Verderame F, Pezzella G, Borsellino N, Durini E, Valenza R, Agostara B, Colucci G; Gruppo Oncologico Italia Meridionale. Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine on days 1 and 8 in advanced non-small cell lung cancer: a prospective randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale). Lung Cancer. 2008 Sep;61(3):369-77. Epub 2008 Mar 4. link to original article contains protocol PubMed
  16. SPIRIT I: Ramlau R, Zatloukal P, Jassem J, Schwarzenberger P, Orlov SV, Gottfried M, Rodrigues Pereira J, Temperley G, Negro-Vilar R, Rahal S, Zhang JK, Negro-Vilar A, Dziewanowska ZE. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008 Apr 10;26(11):1886-92. link to original article contains verified protocol PubMed
  17. FLEX: Pirker R, Rodrigues Pereira J, 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
  18. 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 Comparative Efficacy
Pirker et al. 2009 (FLEX) Phase III (E-esc) Cisplatin & Vinorelbine Seems to have superior OS

Chemotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV once on day 1
  • Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
    • Cycles 2 to 6: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

Subsequent treatment

  • Cetuximab maintenance

References

  1. FLEX: Pirker R, Rodrigues Pereira J, 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

Gemcitabine & Paclitaxel

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GT: Gemcitabine & Taxol (Paclitaxel)

Variant #1, 1000/125

Study Evidence Comparator Comparative Efficacy
Kosmidis et al. 2002 Phase III (E-switch-ic) Carboplatin & Paclitaxel Did not meet primary endpoint of OS
Comella et al. 2006 (SICOG 0101) Phase III (C) 1. GV
2. PGT
3. PGV
Did not meet primary endpoint of OS
Kosmidis et al. 2007 Phase III (E-switch-ic) Carboplatin & Gemcitabine Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #2, 1000/200

Study Evidence Comparator Comparative Efficacy
Kosmidis et al. 2010 Phase III (C) Paclitaxel & Vinorelbine Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains protocol PubMed
  2. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008 Jan;19(1):115-22. Epub 2007 Oct 15. link to original article contains protocol PubMed
  3. SICOG 0101: Comella P, Filippelli G, De Cataldis G, Massidda B, Frasci G, Maiorino L, Putzu C, Mancarella S, Palmeri S, Cioffi R, Roselli M, Buzzi F, Milia V, Gambardella A, Natale D, Bianco M, Ghiani M, Masullo P; Southern Italy Cooperative Oncology Group. Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101). Ann Oncol. 2007 Feb;18(2):324-30. Epub 2006 Oct 27. link to original article contains protocol PubMed
  4. Kosmidis PA, Fountzilas G, Eleftheraki AG, Kalofonos HP, Pentheroudakis G, Skarlos D, Dimopoulos MA, Bafaloukos D, Pectasides D, Samantas E, Boukovinas J, Lambaki S, Katirtzoglou N, Bakogiannis C, Syrigos KN. Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2011 Apr;22(4):827-34. Epub 2010 Sep 29. link to original article contains protocol PubMed

Gemcitabine & Vinorelbine

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VG: Vinorelbine & Gemcitabine G+V: Gemcitabine & Vinorelbine

Variant #1, 1000/25, 2 weeks out of 3 (IV vinorelbine)

Study Evidence Comparator Comparative Efficacy
Laack et al. 2004 Phase III (E-de-esc) GVP Did not meet primary endpoint of OS
Tan et al. 2005 (GLOB 2) Phase III (E-switch-ic) Carboplatin & Vinorelbine Did not meet primary endpoint of ORR

Chemotherapy

Supportive medications

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

21-day cycles

Variant #2, 1000/25, 3 weeks out of 4 (IV vinorelbine)

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Greco et al. 2007 Phase III (E-switch-ic) PCG Did not meet primary endpoint of OS Less toxic

Chemotherapy

28-day cycles

Variant #3, 1000/60 (PO vinorelbine)

Study Evidence Comparator Comparative Efficacy
Fløtten et al. 2012 Phase III (E-switch-ic) Carboplatin & Vinorelbine Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 3 cycles

Variant #4, 1200/30

Study Evidence Comparator Comparative Efficacy
Frasci et al. 2001 Phase III (E-esc) Vinorelbine Superior OS

Chemotherapy

21-day cycles

References

  1. Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, DeCataldis G, Belli M, Iannelli N, Massidda B, Mascia V, Comella G, De Lena M. Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer: a Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer. 2001 Dec;34 Suppl 4:S65-9. link to original article contains protocol PubMed
  2. Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Aug 15;21(16):3025-34. Epub 2003 Jul 1. link to original article contains verified protocol PubMed
  3. 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
  4. 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
  5. Greco FA, Spigel DR, Kuzur ME, Shipley D, Gray JR, Thompson DS, Burris HA, Yardley DA, Pati A, Webb CD, Gandhi JG, Hainsworth JD. Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network. Clin Lung Cancer. 2007 Sep;8(8):483-7. link to original article PubMed
  6. 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

Ipilimumab & Nivolumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Hellmann et al. 2018 (CheckMate 227) Phase III (E-switch-ooc) 1. Nivolumab Not reported
2. Platinum doublet Superior PFS

Immunotherapy

42-day cycles

References

  1. CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article contains verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Comparator Efficacy ORR
Carbone et al. 2017 (CheckMate 026) Phase III (E-switch-ooc) Platinum doublet (see note) Did not meet primary endpoint of PFS 26% (95% CI 20 - 33)

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
  2. CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Garon et al. 2015 (KEYNOTE-001) Phase 1, >20 pts in dosing cohort
Reck et al. 2016 (KEYNOTE-024) Phase III (E-RT-switch-ooc) 1. Carboplatin & Gemcitabine
2. Carboplatin & Paclitaxel
3. Carboplatin & Pemetrexed
4. Cisplatin & Gemcitabine
5. Cisplatin & Pemetrexed
Superior OS Superior HRQoL
Mok et al. 2019 (KEYNOTE-042) Phase III (E-RT-switch-ooc) 1. Carboplatin & Paclitaxel
2. 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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
  3. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Advanced or metastatic disease, first-line, nonsquamous

