Difference between revisions of "Non-small cell lung cancer"
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|style="background-color:#fc8d59"|Seems to have inferior PFS | |style="background-color:#fc8d59"|Seems to have inferior PFS | ||
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|style="background-color:#1a9851"|Phase III (C) | |style="background-color:#1a9851"|Phase III (C) | ||
|[[Complex_multipart_regimens#PRONOUNCE|See link]] | |[[Complex_multipart_regimens#PRONOUNCE|See link]] | ||
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!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
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− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276572/ Zinner et al. 2015 (PRONOUNCE)] |
|style="background-color:#1a9851"|Phase III (E) | |style="background-color:#1a9851"|Phase III (E) | ||
|[[Complex_multipart_regimens#PRONOUNCE|See link]] | |[[Complex_multipart_regimens#PRONOUNCE|See link]] | ||
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− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276572/ Zinner et al. 2015 (PRONOUNCE)] |
|style="background-color:#1a9851"|Phase III (C) | |style="background-color:#1a9851"|Phase III (C) | ||
|[[Complex_multipart_regimens#PRONOUNCE|See link]] | |[[Complex_multipart_regimens#PRONOUNCE|See link]] | ||
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|style="background-color:#1a9850"|Superior PFS | |style="background-color:#1a9850"|Superior PFS | ||
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− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276572/ Zinner et al. 2015 (PRONOUNCE)] |
|style="background-color:#1a9851"|Phase III (E) | |style="background-color:#1a9851"|Phase III (E) | ||
|[[Complex_multipart_regimens#PRONOUNCE|See link]] | |[[Complex_multipart_regimens#PRONOUNCE|See link]] |
Revision as of 03:52, 29 January 2019
Section editor | |
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Travis Osterman, DO, MS Nashville, TN Twitter: TravisOsterman |
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:
118 regimens on this page
227 variants on this page
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Guidelines
ASCO
- 2017: Hanna et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update PubMed
Older
- 2015: Masters et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update
ASCO/CCO
Current
- 2017: Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non–small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update PubMed
Former
- 2007: Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline PubMed
ESMO
- 2018: Planchard et al. Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
- 2016: Novello et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
- 2015: Eberhardt et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. PubMed
Older
- 2014: Vansteenkiste et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. PubMed
- 2014: Besse et al. 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease. PubMed
- 2014: Kerr et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. PubMed
NCCN
Neoadjuvant therapy
Cisplatin & Docetaxel
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pless et al. 2015 (SAKK 16/00) | Phase III (C) | Cisplatin & Docetaxel, then RT | Seems not superior |
This trial included patients with Stage IIIA or N2 NSCLC.
Chemotherapy
Subsequent treatment
- Complete resection
References
- 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 | Efficacy |
---|---|---|---|
Scagliotti et al. 2011 | Phase III (E) | Surgery alone | Seems to have superior OS |
This trial included patients with Stage IB to IIIA NSCLC.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given at least 4 hours after gemcitabine
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 3 cycles
Subsequent treatment
- Complete resection, 2 to 6 weeks after last dose of chemotherapy
References
- Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. link to original article contains verified protocol PubMed
No neoadjuvant therapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mattson et al. 2003 | Phase III (C) | Docetaxel | Seems not superior |
Gilligan et al. 2007 (MRC LU22/NVALT 2/EORTC 08012) | Phase III (C) | Platinum doublet | Seems not superior |
Pisters et al. 2010 (SWOG S9900) | Phase III (C) | Carboplatin & Paclitaxel | Seems not superior |
Scagliotti et al. 2011 | Phase III (C) | Cisplatin & Gemcitabine | Seems to have inferior OS |
These trials included patients with Stage IB to IIIA NSCLC. No preoperative therapy is given.
Subsequent treatment
- Complete resection
References
- 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
- 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
- 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
- Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M, Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8. Epub 2011 Nov 28. link to original article contains verified protocol PubMed
Adjuvant therapy
Carboplatin & Paclitaxel
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Strauss et al. 2008 (CALGB 9633) | Phase III (E) | Observation | Seems not superior |
Preceding treatment
- Lobectomy or pneumonectomy, within 4 to 8 weeks
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 45 to 60 minutes once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for 4 cycles
References
- CALGB 9633: Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51. Epub 2008 Sep 22. link to original article contains protocol link to PMC article PubMed
Cisplatin & Docetaxel
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DC: Docetaxel & Cisplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2015 | Phase III (E) | Cisplatin & Gemcitabine | Seems not superior |
Wakelee et al. 2017 (ECOG-ACRIN E1505) | Phase III (C) | 1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
Preceding treatment
- Barlesi et al. 2015: Complete R0 resection, within 8 weeks
- ECOG-ACRIN E1505: Complete surgical resection, within 6 to 12 weeks
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 3 cycles (Barlesi et al. 2015) or 4 cycles (ECOG-ACRIN E1505)
References
- 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
- ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed
Cisplatin & Etoposide
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 (IALT) | Phase III (E) | Observation | Seems to have superior OS |
Preceding treatment
- Complete surgical resection, within 60 days
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
28-day cycle for 4 cycles
References
- 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
- Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
Cisplatin & Gemcitabine
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GC: Gemcitabine & Cisplatin
Variant #1, 75/1200 x 4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wakelee et al. 2017 (ECOG-ACRIN E1505) | Phase III (C) | 1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
Preceding treatment
- Complete surgical resection, within 6 to 12 weeks
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1200 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Variant #2, 75/1250 x 3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2015 | Phase III (E) | Cisplatin & Docetaxel | Seems not superior |
This trial included patients with Stage IB–III NSCLC.
Preceding treatment
- Complete R0 resection, within 8 weeks
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 3 cycles
References
- 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
- ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed
Cisplatin & Pemetrexed
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CPx: Cisplatin & Pemetrexed
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kreuter et al. 2013 (TREAT) | Randomized Phase II (E) | Cisplatin & Vinorelbine | Seems not superior (*) |
Wakelee et al. 2017 (ECOG-ACRIN E1505) | Phase III (C) | 1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
In TREAT, intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1. Efficacy reported for TREAT based on 2016 update.