ABCP

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ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel

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

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E-RT-esc) 1. ACP Not reported
2. 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. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E-RT-esc) 1. ACP Not reported
2. 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. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

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

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) Phase III (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

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 Comparative Efficacy Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380) Phase III (C) Carboplatin & Pemetrexed Did not meet primary endpoint of OS Inferior survival without treatment-emergent grade 3/4 toxicity

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed

Carboplatin & Gemcitabine

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CG: Carboplatin & Gemcitabine

Regimen

Study Evidence
Jian et al. 2017 Non-randomized portion of RCT

Note: the manuscript does not specify whether gemcitabine is given more than once per cycle.

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • Continued CG x 4 versus CG & Gefitinib

References

  1. Jian H, Li W, Ma Z, Huang J, Feng J, Song Y, Gao B, Zhu H, Tao M, Bai C, Ma S, Pan H, Qin S, Hua D, Yu Y, Lu S. Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status. Sci Rep. 2017 Aug 16;7(1):8483. link to original article link to PMC article contains verified protocol PubMed

Carboplatin, nab-Paclitaxel, Atezolizumab

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Regimen

Study Evidence Comparator Comparative Efficacy
West et al. 2019 (IMpower130) Phase III (E-esc) Carboplatin & nab-Paclitaxel Seems to have superior OS

Chemotherapy

Immunotherapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

  • Atezolizumab maintenance

References

  1. IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article contains protocol PubMed

Carboplatin & Paclitaxel

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

Variant #1, 6/175

Study Evidence Comparator Comparative Efficacy
Zhou et al. 2015 (BEYOND) Phase III (C) Carboplatin, Paclitaxel, Bevacizumab Seems to have inferior OS

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Variant #2, 6/200

Study Evidence Comparator Comparative Efficacy
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
Scagliotti et al. 2012 (MONET1) Phase III (C) TC & Motesanib Did not meet primary endpoint of OS
Kubota et al. 2017 (MONET-A) Phase III (C) TC & Motesanib Might have inferior PFS

Chemotherapy

21-day cycle for 3 or more 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. 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. Dataset: Project Data Sphere
  3. 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
  4. 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
  5. 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

Carboplatin, Paclitaxel, Bevacizumab

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PacCBev: Paclitaxel, Carboplatin, Bevacizumab
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel
CbTB: Carboplatin, Taxol (Paclitaxel), Bevacizumab

Variant #1, 6/175/15 x 4

Study Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) Phase III (C) 1. ACP Not reported
2. 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 Comparative Efficacy
Socinski et al. 2018 (IMpower150) Phase III (C) 1. ACP Not reported
2. 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 Comparative 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) 1. ACP Not reported
2. 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 Comparative Efficacy
Sandler et al. 2006 (ECOG E4599) Phase III (E-RT-esc) See link See link
Zhou et al. 2015 (BEYOND) Phase III (E-esc) Carboplatin & Paclitaxel Seems to have superior OS
Socinski et al. 2018 (IMpower150) Phase III (C) 1. ACP Not reported
2. 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 once on day 1, given third, starting 60 minutes after the completion of carboplatin
    • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later

21-day cycle for up to 6 cycles

Subsequent treatment

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. 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
    1. Dataset: Project Data Sphere
  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. 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
  5. 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 & Pemetrexed

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

Example orders

Variant #1, 5/500 x 4

Study Evidence Comparator Comparative 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

21-day cycle for up to 4 cycles

Subsequent treatment

Variant #2, 5/500 x 6

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380) Phase III (E-switch-ic) Carboplatin & Docetaxel Did not meet primary endpoint of OS Superior survival without treatment-emergent grade 3/4 toxicity
Mok et al. 2019 (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

Variant #3, 6/500 x 4

Study Evidence Comparator Comparative Efficacy
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

21-day cycle for up to 4 cycles

Subsequent treatment

Variant #4, 6/500 x 6

Study Evidence Comparator Comparative Efficacy
Mok et al. 2019 (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

Variant #5, 6/500 indefinitely

Study Evidence Comparator Comparative Efficacy
Edelman et al. 2017 (CALGB 30801) Phase III (C) CP & Celecoxib Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

References

  1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed
  2. 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
  3. 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
  4. 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
  5. CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains verified protocol PubMed
  6. 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
  7. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Carboplatin, Pemetrexed, Bevacizumab

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PemCBev: Pemetrexed, Carboplatin, Bevacizumab

Regimen

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

Chemotherapy

Supportive medications

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

21-day cycle for 4 cycles

Subsequent treatment

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
    1. Dataset: Project Data Sphere

Cisplatin & Docetaxel

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

Regimen

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

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. 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 & Gemcitabine

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

Variant #1, 75/1000

Study Evidence Comparator Comparative 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 Comparative Efficacy
Paz-Ares et al. 2012 (NExUS) Phase III (C) GC & Sorafenib Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #3, 80/1250 x 6

Study Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) Phase III (C) 1. GC & Bevacizumab; low-dose Inferior PFS
2. GC & Bevacizumab; standard-dose Seems to have inferior PFS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #4, 80/1250 x 9

Study Evidence Comparator Comparative Efficacy
Han et al. 2012 (First-SIGNAL) Phase III (C) Gefitinib Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 9 cycles

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 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
  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
  3. 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
    1. Dataset: Project Data Sphere
  4. 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

Cisplatin, Gemcitabine, Bevacizumab

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Variant #1, low-dose bev

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

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

Variant #2, standard-dose bev

Study Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) Phase III (E-RT-esc) 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 & Pemetrexed

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

Variant #1, 70/500

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

Chemotherapy

21-day cycle for up to 4 cycles

Variant #2, 75/500

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Paz-Ares et al. 2012 (PARAMOUNT) Non-randomized portion of RCT
Sequist et al. 2013 (LUX-Lung 3) Phase III (C) Afatinib Inferior PFS
Wu et al. 2014 (JMIL) Phase III (C) GC Did not meet primary endpoint of OS
Solomon et al. 2014 (PROFILE 1014) Phase III (C) Crizotinib Inferior PFS
Paz-Ares et al. 2015 (INSPIRE) Phase III (C) Pem-Cis & Necitumumab Did not meet primary endpoint of OS
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: Patients in LUX-Lung 3 had adenocarcinoma with activating mutations in EGFR. Patients in PROFILE 1014 & ASCEND-4 had ALK-rearranged NSCLC. Patients in CONVINCE had stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. 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. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  2. 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
  3. JMIL: Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M. Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2014 Sep;85(3):401-7. Epub 2014 Jul 17. link to original article 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. Pooled subgroup analysis: Nishio M, Kim DW, Wu YL, Nakagawa K, Solomon BJ, Shaw AT, Hashigaki S, Ohki E, Usari T, Paolini J, Polli A, Wilner KD, Mok T. Crizotinib versus chemotherapy in Asian patients with ALK-positive advanced non-small cell lung cancer. Cancer Res Treat. 2018 Jul;50(3):691-700. Epub 2017 Jul 6. link to original article link to PMC article PubMed
    3. 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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article 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

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
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed

Cisplatin, Pemetrexed, Pembrolizumab

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Regimen

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

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

Chemotherapy

Immunotherapy

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

Gefitinib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Mok et al. 2009 (IPASS) Phase III (E-RT-switch-ooc) Carboplatin & Paclitaxel Superior PFS
Han et al. 2012 (First-SIGNAL) Phase III (E-switch-ooc) Cisplatin & Gemcitabine Did not meet primary endpoint of OS
Yang et al. 2014 (H3E-CR-S131) Phase III (E-de-esc) Cisplatin & Pemetrexed, then Gefitinib maint. Did not meet primary endpoint of PFS

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. Dataset: Project Data Sphere
  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
  3. H3E-CR-S131: Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, Kim DW, Tsai CM, Barraclough H, Altug S, Orlando M, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer. 2014 Sep;50(13):2219-30. Epub 2014 Jun 18. link to original article PubMed
    1. Update: Yang JC, Srimuninnimit V, Ahn MJ, Lin CC, Kim SW, Tsai CM, Mok T, Orlando M, Puri T, Wang X, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol. 2016 Mar;11(3):370-9. Epub 2015 Dec 25. link to original article PubMed

Advanced or metastatic disease, first-line, squamous

Carboplatin & Gemcitabine

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Variant #1, 5/1000

Study Evidence Comparator Comparative Efficacy
Patil et al. 2019 Phase III (C) Carboplatin & low-dose Gemcitabine Non-inferior OS

Note: CrCl was calculated using Cockcroft–Gault.

Chemotherapy

21-day cycle for up to 6 cycles

Variant #2, 5.5/1000

Study Evidence Comparator Comparative Efficacy
Edelman et al. 2017 (CALGB 30801) Phase III (C) CG & Celecoxib Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

References

  1. CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains verified protocol PubMed
  2. Patil V, Noronha V, Joshi A, Chougule A, Kannan S, Bhattacharjee A, Goud S, More S, Chandrasekharan A, Menon N, Srinivas S, Vallathol DH, Dsouza H, Majumdar S, Das S, Zawar A, Khaddar S, Kumar A, Singh G, Kumar KAP, Ravind R, Trivedi V, Behel V, Mahajan A, Janu A, Purandare N, Prabhash K. Phase III non-inferiority study evaluating efficacy and safety of low dose gemcitabine compared to standard dose gemcitabine with platinum in advanced squamous lung cancer. EClinicalMedicine. 2019 Apr 9;9:19-25. link to PMC article contains verified protocol PubMed

Carboplatin & nab-Paclitaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) Phase III (C) Carboplatin, nab-Paclitaxel, Pembrolizumab x 4, then Pembrolizumab maint. Inferior OS

Chemotherapy

21-day cycle for 4 cycles

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Carboplatin, nab-Paclitaxel, Pembrolizumab

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) Phase III (E-RT-esc) See link See link

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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

Variant #1, 5/200

Study Evidence Comparator Comparative Efficacy
Mok et al. 2019 (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

Variant #2, 6/175

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

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Variant #3, 6/200

Study Evidence Comparator Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042) Phase III (C) Pembrolizumab Inferior OS
Paz-Ares et al. 2018 (KEYNOTE-407) Phase III (C) CP & Pembrolizumab x 4, then Pembrolizumab maint. Inferior OS

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

Chemotherapy

21-day cycle for 4 cycles (KEYNOTE-407) or up to 6 cycles (KEYNOTE-042)

References

  1. CA184-104: Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed
  2. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed
  3. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Carboplatin, Paclitaxel, Ipilimumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Govindan et al. 2017 (CA184-104) Phase III (E-esc) Carboplatin & Paclitaxel Did not meet primary endpoint of OS

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

Chemotherapy

Immunotherapy

Supportive medications

21-day cycle for up to 6 cycles

Subsequent treatment

References

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

Carboplatin, Paclitaxel, Pembrolizumab

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) Phase III (E-RT-esc) See link See link

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Cisplatin & Docetaxel

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DC: Docetaxel & Cisplatin
CD: Cisplatin & Docetaxel

Variant #1, 75/75

Study Evidence Comparator Comparative Efficacy
Lu et al. 2018 (5501068) Phase III (C) Docetaxel & Nedaplatin Might have inferior PFS

Note: the cycle length is not specified in the abstract; 21-day cycles are standard.