Preceding treatment
- TREAT: Complete surgical resection, within 4 to 6 weeks
- ECOG-ACRIN E1505: Complete surgical resection, within 6 to 12 weeks
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
References
- 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
- 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
- ECOG-ACRIN E1505: Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, Adjei AA, Leighl NB, Aisner SC, Rothman JM, Patel JD, Sborov MD, McDermott SR, Perez-Soler R, Traynor AM, Butts C, Evans T, Shafqat A, Chapman AE, Kasbari SS, Horn L, Ramalingam SS, Schiller JH; ECOG-ACRIN. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1610-1623. Epub 2017 Nov 9. link to original article contains protocol PubMed
Cisplatin & Vinblastine
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 (IALT) | Phase III (E) | Observation | Seems to have superior OS |
Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vinblastine schedule is extrapolated from regimen information in Table 1 in which vinblastine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.
Preceding treatment
- Complete surgical resection, within 60 days
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once per day on days 1, 22, 43, 64
- Vinblastine (Velban) 4 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 43, 57
12-week course
References
- 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
- Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
Cisplatin & Vindesine
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 (IALT) | Phase III (E) | Observation | Seems to have superior OS |
Note: Exact days for parts of the regimen were not specified by Arriagada et al. 2004. This vindesine schedule is extrapolated from regimen information in Table 1 in which vindesine is said to be given "weekly from days 1 to 29" and "then every 2 weeks after day 43 until last cisplatin administration.
Preceding treatment
- Complete surgical resection, within 60 days
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once per day on days 1, 22, 43, 64
- Vindesine (Eldisine) 3 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 43, 57
12-week course
References
- 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
- Update: Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, Kozlowski M, Le Péchoux C, Pirker R, Pinel MI, Tarayre M, Le Chevalier T. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010 Jan 1;28(1):35-42. Epub 2009 Nov 23. link to original article PubMed
Cisplatin & Vinorelbine
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CVb: Cisplatin & Vinorelbine
Variant #1, cisplatin 50 mg/m2, 2 weeks out of 4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Winton et al. 2005 (JBR.10) | Phase III (E) | Observation | Seems to have superior OS |
Kreuter et al. 2013 (TREAT) | Randomized Phase II (C) | Cisplatin & Pemetrexed | Seems not superior (*) |
Efficacy for TREAT based on 2016 update.
Preceding treatment
- JBR.10: Complete surgical resection, within 6 weeks
- TREAT: Complete surgical resection, within 4 to 6 weeks
Chemotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
Variant #2, cisplatin 75 mg/m2, q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wakelee et al. 2017 (ECOG-ACRIN E1505) | Phase III (C) | 1. Cisplatin, Docetaxel, Bevacizumab 2. Cisplatin, Gemcitabine, Bevacizumab 3. Cisplatin, Pemetrexed, Bevacizumab 4. Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
Zhong et al. 2017 (ADJUVANT/CTONG1104) | Phase III (C) | Gefinitib | Inferior DFS |
Patients enrolled in ADJUVANT/CTONG1104 had EGFR-mutated lung cancer.
Preceding treatment
- Complete surgical resection, within 6 to 12 weeks
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Variant #3, cisplatin 100 mg/m2, q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 (IALT) | Phase III (E) | Observation | Seems to have superior OS |
Douillard et al. 2006 (ANITA) | Phase III (E) | Observation | Seems to have superior OS |
Preceding treatment
- IALT: Complete surgical resection, within 60 days
- ANITA: Complete surgical resection
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- ADJUVANT/CTONG1104: Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, Wang J, Fei K, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yan HH, Yang XN, Zhou Q, Wu YL; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. Epub 2017 Nov 21. link to original article contains protocol PubMed
Observation
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
McKneally et al. 1976 | Phase III (C) | Intrapleural BCG | Inferior OS |
Feld et al. 1993 (LCSG 801) | Phase III (C) | CAP | Seems not superior |
Ohta et al. 1993 (JCOG8601) | Phase III (C) | Cisplatin & Vindesine | Seems not superior |
Scagliotti et al. 2003 (ALPI) | Phase III (C) | MVP | Seems not superior |
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 | Seems not superior |
Kato et al. 2004 | Phase III (C) | Tegafur & Uracil | Seems to have inferior OS |
Nakagawa et al. 2005 (WJSG4) | Phase III (C) | Tegafur & Uracil | Seems not superior |
Winton et al. 2005 (JBR.10) | Phase III (C) | Cisplatin & Vinorelbine | Seems to have inferior OS |
Douillard et al. 2006 (ANITA) | Phase III (C) | Cisplatin & Vinorelbine | Seems to have inferior OS |
Strauss et al. 2008 (CALGB 9633) | Phase III (C) | Carboplatin & Paclitaxel | Seems not superior |
Felip et al. 2010 | Phase III (C) | 1. Adjuvant Carboplatin & Paclitaxel 2. Neoadjuvant Carboplatin & Paclitaxel |
Seems not superior |
No systemic treatment after surgery. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.
Preceding treatment
References
- McKneally MF, Maver C, Kausel HW. Regional immunotherapy of lung cancer with intrapleural BCG. Lancet. 1976 Feb 21;1(7956):377-9. link to original article PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Tegafur & Uracil
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kato et al. 2004 | Phase III (E) | Observation | Seems to have superior OS |
Preceding treatment
Chemotherapy
- Tegafur and uracil (UFT) 250 mg PO once per day
2-year course
References
- Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article 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 | 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) | No induction | Seems not superior |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 2 cycles
Subsequent treatment
- LAMP: RT x 63 Gy
- CTRT99/97: Paclitaxel & RT versus RT
- CALGB 39801: Carboplatin, Paclitaxel, RT
Variant #2, 6/225
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hoang et al. 2012 (ECOG 3598) | Phase III (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
21-day cycle for 2 cycles
Subsequent treatment
References
- 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
- 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
- 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
- ECOG 3598: Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article contains verified protocol PubMed
Cisplatin & Vinblastine
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Dillman et al. 1990 (CALGB 8433) | Phase III (E) | No induction | Seems to have superior OS (*) |
Sause et al. 1995 (RTOG 88-08) | Phase III (E) | 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
- Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 29
- Vinblastine (Velban) 5 mg/m2 IV once per day on days 1, 8, 15, 22, 29
5-week course
Subsequent treatment
- RT x 60 to 63 Gy
References
- 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
- 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
- RTOG 88-08: Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT, et al. 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
- RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed
No induction
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Vokes et al. 2007 (CALGB 39801) | Phase III (C) | Carboplatin & Paclitaxel | Seems not superior |
No treatment given prior to definitive therapy.