Chemotherapy

21-day cycles

Variant #2, 80/60

Study Evidence Comparator Comparative Efficacy
Shukuya et al. 2015 (WJOG5208L) Phase III (C) Docetaxel & Nedaplatin Seems to have inferior OS

Chemotherapy

21-day cycle for 4 to 6 cycles

References

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

Cisplatin & Gemcitabine

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

Regimen

Study Evidence Comparator Comparative Efficacy
Thatcher et al. 2015 (SQUIRE) Phase III (C) Cisplatin, Gemcitabine, Necitumumab Seems to have inferior OS

Chemotherapy

21-day cycle for up to 6 cycles

References

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

Cisplatin, Gemcitabine, Necitumumab

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Regimen

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

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. 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
    1. Dataset: Project Data Sphere

Docetaxel & Nedaplatin

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Regimen

Study Evidence Comparator Comparative Efficacy
Shukuya et al. 2015 (WJOG5208L) Phase III (E-switch-ic) Cisplatin & Docetaxel Seems to have superior OS

Chemotherapy

21-day cycle for 4 to 6 cycles

References

  1. WJOG5208L: Shukuya T, Yamanaka T, Seto T, Daga H, Goto K, Saka H, Sugawara S, Takahashi T, Yokota S, Kaneda H, Kawaguchi T, Nagase S, Oguri T, Iwamoto Y, Nishimura T, Hattori Y, Nakagawa K, Nakanishi Y, Yamamoto N; West Japan Oncology Group. Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1630-8. Epub 2015 Oct 28. link to original article contains protocol PubMed

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

Best supportive care

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Regimen

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

No active antineoplastic treatment.

References

  1. ELVIS: Gridelli C, Perrone F, Gallo C; The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
  2. De Marinis F, Rinaldi M, Ardizzoni A, Bruzzi P, Pennucci MC, Portalone L, D'Aprile M, Ripanti P, Romano F, Belli M, Altavilla G, Migliorino MR, Rosso R, Salvati F; Italian Lung Cancer Task Force. The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Tumori. 1999 May-Jun;85(3):177-82. link to original article PubMed

Carboplatin & Gemcitabine

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CG: Carboplatin & Gemcitabine

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Biesma et al. 2011 (NVALT-3) Phase III (C) CP Similar QoL

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. NVALT-3: Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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

Variant #1, 5/175

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Biesma et al. 2011 (NVALT-3) Phase III (C) CG Similar QoL

Chemotherapy

21-day cycle for up to 4 cycles

Variant #2, 6/90

Study Evidence Comparator Comparative Efficacy
Quoix et al. 2011 (IFCT-0501) Phase III (E-esc) 1. Gemcitabine Superior OS
2. 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

Variant #3, 6/200

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

Chemotherapy

21-day cycle for up to 4 cycles

Variant #4, 6/225

Study Evidence Comparator Comparative Efficacy
Langer et al. 2008 Phase III (C) Carboplatin & PPX Did not meet primary endpoint of OS

Chemotherapy

21-day 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. Langer CJ, O'Byrne KJ, Socinski MA, Mikhailov SM, Leśniewski-Kmak K, Smakal M, Ciuleanu TE, Orlov SV, Dediu M, Heigener D, Eisenfeld AJ, Sandalic L, Oldham FB, Singer JW, Ross HJ. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6):623-30. link to original article contains protocol PubMed
  3. NVALT-3: Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ; Dutch Chest Physician Study Group. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul;22(7):1520-7. Epub 2011 Jan 20. link to original article contains verified 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

Carboplatin & Pemetrexed

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Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Zukin et al. 2013 (INCA-Lung001) Phase III (E-esc) 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 Comparative Efficacy
Spigel et al. 2018 Randomized Phase II (E-esc) 1. Pemetrexed
2. Pemetrexed & Bevacizumab
PFS: 4.8 mo

Chemotherapy

Supportive medications

  • Premedications, Folic acid (Folate), 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

Cisplatin & Gemcitabine

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Regimen

Study Evidence Comparator Comparative Efficacy
Morabito et al. 2013 (CAPPA-2) Phase III (E-esc) Gemcitabine Seems to have superior OS
Gridelli et al. 2018 (MILES-3) Phase III (E-esc) Gemcitabine Did not meet primary endpoint of OS
Gridelli et al. 2018 (MILES-4) Phase III (E-esc) Gemcitabine Did not meet primary endpoint of OS

MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.

Chemotherapy

References

  1. CAPPA-2: Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. link to original article contains protocol PubMed
  2. 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

Docetaxel monotherapy

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Example orders

Variant #1, 25 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Comparative Efficacy
Tsukada et al. 2014 (JCOG0207) Phase III (C) Cisplatin & Docetaxel Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

Variant #2, 36 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Comparative Efficacy
Hainsworth et al. 2007 Phase III (C) Docetaxel & Gemcitabine Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

Variant #3, 38 mg/m2, 2 out of 3 weeks

Study Evidence Comparator Comparative Efficacy
Karampeazis et al. 2011 Phase III (E-switch-ic) Vinorelbine Might have superior OS

Chemotherapy

21-day cycle for up to 6 cycles

Variant #4, 60 mg/m2 q3wk

Study Evidence Comparator Comparative Efficacy
Kudoh et al. 2006 (WJTOG 9904) Phase III (E-switch-ic) Vinorelbine Did not meet primary endpoint of OS
Abe et al. 2015 (JCOG0803/WJOG4307L) Phase III (C) Cisplatin & Docetaxel Did not meet primary endpoint of OS

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. Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. link to original article contains verified protocol PubMed
  4. JCOG0207: Tsukada H, Yokoyama A, Goto K, Shinkai T, Harada M, Ando M, Shibata T, Ohe Y, Tamura T, Saijo N; Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Randomized controlled trial comparing docetaxel-cisplatin combination with weekly docetaxel alone in elderly patients with advanced non-small-cell lung cancer: Japan Clinical Oncology Group (JCOG) 0207. Jpn J Clin Oncol. 2015 Jan;45(1):88-95. Epub 2014 Nov 6. link to original article contains protocol PubMed
  5. 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, 1000 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Comparative Efficacy
O'Brien et al. 2008 Phase III (C) Paclitaxel poliglumex Did not meet primary endpoint of OS

Chemotherapy

28-day cycle for up to 6 cycles

Variant #2, 1150 mg/m2, 2 out of 3 weeks

Study Evidence Comparator Comparative 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 #3, 1200 mg/m2, 2 out of 3 weeks

Study Evidence Comparator Comparative Efficacy
Gridelli et al. 2003 (MILES) Phase III (E-switch-ic) 1. Gemcitabine & Vinorelbine Did not meet primary endpoint of OS
2. Vinorelbine Did not meet primary endpoint of OS
Reynolds et al. 2009 (USO-03012) Phase III (C) Carboplatin & Gemcitabine Did not meet primary endpoint of OS
Morabito et al. 2013 (CAPPA-2) Phase III (C) Cisplatin & Gemcitabine Seems to have inferior OS
Gridelli et al. 2018 (MILES-3) Phase III (C) Cisplatin & Gemcitabine Did not meet primary endpoint of OS
Gridelli et al. 2018 (MILES-4) Phase III (C) Cisplatin & Gemcitabine Did not meet primary endpoint of OS

MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.

Chemotherapy

Supportive medications

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

21-day cycle for 4 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. O'Brien ME, Socinski MA, Popovich AY, Bondarenko IN, Tomova A, Bilynsky BT, Hotko YS, Ganul VL, Kostinsky IY, Eisenfeld AJ, Sandalic L, Oldham FB, Bandstra B, Sandler AB, Singer JW. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jul;3(7):728-34. link to original article contains verified protocol PubMed
  4. USO-03012: Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O'Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J, Peng G, Monberg MJ, Bepler G. Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009 Dec 1;27(34):5808-15. Epub 2009 Nov 2. link to original article link to PMC article contains verified protocol PubMed
  5. 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
  6. CAPPA-2: Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, Barbera S, Cavanna L, De Marinis F, Montesarchio V, Costanzo R, Sandomenico C, Montanino A, Mancuso G, Russo P, Nacci A, Giordano P, Daniele G, Piccirillo MC, Rocco G, Gridelli C, Gallo C, Perrone F. Randomized phase III trial of gemcitabine and cisplatin vs gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013 Jul;81(1):77-83. Epub 2013 May 1. link to original article contains protocol PubMed
  7. 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 Comparative Efficacy
Comella et al. 2004 (SICOG 9909) Phase III (E-esc) 1. Gemcitabine
2. Paclitaxel
Seems to have superior OS
3. GV Not reported

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 Comparative Efficacy
Gridelli et al. 2003 (MILES) Phase III (E-esc) 1. Gemcitabine Did not meet primary endpoint of OS
2. Vinorelbine Did not meet primary endpoint of OS

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 Comparative Efficacy
Frasci et al. 2000 Phase III (E-esc) 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 Comparative Efficacy
Zukin et al. 2013 (INCA-Lung001) Phase III (C) Carboplatin & Pemetrexed Inferior OS
Gridelli et al. 2018 (MILES-4) Phase III (C) 1. Cisplatin & Gemcitabine
2. Cisplatin & Pemetrexed
Did not meet primary endpoint of OS

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 Comparative Efficacy
Spigel et al. 2018 Randomized Phase II (E-esc) 1. Pemetrexed
2. Carboplatin, Pemetrexed, Bevacizumab
PFS: 4.0 mo

Chemotherapy

Supportive medications

  • Premedications, Folic acid (Folate), 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 Comparative Efficacy
Lee et al. 2012 (TOPICAL) Phase III (C) Erlotinib Did not meet primary endpoint of OS

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

References

  1. TOPICAL: Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, Marshall E, Woll PJ, Hatton M, Lal R, Jones R, Toy E, Chao D, Middleton G, Bulley S, Ngai Y, Rudd R, Hackshaw A, Boshoff C. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1161-70. Epub 2012 Oct 16. link to original article link to PMC article PubMed

Vinorelbine monotherapy

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Variant #1, 25 mg/m2

Study Evidence Comparator Comparative Efficacy
Kudoh et al. 2006 (WJTOG 9904) Phase III (C) Docetaxel Did not meet primary endpoint of OS
Karampeazis et al. 2011 Phase III (E-switch-ic) Docetaxel Might have inferior OS
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), 5 cycles (IFCT-0501), or 6 cycles (Karampeazis et al. 2011)

Variant #2, 30 mg/m2

Study Evidence Comparator Comparative Efficacy
Gridelli et al. 1999 (ELVIS) Phase III (E-esc) Best supportive care Seems to have superior OS
Gridelli et al. 2003 (MILES) Phase III (C) 1. Gemcitabine Did not meet primary endpoint of OS
2. Gemcitabine & Vinorelbine Did not meet primary endpoint of OS

Study involved only patients at least 70 years old

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

References

  1. ELVIS: Gridelli C, Perrone F, Gallo C; The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
  2. 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. Karampeazis A, Vamvakas L, Agelidou A, Kentepozidis N, Chainis K, Chandrinos V, Vardakis N, Pallis AG, Christophyllakis C, Georgoulias V. Docetaxel vs vinorelbine in elderly patients with advanced non--small-cell lung cancer: a Hellenic Oncology Research Group randomized phase III study. Clin Lung Cancer. 2011 May;12(3):155-60. Epub 2011 Apr 27. link to original article contains verified protocol PubMed
  5. 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

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

Note: this is the FDA-recommended dose for atezolizumab.