Subsequent treatment
References
- 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 | Efficacy |
---|---|---|---|
Yamamoto et al. 2010 (WJTOG0105) | Phase III (E) | 1. MVP & RT 2. Carboplatin, Irinotecan, RT |
Inconclusive whether non-inferior |
Chemoradiotherapy
- Carboplatin (Paraplatin) AUC 2 IV once per week
- Paclitaxel (Taxol) 40 mg/m2 IV once per week
- Concurrent radiation therapy, 60 Gy
6-week course
Variant #2, 2/45/60
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Lu et al. 2010 | Phase III (C) | PC, AE-941, RT | Seems not superior |
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 | Seems not superior |
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
Chemoradiotherapy
- Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
- Paclitaxel (Taxol) 45 mg/m2 IV over 1 to 3 hours once per day on days 1, 8, 15, given first
- Concurrent radiation therapy: 2 Gy fractions x 30 fractions given 5 days per week, over a 6 week course of treatment
21-day cycle for 2 cycles
Subsequent treatment
- RTOG 0617: PC consolidation x 2
Variant #3, 2/45/63
Study | Evidence |
---|---|
Belani et al. 2005 (LAMP) | Phase II |
Preceding treatment
Chemoradiotherapy
- Carboplatin (Paraplatin) AUC 2 IV over 30 minutes once per day on days 1, 8, 15, given second
- Paclitaxel (Taxol) 45 mg/m2 IV over 1 to 3 hours once per day on days 1, 8, 15, given first
- Concurrent radiation therapy: 1.8 Gy fractions x 25 fractions given 5 days per week, then 2 Gy fractions x 9 fractions given 5 days per week, over a 7 week course of treatment
21-day cycle for 2 cycles
Subsequent treatment
- PC consolidation x 2
Variant #4, 2/50/66
Study | Evidence |
---|---|
Vokes et al. 2007 (CALGB 39801) | Non-randomized portion of RCT |
Preceding treatment
- PC x 2 versus no induction
Chemoradiotherapy
- Carboplatin (Paraplatin) AUC 2 IV once per week
- Paclitaxel (Taxol) 50 mg/m2 IV once per week
- Concurrent radiation therapy, 66 Gy
One course
References
- 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
- 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
- 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
- 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
- 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
- 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
- Dataset: Project Data Sphere
- 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 | Efficacy |
---|---|---|---|
Strøm et al. 2013 | Phase III (E) | Carboplatin & Vinorelbine | Superior OS |
Chemoradiotherapy
References
- 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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RT: Radiation Therapy
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Atagi et al. 2012 (JCOG0301) | Phase III (E) | RT | Seems to have superior OS |
Chemoradiotherapy
- Carboplatin (Paraplatin) 30 mg/m2 IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26
- Concurrent radiation therapy: 60 Gy, details not available in abstract
References
- JCOG0301: Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T; Japan Clinical Oncology Group Lung Cancer Study Group. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012 Jul;13(7):671-8. Epub 2012 May 22. link to original article contains protocol PubMed
Cisplatin & RT
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RT: Radiation Therapy
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schaake-Koning et al. 1992 | Phase III (E) | 1. Cisplatin & RT (weekly dosing) | Seems not superior |
2. RT | Superior OS |
Chemoradiotherapy
- Cisplatin (Platinol) 6 mg/m2 IV once per day on days of radiation
- Concurrent radiation therapy as follows:
- Weeks 1 & 2: 3 Gy fractions, five fractions per week
- Weeks 3 to 5: no radiation
- Weeks 6 & 7: 2.5 Gy fractions, five fractions per week
7-week course
References
- Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier JP, van Zandwijk N, Bartelink H. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992 Feb 20;326(8):524-30. link to original article contains protocol PubMed
Cisplatin, Docetaxel, RT
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RT: Radiation Therapy
Variant #1, 20/20
Study | Evidence |
---|---|
Ahn et al. 2015 (KCSG-LU05-04) | Non-randomized portion of RCT |
In this trial, no benefit was observed to giving post-definitive consolidation.
Chemoradiotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
- Docetaxel (Taxotere) 20 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
- Concurrent radiation therapy, 2.00 Gy fractions x 33 fractions (total dose: 66 Gy), given 5 days per week, started on day 1
One course
Subsequent treatment
- Cisplatin & Docetaxel consolidation versus no further treatment
Variant #2, 40/40
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Segawa et al. 2010 (OLCSG 0007) | Phase III (E) | MVP & RT | Might have superior OS |
Chemoradiotherapy
- Cisplatin (Platinol) 40 mg/m2 IV once per day on days 1 & 8
- Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1 & 8
- Concurrent radiation therapy
28-day cycle for 2 cycles
References
- 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
- KCSG-LU05-04: Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, Chen M, Kim DW, Kim HK, Min YJ, Kang JH, Choi JH, Kim SW, Zhu G, Wu YL, Kim SR, Lee KH, Song HS, Choi YL, Sun JM, Jung SH, Ahn MJ, Park K. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015 Aug 20;33(24):2660-6. Epub 2015 Jul 6. link to original article contains verified protocol PubMed
Cisplatin, Etoposide, RT
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EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy
Variant #1, 45 Gy with response-adapted treatment
Study | Evidence |
---|---|
Albain et al. 2002 (SWOG 9019) | Phase II |
Albain et al. 2009 (RTOG 93-09) | Non-randomized portion of RCT |
Chemoradiotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
- Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
- Concurrent radiation therapy, 1.80 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of cycle 1 day 1
28-day cycle for 2 cycles
Subsequent treatment
- SWOG 9019: Patients were re-imaged with CT scan (bone scan and head imaging were only done if patients had new symptoms), and those without progression or new metastatic disease received an additional 2.00 Gy per day x 8 fractions for a total of 61 Gy administered overall
- RTOG 93-09: Additional radiation to 61 Gy, then cisplatin & etoposide consolidation versus surgery, then cisplatin & etoposide consolidation
Variant #2, 60 to 66 Gy
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kelly et al. 2008 (SWOG S0023) | Non-randomized portion of RCT | ||
Hanna et al. 2008 (HOG Lun 01-24) | Non-randomized portion of RCT | ||
Senan et al. 2016 (PROCLAIM) | Phase III (C) | Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation | Seems not superior |
Liang et al. 2017 | Phase III (C) | PC & RT | Might have superior OS |
Chemoradiotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
- Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
- Concurrent radiation therapy, 1.80 to 2.00 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy), given 5 days per week, started on cycle 1 day 1
28-day cycle for 2 cycles
Subsequent treatment
- SWOG S0023: Docetaxel x 3, then gefitinib versus placebo
- HOG Lun 01-24: Docetexal consolidation versus observation
- PROCLAIM: Investigator's choice of: Carboplatin & Paclitaxel or Cisplatin & Etoposide or Cisplatin & Vinorelbine consolidation
- Liang et al. 2017: Optional consolidation chemotherapy
Variant #3, 66 Gy, split cisplatin
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fournel et al. 2005 (NPC 95-01) | Phase III (E) | Cisplatin & Vinorelbine, then RT | Seems not superior |
Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
Chemoradiotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 5
- Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
- Concurrent radiation therapy, 2.00 Gy fractions x 33 fractions (total dose: 66 Gy), given 5 days per week, started on cycle 1 day 1
28-day cycle for 2 cycles
Subsequent treatment
Variant #4, 69.6 Gy (hyperfractionated)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Curran et al. 2011 (RTOG 9410) | Phase III (E) | 1. Cisplatin, Vinblastine, RT | Seems not superior |
2. Cisplatin & Vinblastine, then RT | Might have superior OS |
Chemoradiotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
- Etoposide (Vepesid) 50 mg PO twice per day on days 1 to 5, 8 to 12
- 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
28-day cycle for 2 cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Dataset: Project Data Sphere
- Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains verified protocol PubMed
Cisplatin, Vinblastine, RT
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Curran et al. 2011 (RTOG 9410) | Phase III (E) | 1. Cisplatin, Etoposide, RT | Seems not superior |
2. Cisplatin & Vinblastine, then RT | Seems to have superior OS |
Chemoradiotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 29
- Vinblastine (Velban) 5 mg/m2 IV once per day on days 1, 8, 15, 22, 29
- Concurrent radiation therapy
5-week course of chemotherapy
References
- RTOG 9410: Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed
Radiation therapy
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RT: Radiation Therapy
Variant #1, 45 Gy + 18 Gy boost (63 Gy total)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Belani et al. 2005 (LAMP) | Phase II | ||
Curran et al. 2011 (RTOG 9410) | Phase III (C) | See link | See link |
Preceding treatment
- LAMP: Carboplatin & Paclitaxel x 2
- RTOG 9410: Cisplatin & Vinblastine x 5 wk
Radiotherapy
- External beam radiotherapy 45 Gy in 1.80 Gy fractions x 25 fractions, given once per day 5 days per week, then 18 Gy boost in 2.00 Gy fractions x 9 fractions, given once per day 5 days per week.
7-week course
Variant #2, 60 Gy
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Clamon et al. 1999 | Phase III (C) | Carboplatin & RT | Seems not superior |
Bradley et al. 2002 (RTOG 93-04) | Phase III (C) | Beta-interferon & RT | Seems not superior |
Groen et al. 2004 | Phase III (C) | Carboplatin & RT | Seems not superior |
Atagi et al. 2012 (JCOG0301) | Phase III (C) | Carboplatin & RT | Seems to have inferior OS |
Preceding treatment
- Clamon et al. 1999: Cisplatin & Vinblastine x 5 wk
Radiotherapy
One course
References
- 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
- 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
- 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
- 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
- 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
- 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
- LAMP and RTOG 0617: Carboplatin, Paclitaxel, RT
- PROCLAIM: Cisplatin, Etoposide, RT
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 2 cycles
References
- 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
- 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
- Dataset: Project Data Sphere
- 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
- 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
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
- Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
28-day cycle for 2 cycles
References
- PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
- 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
- Cisplatin (Platinol) (dose not specified) mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycle for 2 cycles
References
- PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
- Dataset: Project Data Sphere
Durvalumab monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Antonia et al. 2017 (PACIFIC) | Phase III (E) | 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
- Durvalumab (Imfinzi) 10 mg/kg IV once every 2 weeks
Up to 12-month course
References
- 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
- 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 Sep 25. [Epub ahead of print] link to original article PubMed
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kelly et al. 2008 (SWOG S0023) | Phase III (C) | Gefitinib | Seems to have superior OS |
Butts et al. 2013 (START) | Phase III (C) | Tecemotide | Seems not superior |
Antonia et al. 2017 (PACIFIC) | Phase III (C) | Durvalumab | Inferior OS (*) |
Note: reported efficacy for PACIFIC is based on the 2018 update. No further antineoplastic treatment.
Preceding treatment
- SWOG S0023: Cisplatin, Etoposide, RT, then Docetaxel x 3
- START: Chemoradiotherapy (type not specified in protocol)
- PACIFIC: "Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."
References
- SWOG S0023: Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DH, Crowley JJ, Gandara DR. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31. link to original article contains verified protocol PubMed
- 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
- 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
- Dataset: Project Data Sphere
- PACIFIC: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains verified protocol PubMed
- 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 Sep 25. [Epub ahead of print] link to original article PubMed
Observation
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pines 1976 | Randomized (C) | BCG | Seems to have inferior OS |
Hanna et al. 2008 (HOG Lun 01-24) | Phase III (C) | Docetaxel | Seems not superior |
Gore et al. 2010 (RTOG 0214) | Phase III (C) | Prophylactic cranial irradiation | Seems not superior |
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 | Seems not superior |
de Ruysscher et al. 2018 (NVALT-11/DLCRG-02) | Phase III (C) | Prophylactic cranial irradiation | Inferior time to symptomatic CNS metastases |
No further treatment.
Preceding treatment
- HOG Lun 01-24: EP & RT
- GILT: Cisplatin, Vinorelbine, RT
- NVALT-11/DLCRG-02: Definitive therapy
References
- Pines A. A 5-year controlled study of BCG and radiotherapy inoperable lung cancer. Lancet. 1976 Feb 21;1(7956):380-1. link to original article PubMed
- 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
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Fossella et al. 2003 (TAX 326) | Phase III (E) | 1. Cisplatin & Docetaxel | Not reported |
2. Cisplatin & Vinorelbine | Seems not superior | ||
Booton et al. 2006 (BTOG1) | Phase III (E) | 1. MIC 2. MVP |
Seems not superior |
Lynch et al. 2010 (BMS099) | Phase III (C) | Carboplatin, Docetaxel, Cetuximab | Seems not superior |
Groen et al. 2011 (NVALT-4) | Phase III (C) | Carboplatin, Docetaxel, Celecoxib | Seems not superior |
Rossell et al. 2012 (EURTAC) | Phase III (C) | Erlotinib | Inferior PFS |
Note: Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 5 cycles (NVALT-4), 6 cycles (BMS099), or indefinitely
References
- 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
- 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
- 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
- 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
- EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed
Carboplatin & Etoposide
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Klastersky et al. 1990 (EORTC 07861) | Phase III (E) | Cisplatin & Etoposide | Might have inferior ORR |
Chemotherapy
- Carboplatin (Paraplatin) 325 mg/m2 IV over 60 minutes once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
3- to 4-week cycles
References
- 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 | Efficacy |
---|---|---|---|
Helbekkmo et al. 2007 | Phase III (E) | VC | Seems not superior |
Note: AUC was calculated using the Chatelut formula.