Preceding treatment

Immunotherapy

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 Comparative 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 Comparative Efficacy Comparative Toxicity
Sandler et al. 2006 (ECOG E4599) Phase III (E-RT-esc) See link See link
Reck et al. 2009 (AVAil) Non-randomized portion of RCT
Johnson et al. 2013 (ATLAS-NSCLC) 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." Also, this trial should not be confused with the ones with the same name in breast cancer and in renal cell carcinoma.

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
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article 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
    1. Dataset: Project Data Sphere
  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

Gemcitabine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Brodowicz et al. 2006 Phase III (E-esc) Observation Superior TTP
Pérol et al. 2012 Phase III (E-esc) 1. Erlotinib Not reported
2. Observation Superior PFS

Preceding treatment

Chemotherapy

21-day cycles

References

  1. Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group CECOG. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006 May;52(2):155-63. Epub 2006 Mar 29. link to original article 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 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
    1. Dataset: Project Data Sphere

Observation

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Regimen

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

Pembrolizumab monotherapy

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2018 (KEYNOTE-407) Phase III (E-RT-esc) See link See link

Preceding treatment

Immunotherapy

21-day cycle for up to 35 cycles (including induction)

References

  1. KEYNOTE-407: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article contains verified protocol PubMed

Pemetrexed monotherapy

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Example orders

Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Ciuleanu et al. 2009 (JMEN) Phase III (E-RT-esc) Placebo Seems to have superior OS
Paz-Ares et al. 2012 (PARAMOUNT) Phase III (E-RT-esc) 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
Shi et al. 2017 (CONVINCE) Phase III (C) See link See link
Gandhi et al. 2018 (KEYNOTE-189) Non-randomized portion of RCT
Mok et al. 2019 (KEYNOTE-042) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Supportive medications

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, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. link to original article contains protocol PubMed
  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. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  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
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article 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. 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
  7. 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
  8. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed

Pemetrexed & Bevacizumab

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Variant #1, 500/7.5

Study Evidence Comparator Comparative Efficacy
Barlesi et al. 2013 (AVAPERL) Phase III (E-esc) 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 (Folate), 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
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article 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
    1. Dataset: Project Data Sphere
  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 Comparative 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 Comparative Efficacy
Johnson et al. 2008 (NCCTG 97-24-51) Phase III (C) CAI Did not meet primary endpoint of OS
Ciuleanu et al. 2009 (JMEN) Phase III (C) Pemetrexed Seems to have inferior OS
Lee et al. 2009 Phase III (C) Thalidomide Did not meet primary endpoint of OS
Cappuzzo et al. 2010 (SATURN) Phase III (C) Erlotinib Inferior PFS
Koch et al. 2011 (CYCLUS) Phase III (C) Celecoxib Did not meet primary endpoint of OS
Gaafar et al. 2011 (EORTC 08021) Phase III (C) Gefitinib Did not meet primary endpoint of OS
Paz-Ares et al. 2012 (PARAMOUNT) Phase III (C) Pemetrexed Inferior PFS
Zhang et al. 2012 (INFORM) Phase III (C) Gefitinib Inferior PFS
O'Brien et al. 2015 (EORTC 08092) Phase III (C) Pazopanib Did not meet primary endpoint of OS
Giaccone et al. 2015 (STOP) Phase III (C) Belagenpumatucel-L Did not meet primary endpoint of OS
Cicènas et al. 2016 (IUNO) Phase III (C) See link See link
Baggstrom et al. 2017 (CALGB 30607) Phase III (C) Sunitinib Inferior PFS

No further antineoplastic treatment after first-line therapy. Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks.

Preceding treatment

Subsequent treatment

References

  1. NCCTG 97-24-51: Johnson EA, Marks RS, Mandrekar SJ, Hillman SL, Hauge MD, Bauman MD, Wos EJ, Moore DF, Kugler JW, Windschitl HE, Graham DL, Bernath AM Jr, Fitch TR, Soori GS, Jett JR, Adjei AA, Perez EA. Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Lung Cancer. 2008 May;60(2):200-7. Epub 2007 Nov 28. link to original article PubMed
  2. JMEN: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Rodrigues Pereira J, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. Epub 2009 Sep 18. link to original article contains protocol PubMed
  3. Lee SM, Rudd R, Woll PJ, Ottensmeier C, Gilligan D, Price A, Spiro S, Gower N, Jitlal M, Hackshaw A. Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Nov 1;27(31):5248-54. Epub 2009 Sep 21. link to original article PubMed
  4. SATURN: Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010 Jun;11(6):521-9. Epub 2010 May 20. link to original article contains protocol PubMed
  5. CYCLUS: Koch A, Bergman B, Holmberg E, Sederholm C, Ek L, Kosieradzki J, Lamberg K, Thaning L, Ydreborg SO, Sörenson S; Swedish Lung Cancer Study Group. Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: a double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group. Eur J Cancer. 2011 Jul;47(10):1546-55. Epub 2011 May 10. link to original article PubMed
  6. EORTC 08021: Gaafar RM, Surmont VF, Scagliotti GV, Van Klaveren RJ, Papamichael D, Welch JJ, Hasan B, Torri V, van Meerbeeck JP; EORTC Lung Cancer Group and the Italian Lung Cancer Project. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer. 2011 Oct;47(15):2331-40. Epub 2011 Jul 28. link to original article PubMed
  7. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  8. INFORM: Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, Yang S, Liu X, Liu Y, Lu S, Wang J, Zhang S, Zhou C, Zhang X, Hayashi N, Wang M; INFORM investigators. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. Lancet Oncol. 2012 May;13(5):466-75. Epub 2012 Apr 17. link to original article PubMed
    1. Update: Zhao H, Fan Y, Ma S, Song X, Han B, Cheng Y, Huang C, Yang S, Liu X, Liu Y, Lu S, Wang J, Zhang S, Zhou C, Wang M, Zhang L; INFORM investigators. Final overall survival results from a phase III, randomized, placebo-controlled, parallel-group study of gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804). J Thorac Oncol. 2015 Apr;10(4):655-64. link to original article PubMed
  9. EORTC 08092: O'Brien ME, Gaafar R, Hasan B, Menis J, Cufer T, Popat S, Woll PJ, Surmont V, Georgoulias V, Montes A, Blackhall F, Hennig I, Schmid-Bindert G, Baas P; EORTC-LCG. Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: a double blind randomised phase III study of the lung cancer group, EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064). Eur J Cancer. 2015 Aug;51(12):1511-28. Epub 2015 Jun 11. link to original article PubMed
  10. STOP: Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhász E, Ramlau R, van den Heuvel MM, Lal R, Kloecker GH, Eaton KD, Chu Q, Dunlop DJ, Jain M, Garon EB, Davis CS, Carrier E, Moses SC, Shawler DL, Fakhrai H. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer. 2015 Nov;51(16):2321-9. Epub 2015 Aug 14. link to original article PubMed
  11. IUNO: Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. link to original article contains verified protocol PubMed
  12. CALGB 30607: Baggstrom MQ, Socinski MA, Wang XF, Gu L, Stinchcombe TE, Edelman MJ, Baker S Jr, Feliciano J, Novotny P, Hahn O, Crawford JA, Vokes EE. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study-CALGB 30607 (Alliance). J Thorac Oncol. 2017 May;12(5):843-849. Epub 2017 Feb 1. link to original article PubMed

Advanced or metastatic disease, second-line

Afatinib monotherapy

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Variant #1, 30 mg/day

FDA-recommended dose

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

Chemotherapy

Continued indefinitely

Variant #2, 40 mg/day

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

Chemotherapy

Continued indefinitely

References

  1. LUX-Lung 8: Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains protocol PubMed

Cabozantinib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512) Randomized Phase II (E-switch-ic) 1. Cabozantinib & Erlotinib Not reported
2. 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 Comparative Efficacy
Neal et al. 2016 (ECOG-ACRIN 1512) Randomized Phase II (E-esc) 1. Cabozantinib Not reported
2. 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 Comparative Efficacy
Ardizzoni et al. 2012 (GOIRC 02-2006) Randomized Phase II (E-esc) Pemetrexed Did not meet primary endpoint of PFS
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

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. 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
  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, 33.3 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Comparative Efficacy
Gebbia et al. 2008 (DISTAL-2 Phase III (C) 1. Capecitabine & Docetaxel
2. Docetaxel & Gemcitabine
3. Docetaxel & Vinorelbine
Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

Variant #2, 35 mg/m2, 3 out of 4 weeks

Study Evidence Comparator Comparative Efficacy
Schuette et al. 2005 Phase III (E-switch-ic) Docetaxel; 75 mg/m2, every 3 wks Might have superior OS
Garassino et al. 2013 (TAILORNSCLC) Phase III (C) Erlotinib Seems to have superior OS

Note that there is another trial named TAILOR in colorectal cancer.

Chemotherapy

Supportive medications

28-day cycles

Variant #3, 50 mg/m2 q2wk, limited duration

Study Evidence Comparator Comparative Efficacy
Pallis et al. 2010 Phase III (C) Carboplatin & Docetaxel Did not meet primary endpoint of OS

These patients had previously been treated with a platinum-free regimen.

Chemotherapy

28-day cycle for up to 6 cycles

Variant #4, 60 mg/m2 q3wk, limited duration

Study Evidence Comparator Comparative 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 #5, 60 mg/m2 q3wk, indefinite

Study Evidence Comparator Comparative Efficacy
Takeda et al. 2009 (JCOG 0104) Phase III (C) Docetaxel & Gemcitabine Did not meet primary endpoint of OS
Kawaguchi et al. 2014 (DELTANSCLC) Phase III (C) Erlotinib Might have superior PFS
Garon et al. 2014 (REVEL) Phase III (C) Docetaxel & Ramucirumab Seems to have inferior OS
Gridelli et al. 2018 (AvaALL) Phase III (C) Investigator's choice of:
1. Docetaxel & Bevacizumab
2. Erlotinib & Bevacizumab
3. Pemetrexed & Bevacizumab
Did not meet primary endpoint of OS

This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in EAST-LC. Note that there is another trial named DELTA in indolent lymphoma.

Chemotherapy

21-day cycles

Variant #6, 75 mg/m2 q3wk, limited duration

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

Note: while statistically inferior, the median PFS difference in ZODIAC was only 0.8 months.

Chemotherapy

21-day cycle for up to 6 cycles

Variant #7, 75 mg/m2 q3wk, indefinite

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Gridelli et al. 2004 (DISTAL 01) Phase III (C) Docetaxel; 33.3 mg/m2, 6 out of 8 wks Did not meet primary endpoint of QoL
Schuette et al. 2005 Phase III (C) Docetaxel; 35 mg/m2, 3 out of 4 wks Might have inferior OS
Paz-Ares et al. 2008 (STELLAR 2) Phase III (C) Paclitaxel poliglumex Did not meet primary endpoint of OS
Krzakowski et al. 2010 Phase III (C) Vinflunine Non-inferior PFS
Ciuleanu et al. 2012 (TITAN) Phase III (C) Erlotinib Did not meet primary endpoint of OS
Sun et al. 2012 (JMID) Phase III (C) Pemetrexed Inconclusive whether non-inferior OS
Garassino et al. 2013 (TAILORNSCLC) Phase III (C) Erlotinib Seems to have superior OS
Garon et al. 2014 (REVEL) Phase III (C) Docetaxel & Ramucirumab Seems to have inferior OS
Gridelli et al. 2018 (AvaALL) Phase III (C) Investigator's choice of:
1. Docetaxel & Bevacizumab
2. Erlotinib & Bevacizumab
3. Pemetrexed & Bevacizumab
Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