Chemotherapy
- Carboplatin (Paraplatin) AUC 4 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycle for 3 cycles
Variant #2, 5/1000 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Grønberg et al. 2009 | Phase III (C) | Carboplatin & Pemetrexed | Seems not superior |
Zhou et al. 2011 (OPTIMAL) | Phase III (C) | Erlotinib | Inferior PFS |
Rossell et al. 2012 (EURTAC) | Phase III (C) | Erlotinib | Inferior PFS |
Patients in OPTIMAL were EGFR mutation positive; patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21. It is unclear from the abstract how many cycles of therapy were given in EURTAC.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 4 cycles
Variant #3, 5/1000 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Danson et al. 2003 | Phase III (E) | 1. MIC 2. MVP |
Seems not superior |
Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for 4 cycles
Variant #4, 5/1200
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Zatloukal et al. 2003 | Phase III (E) | Cisplatin & Gemcitabine | Seems not superior |
Rudd et al. 2005 | Phase III (E) | MIC | Superior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1200 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #5, 5/1250 q3wk
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Sederholm et al. 2005 | Phase III (C) | Gemcitabine | Seems to have superior OS | |
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 to 6 cycles
Variant #6, 5/1250 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wu et al. 2013 (FASTACT-2) | Phase III (C) | Carboplatin & Gemcitabine/Erlotinib | Seems to have inferior OS |
Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
28-day cycle for 4 cycles
Variant #7, 6/1000
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kosmidis et al. 2007 | Phase III (C) | Gemcitabine & Paclitaxel | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycles
Variant #8, 6/1250 ("GCb6")
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Ferry et al. 2017 (BTOG2) | Phase III (E) | 1. GC50 | Seems to have superior OS | |
2. GC80 | Non-inferior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 to 6 cycles
Variant #9, 300/1000
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Grigorescu et al. 2002 | Phase III (E) | Cisplatin & Vinblastine | Superior OS |
Chemotherapy
- Carboplatin (Paraplatin) 300 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 | Efficacy | Toxicity |
---|---|---|---|---|
Mok et al. 2009 (IPASS) | Phase III (C) | Gefitinib | Inferior PFS | |
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 4 to 6 cycles
Subsequent treatment
- KEYNOTE-024: Patients with nonsquamous histology could optionally proceed to pemetrexed switch maintenance
Variant #2, 6/175
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Stathopoulos et al. 2004 | Phase III (C) | Paclitaxel & Vinorelbine | Seems not superior |
Lynch et al. 2012 | Randomized Phase II (C) | CP & Ipilimumab | Seems to have inferior PFS |
Govindan et al. 2017 (CA184-104) | Phase III (C) | CP & Ipilimumab | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive medications
- Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion.
21-day cycle for up to 6 cycles
Variant #3, 6/200
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Socinski et al. 2002 | Phase III (E) | Indefinite CP | Seems not superior | |
Kosmidis et al. 2002 | Phase III (E) | Gemcitabine & Paclitaxel | Seems not superior | |
Rosell et al. 2002 | Phase III (E) | Cisplatin & Paclitaxel | Seems to have inferior OS | |
Johnson et al. 2004 | Randomized Phase II (C) | PacCBev | Seems to have inferior TTP | |
Leighl et al. 2005 (NCIC CTG BR.18) | Phase III (C) | CP & BMS-275291 | Seems not superior | Less toxic |
Herbst et al. 2005 (TRIBUTE) | Phase III (C) | CP & Erlotinib | Seems not superior | |
Schuette et al. 2006 | Phase III (C) | Weekly CP | Seems not superior | Mixed toxicity |
Ohe et al. 2006 | Phase III (E) | 1. Cisplatin & Gemcitabine | Seems not superior | |
2. Cisplatin & Irinotecan | Seems not superior | |||
3. Cisplatin & Vinorelbine | Seems not superior | |||
Blumenschein et al. 2008 (SPIRIT II) | Phase III (C) | CP & Bexarotene | Seems not superior | |
Scagliotti et al. 2010 (ESCAPE) | Phase III (C) | CP & Sorafenib | Seems not superior | |
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 | Seems not superior | |
Lara et al. 2011 | Phase III (C) | CP & Vadimezan | Seems not superior | |
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 | Seems not superior | 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 | Randomized Phase II (C) | CP & Veliparib | Seems not superior | |
Herbst et al. 2017 (SWOG S0819) | Phase III (C) | CP & Cetuximab | Seems not superior |
Note: Patients in TRIBUTE received a maximum of 6 cycles. Patients in SWOG S0819 were EGFR FISH positive.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 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 | Efficacy |
---|---|---|---|
Kelly et al. 2001 (SWOG 9509) | Phase III (E) | Cisplatin & Vinorelbine | Seems not superior |
Schiller et al. 2002 (ECOG E1594) | Phase III (E) | 1. Cisplatin & Docetaxel | Seems not superior |
2. Cisplatin & Gemcitabine | Seems not superior | ||
3. Cisplatin & Paclitaxel | Seems not superior | ||
Herbst et al. 2004 (INTACT 2) | Phase III (C) | CP & Gefitinib | Seems not superior |
Lilenbaum et al. 2005 (CALGB 9730) | Phase III (E) | Paclitaxel | Superior FFS |
Williamson et al. 2005 (SWOG S0003) | Phase III (C) | CP & Tirapazamine | Seems not superior |
Belani et al. 2008 | Phase III (C) | CP, weekly paclitaxel | Seems not superior |
Kubota et al. 2008 (JMTO LC00-03) | Phase III (C) | Gemcitabine & Vinorelbine, then Docetaxel | Seems not superior |
Treat et al. 2009 (ALPHA A1-99002L) | Phase III (C) | 1. Carboplatin & Gemcitabine 2. Gemcitabine & Paclitaxel |
Seems not superior |
Lynch et al. 2010 (BMS099) | Phase III (C) | CP & Cetuximab | Seems not superior |
Weissman et al. 2011 | Phase III (C) | GEMOX | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1, given second
- Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1, given first
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Dataset: Project Data Sphere
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Dataset: Project Data Sphere
- 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
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Socinski et al. 2012 (CA031) | Phase III (E) | Carboplatin & Paclitaxel | Superior ORR |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 mg/mL/min (per Calvert formula) IV once on day 1, given second
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first
21-day cycle for 6 cycles; treatment could continue at physician's discretion if there was no progressive disease or unacceptable toxicity
References
- 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
- 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 | Efficacy |
---|---|---|---|
Johnson et al. 2004 | Randomized Phase II (E) | Carboplatin & Paclitaxel | Seems to have superior TTP |
Herbst et al. 2017 (SWOG S0819) | Phase III (C) | Carboplatin, Paclitaxel, Bevacizumab, Cetuximab | Seems not superior |
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
- 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
- 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 | Efficacy |
---|---|---|---|
Lynch et al. 2012 | Randomized Phase II (E) | Carboplatin & Paclitaxel | Seems to have superior PFS |
Note: this is the "phased" approach to this regimen.
Chemoimmunotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
- Ipilimumab (Yervoy) as follows:
- Cycles 3 to 6: 10 mg/kg IV once on day 1
Supportive medications
- Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion or for toxicity management.
21-day cycle for up to 6 cycles
Subsequent treatment
References
- 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 | Efficacy | Toxicity |
---|---|---|---|---|
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for up to 6 cycles
Subsequent treatment
- Optional pemetrexed maintenance
Variant #2, 6/500 x 4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Grønberg et al. 2009 | Phase III (E) | Carboplatin & Gemcitabine | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for up to 4 cycles
Variant #3, 6/500 x 6
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Supportive medications
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose prior to Pemetrexed (Alimta)
- Folic acid 1 mg PO once per day
21-day cycle for up to 6 cycles
Subsequent treatment
- Optional pemetrexed maintenance
References
- 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
- 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
- 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
Carboplatin, Pemetrexed, Pembrolizumab
Source: Carboplatin, Pemetrexed, Pembrolizumab in advanced or metastatic non-small cell lung cancer
Regimen
Carboplatin & Vinorelbine
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VC: Vinorelbine & Carboplatin
Variant #1, IV vinorelbine
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Tan et al. 2005 (GLOB 2) | Phase III (C) | Gemcitabine & Vinorelbine | Seems not superior |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #2, PO vinorelbine
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fløtten et al. 2012 | Phase III (C) | Gemcitabine & Vinorelbine | Seems not superior |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Vinorelbine (Navelbine) 60 mg/m2 PO once per day on days 1 & 8
21-day cycle for 3 cycles
References
- 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
- Fløtten Ø, Grønberg BH, Bremnes R, Amundsen T, Sundstrøm S, Rolke H, Hornslien K, Wentzel-Larsen T, Aasebø U, von Plessen C. Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC: a phase III randomised controlled trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2012 Jul 24;107(3):442-7. Epub 2012 Jul 3. link to original article link to PMC article contains protocol PubMed
Cisplatin & Docetaxel
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DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin
Variant #1, 50/75
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Berghmans et al. 2013 (ELCWP-01041) | Phase III (C) | 1. GIP 2. IG |
Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
Variant #2, 75/75
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schiller et al. 2002 (ECOG E1594) | Phase III (E) | 1. Carboplatin & Paclitaxel | Seems not superior |
2. Cisplatin & Gemcitabine | Seems not superior | ||
3. Cisplatin & Paclitaxel | Seems not superior | ||
Fossella et al. 2003 (TAX 326) | Phase III (E) | 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 | Seems not superior |
Rossell et al. 2012 (EURTAC) | Phase III (C) | Erlotinib | Inferior PFS |
Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles (EURTAC), 6 cycles (GLOB3), or indefinitely (E1594, TAX326)
Variant #3, 80/60
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kubota et al. 2004 | Phase III (E) | 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 | Seems not superior |
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
- Cisplatin (Platinol) 80 mg/m2 IV over 90 minutes once on day 1, given second
- Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1, given first
21-day cycle for 3 to 6 cycles
Variant #4, 80/100
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Georgoulias et al. 2001 | Phase III (C) | Docetaxel & Gemcitabine | Seems not superior |
Georgoulias et al. 2004 | Phase III (C) | Docetaxel | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 2
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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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EC: Etoposide & Cisplatin
Variant #1, 60/360
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ruckdeschel et al. 1986 (ECOG E1581) | Phase III (E) | 1. CAMP 2. Cisplatin & Vindesine 3. MVP |
Seems not superior |
Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
Chemotherapy
- Cisplatin (Platinol) 60 mg/m2 IV once on day 1
- Etoposide (Vepesid) 120 mg/m2 IV once per day on days 4, 6, 8
21-day cycles
Variant #2, 75/300
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Bonomi et al. 2000 (ECOG E5592) | Phase III (C) | Cisplatin & Paclitaxel | Seems to have inferior OS |
Belani et al. 2005 | Phase III (C) | Carboplatin & Paclitaxel | Might have superior OS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV over 45 minutes once per day on days 1 to 3
21-day cycles
Variant #3, 100/300
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cardenal et al. 1999 | Phase III (C) | Cisplatin & Gemcitabine | Inferior TTP |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
21-day cycles
Variant #4, 120/300
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Klastersky et al. 1990 (EORTC 07861) | Phase III (C) | Carboplatin & Etoposide | Might have superior ORR |
Comella et al. 1996 | Phase III (C) | Carboplatin, Cisplatin, Etoposide, Vinorelbine | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 120 mg/m2 IV once on day 1
- Comella et al. 1996 gave 40 mg/m2 IV once per day on days 1 to 3
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
3- to 4-week cycles
References
- 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
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Park et al. 2007 | Phase III (E) | Cisplatin & Gemcitabine x 6 | Non-inferior OS |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Variant #2, 75/1250 q3wk
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Bissett et al. 2005 | Phase III (C) | GC & Prinomastat | Seems not superior | |
Novello et al. 2007 | Phase III (C) | GC x 2, then gemcitabine x 3 | Inconclusive whether non-inferior | |
Manegold et al. 2011 | Phase III (C) | GC & PF-3512676 | Seems not superior | |
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
- Cisplatin (Platinol) 75 mg/m2 IV over 30 minutes once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycle for up to 6 cycles (see note)
Variant #3, 75/1250 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wu et al. 2013 (FASTACT-2) | Phase III (C) | Cisplatin & Gemcitabine/Erlotinib | Seems to have superior OS |
Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
28-day cycle for 4 cycles
Variant #4, 80/1000
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ohe et al. 2006 | Phase III (E) | 1. Carboplatin & Paclitaxel | Seems not superior |
2. Cisplatin & Irinotecan | Seems not superior | ||
3. Cisplatin & Vinorelbine | Seems not superior | ||
Takeda et al. 2009 (WJTOG0203) | Phase III (C) | Platinum doublet x 3, then Gefitinib | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for 6 cycles (WJTOG0203) or indefinitely (Ohe et al. 2006)
Variant #5, 80/1125
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wachters et al. 2003 | Phase III (C) | Epirubicin & Gemcitabine | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 2
- Gemcitabine (Gemzar) 1125 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 5 cycles
Variant #6, 80/1200 x 6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gridelli et al. 2003 | Phase III (C) | Gemcitabine & Vinorelbine | Might have superior OS |
Gridelli et al. 2007 (GECO) | Phase III (C) | 1. Cisplatin, Gemcitabine, Rofecoxib 2. Cisplatin & PCI Gemcitabine 3. Cisplatin, PCI Gemcitabine, Rofecoxib |
Seems not superior |
Gridelli et al. 2012 (TORCH) | Phase III (C) | Erlotinib | Superior OS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1200 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Subsequent treatment
- TORCH, at progression: Erlotinib
Variant #7, 80/1250 x 4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pérol et al. 2012 | Non-randomized portion of RCT | ||
Ferry et al. 2017 (BTOG2) | Phase III (E) | 1. GC50 | Seems to have superior OS |
2. GCb6 | Non-inferior OS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Subsequent treatment
- Pérol et al. 2012: Erlotinib switch maintenance versus gemcitabine maintenance versus observation
Variant #8, 80/1250 x 6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Giaccone et al. 2004 (INTACT 1) | Phase III (C) | Cisplatin, Gefitinib, Gemcitabine | Seems not superior |
Paz-Ares et al. 2006 | Phase III (C) | Aprinocarsen, Cisplatin, Gemcitabine | Seems not superior |
Gatzemeier et al. 2007 (TALENT) | Phase III (C) | Cisplatin, Erlotinib, Gemcitabine | Seems not superior |
Boni et al. 2012 (FAST) | Phase III (C) | 1. GIN 2. GN |
Seems to have superior OS |
3. GIP | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #9, 100/1000 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ridolfi et al. 2011 | Phase III (C) | Cisplatin, Gemcitabine, LD IL-2 | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #10, 100/1000 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Crinò et al. 1999 | Phase III (E) | MIC | Seems to have superior ORR |
Sandler et al. 2000 | Phase III (E) | Cisplatin | Superior OS |
Schiller et al. 2002 (ECOG E1594) | Phase III (E) | 1. Carboplatin & Paclitaxel | Seems not superior |
2. Cisplatin & Docetaxel | Seems not superior | ||
3. Cisplatin & Paclitaxel | Superior PFS | ||
Scagliotti et al. 2008 (JMDB) | Phase III (C) | Cisplatin & Pemetrexed | Seems non-inferior |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Variant #11, 100/1250
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cardenal et al. 1999 | Phase III (E) | Cisplatin & Etoposide | Superior TTP |
Alberola et al. 2003 | Phase III (C) | 1. CGV 2. GV-VI |
Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 6 cycles (Alberola et al. 2003) or indefinitely (Cardenal et al. 1999)
Variant #12, 100/1400
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gebbia et al. 2003 | Phase III (E) | Cisplatin & Vinorelbine | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1400 mg/m2 IV once per day on days 1 & 8
28-day cycles
References
- 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
- 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
- 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
- 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
- Gebbia V, Galetta D, Caruso M, Verderame F, Pezzella G, Valdesi M, Borsellino N, Pandolfo G, Durini E, Rinaldi M, Loizzi M, Gebbia N, Valenza R, Tirrito ML, Varvara F, Colucci G; Gruppo Ocologico Italia Meridionale. Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Lung Cancer. 2003 Feb;39(2):179-89. link to original article contains protocol PubMed
- 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
- Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jiménez U, González-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Peñas R, Felip E, López-Vivanco G; Spanish Lung Cancer Group. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003 Sep 1;21(17):3207-13. link to original article contains protocol PubMed
- 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
- Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Br J Cancer. 2003 Oct 6;89(7):1192-9. link to original article link to PMC article contains protocol PubMed
- INTACT 1: Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. link to original article contains protocol PubMed
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- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Ridolfi L, Bertetto O, Santo A, Naglieri E, Lopez M, Recchia F, Lissoni P, Galliano M, Testore F, Porta C, Maglie M, Dall'agata M, Fumagalli L, Ridolfi R. Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial. Int J Oncol. 2011 Oct;39(4):1011-7. Epub 2011 Jun 24. link to original article contains protocol PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Negoro et al. 2003 | Phase III (E) | Cisplatin & Vindesine | Seems not superior |
Ohe et al. 2006 | Phase III (C) | 1. Carboplatin & Paclitaxel | Seems not superior |
2. Cisplatin & Gemcitabine | Seems not superior | ||
3. Cisplatin & Vinorelbine | Seems not superior | ||
Takeda et al. 2009 (WJTOG0203) | Phase III (C) | Platinum doublet x 3, then Gefitinib | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Irinotecan (Camptosar) 60 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for up to 6 cycles (WJTOG0203) or indefinitely (Ohe et al. 2006)
References
- 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
- 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
- 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
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Park et al. 2007 | Phase III (E) | Cisplatin & Paclitaxel x 6 | Non-inferior OS |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Variant #2, 75/135, q2wk
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Stathopoulos et al. 2010 | Phase III (C) | Liposomal Cisplatin & Paclitaxel | Seems not superior | Inferior toxicity |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given second
- Paclitaxel (Taxol) 135 mg/m2 IV over 3 hours once on day 1, given first
14-day cycle for up to 9 cycles
Variant #3, 75/135, q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Bonomi et al. 2000 (ECOG E5592) | Phase III (E) | Cisplatin & Etoposide | Might have superior OS |
Schiller et al. 2002 (ECOG E1594) | Phase III (C) | 1. Carboplatin & Paclitaxel | Seems not superior |
2. Cisplatin & Docetaxel | Seems not superior | ||
3. Cisplatin & Gemcitabine | Inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 2, given second
- Paclitaxel (Taxol) 135 mg/m2 IV continuous infusion over 24 hours, started on day 1, given first
21-day cycles
Variant #4, 80/175
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gatzemeier et al. 2000 | Phase III (E) | Cisplatin | Seems to have superior TTP |
Smit et al. 2003 (EORTC 08975) | Phase III (C) | 1. Cisplatin & Gemcitabine 2. Gemcitabine & Paclitaxel |
Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
Variant #5, 80/200
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Rosell et al. 2002 | Phase III (E) | Carboplatin & Paclitaxel | Seems to have superior OS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Martoni et al. 2005 | Phase III (E) | Cisplatin & Gemcitabine | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Subsequent treatment
- Vinorelbine maintenance
Variant #2, 80/25
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ohe et al. 2006 | Phase III (E) | 1. Carboplatin & Paclitaxel | Seems not superior |
2. Cisplatin & Gemcitabine | Seems not superior | ||
3. Cisplatin & Irinotecan | Seems not superior | ||
Pirker et al. 2009 (FLEX) | Phase III (C) | Cisplatin, Vinorelbine, Cetuximab | Seems to have inferior OS |
Takeda et al. 2009 (WJTOG0203) | Phase III (C) | Platinum doublet x 3, then Gefitinib | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
21-day cycle for 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 | Efficacy | Toxicity |
---|---|---|---|---|
Gridelli et al. 2003 | Phase III (C) | Gemcitabine & Vinorelbine | Might have superior OS | |
Georgoulias et al. 2005 | Phase III (C) | Docetaxel & Gemcitabine | Seems not superior | |
Gebbia et al. 2008 | Phase III (C) | Cisplatin & Vinorelbine, 3 out of 4 weeks | Seems not superior | Less toxic |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 8
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
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 | Efficacy |
---|---|---|---|
Depierre et al. 1994 | Phase III (E) | Vinorelbine | Superior TTP |
Souquet et al. 2002 (GLOB-1) | Phase III (C) | NIP | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15
21-day cycles
Variant #5, 100/25
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wozniak et al. 1998 | Phase III (E) | Cisplatin | Superior OS |
Kelly et al. 2001 (SWOG 9509) | Phase III (C) | Carboplatin & Paclitaxel | Seems not superior |
Scagliotti et al. 2002 | Phase III (C) | 1. Carboplatin & Paclitaxel 2. Cisplatin & Gemcitabine |
Seems not superior |
Fossella et al. 2003 (TAX 326) | Phase III (C) | 1. Carboplatin & Docetaxel | Seems not superior |
2. Cisplatin & Docetaxel | Seems to have inferior OS | ||
Ramlau et al. 2008 (SPIRIT I) | Phase III (C) | CV & Bexarotene | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for up to 10 cycles (SWOG 9509) or indefinitely (TAX 326, SPIRIT I)
Variant #6, 100/30
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Robinet et al. 2001 (GFPC 95-1) | Phase III (C) | Cisplatin, Vinorelbine, concurrent WBRT | Seems not superior |
Pujol et al. 2005 | Phase III (C) | Docetaxel & Gemcitabine | Seems not superior |
Note: patients in GFPC 95-1 had intracranial metastases.
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV over 60 to 120 minutes once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV over 10 to 20 minutes once per day on days 1, 8, 15, 22
28-day cycle for 6 cycles
Subsequent treatment
- GFPC 95-1: WBRT
Variant #7, 120/30
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Le Chevalier et al. 1994 | Phase III (E) | 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
- Cisplatin (Platinol) 120 mg/m2 IV once per day on days 1, 29, then every 6 weeks
- Vinorelbine (Navelbine) 30 mg/m2 IV once per week
Continued indefinitely (see note)
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- WJTOG0203: Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, Ichinose Y, Katakami N, Yamamoto N, Kudoh S, Sasaki J, Matsui K, Takayama K, Kashii T, Iwamoto Y, Sawa T, Okamoto I, Kurata T, Nakagawa K, Fukuoka M. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). J Clin Oncol. 2010 Feb 10;28(5):753-60. Epub 2009 Dec 28. link to original article contains verified protocol PubMed
Cisplatin, Vinorelbine, Cetuximab
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pirker et al. 2009 (FLEX) | Phase III (E) | Cisplatin & Vinorelbine | Seems to have superior OS |
Chemotherapy
- 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:
- Week 1: 400 mg/m2 IV over 2 hours once on day 1
- Week 2 onwards: 250 mg/m2 IV over 60 minutes once per week
21-day cycle for up to 6 cycles
Subsequent treatment
- Cetuximab maintenance
References
- 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)
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Comella et al. 2006 (SICOG 0101) | Phase III (C) | 1. GV 2. PGT 3. PGV |
Seems not superior |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Paclitaxel (Taxol) 125 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
References
- 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
Gemcitabine & Vinorelbine
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VG: Vinorelbine & Gemcitabine
Variant #1, 1000/25, 2 weeks out of 3 (IV vinorelbine)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Laack et al. 2004 | Phase III (E) | GVP | Seems not superior |
Tan et al. 2005 (GLOB 2) | Phase III (E) | Carboplatin & Vinorelbine | Seems not superior |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
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 | Efficacy | Toxicity |
---|---|---|---|---|
Greco et al. 2007 | Phase III (E) | PCG | Seems not superior | Less toxic |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Variant #3, 1000/60 (PO vinorelbine)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fløtten et al. 2012 | Phase III (E) | Carboplatin & Vinorelbine | Seems not superior |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Vinorelbine (Navelbine) 60 mg/m2 PO once per day on days 1 & 8
21-day cycle for 3 cycles
References
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Hellmann et al. 2018 (CheckMate 227) | Phase III (E) | 1. Nivolumab | Not reported |
2. Platinum doublet | Superior PFS |
Immunotherapy
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1, 15, 29
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1
42-day cycles
References
- CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article 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) | Platinum doublet (see note) | Seems not superior | 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
- 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
- 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 | Efficacy | Toxicity |
---|---|---|---|---|
Garon et al. 2015 (KEYNOTE-001) | Phase 1, >20 pts in dosing cohort | |||
Reck et al. 2016 (KEYNOTE-024) | Phase III (E) | 1. Carboplatin