21-day cycles

References

  1. DISTAL 01: Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, Salvagni S, Piantedosi FV, Palazzolo G, Caffo O, Ceribelli A, Falcone A, Mazzanti P, Brancaccio L, Capuano MA, Isa L, Barbera S, Perrone F. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer: the DISTAL 01 study. Br J Cancer. 2004 Dec 13;91(12):1996-2004. link to original article link to PMC article contains protocol PubMed
  2. Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt EW, Dittrich I, Schweisfurth H, von Weikersthal LF, Raghavachar A, Reissig A, Serke M. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol. 2005 Nov 20;23(33):8389-95. link to original article contains protocol PubMed
  3. STELLAR 2: Paz-Ares L, Ross H, O'Brien M, Riviere A, Gatzemeier U, Von Pawel J, Kaukel E, Freitag L, Digel W, Bischoff H, García-Campelo R, Iannotti N, Reiterer P, Bover I, Prendiville J, Eisenfeld AJ, Oldham FB, Bandstra B, Singer JW, Bonomi P. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br J Cancer. 2008 May 20;98(10):1608-13. Epub 2008 May 13. link to original article link to PMC article contains protocol PubMed
  4. DISTAL-2: Gebbia V, Gridelli C, Verusio C, Frontini L, Aitini E, Daniele B, Gamucci T, Mancuso G, Di Maio M, Gallo C, Perrone F, Morabito A. Weekly docetaxel vs docetaxel-based combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer patients: the DISTAL-2 randomized trial. Lung Cancer. 2009 Feb;63(2):251-8. Epub 2008 Jul 15. link to original article contains protocol PubMed
  5. JCOG 0104: Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Yokota S, Matsui K, Semba H, Nakagawa K, Takada Y, Ando M, Shibata T, Saijo N. Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol. 2009 May;20(5):835-41. Epub 2009 Jan 22. link to original article contains protocol PubMed
  6. Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY. Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol. 2010 May 1;28(13):2167-73. Epub 2010 Mar 29. link to original article contains protocol PubMed
  7. 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
    1. Dataset: Project Data Sphere
  8. Pallis AG, Agelaki S, Agelidou A, Varthalitis I, Syrigos K, Kentepozidis N, Pavlakou G, Kotsakis A, Kontopodis E, Georgoulias V. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer. 2010 Nov 19;10:633. link to original article link to PMC article contains verified protocol PubMed
  9. TITAN: Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24. link to original article contains protocol PubMed
  10. JMID: Sun Y, Wu YL, Zhou CC, Zhang L, Zhang L, Liu XY, Yu SY, Jiang GL, Li K, Qin SK, Ma SL, Han L, Quinlivan M, Orlando M, Zhang XQ. Second-line pemetrexed versus docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer: a randomized, open-label study. Lung Cancer. 2013 Feb;79(2):143-50. Epub 2012 Nov 20. link to original article 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. 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
  13. 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
  14. AvaALL: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. Epub 2018 Dec 13. Erratum in: JAMA Oncol. 2018 Dec 1;4(12):1792. link to original article link to PMC article contains verified protocol in supplement PubMed

Docetaxel & Ramucirumab

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Variant #1, 60 mg/m2 docetaxel

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Garon et al. 2014 (REVEL) Phase III (E-RT-esc) 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 Comparative Efficacy
Garon et al. 2014 (REVEL) Phase III (E-RT-esc) 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 Comparative Efficacy
Herbst et al. 2010 (ZODIAC) Phase III (E-esc) 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 Comparative Efficacy
Herbst et al. 2010 (ZODIAC) Phase III (E-esc) 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 (see note)

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

Gefitinib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Sun et al. 2012 (KCSG-LU08-01) Phase III (E-switch-ooc) Pemetrexed Superior PFS

Chemotherapy

Continued indefinitely

References

  1. KCSG-LU08-01: Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, Kim HK, Song HS, Kim YH, Kim BS, Hwang IG, Lee K, Jo SJ, Lee JW, Ahn JS, Park K, Ahn MJ; Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012 Dec 15;118(24):6234-42. Epub 2012 Jun 6. link to original article contains protocol PubMed

Gemcitabine monotherapy

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Regimen

Study Evidence
Crinò et al. 1999a Phase II

Chemotherapy

28-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

Pemetrexed monotherapy

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Example orders

Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Cullen et al. 2008 Phase III (C) Pemetrexed; high-dose Did not meet primary endpoint of OS
de Boer et al. 2011 (ZEAL) Phase III (C) Pemetrexed & Vandetanib Did not meet primary endpoint of PFS
Ciuleanu et al. 2012 (TITAN) Phase III (C) Erlotinib Did not meet primary endpoint of OS
Sun et al. 2012 (KCSG-LU08-01) Phase III (C) Gefitinib Inferior PFS
Ardizzoni et al. 2012 (GOIRC 02-2006) Randomized Phase II (C) Carboplatin & Pemetrexed Did not meet primary endpoint of PFS
Sun et al. 2012 (JMID) Phase III (E-switch-ic) Docetaxel Inconclusive whether non-inferior OS
Gridelli et al. 2018 (AvaALL) Phase III (C) Investigator's choice of:
1. Docetaxel & Bevacizumab
2. Erlotinib & Bevacizumab
3. Pemetrexed & Bevacizumab
Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

21-day cycles

GOIRC 02-2006 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.

References

  1. Cullen MH, Zatloukal P, Sörenson S, Novello S, Fischer JR, Joy AA, Zereu M, Peterson P, Visseren-Grul CM, Iscoe N. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment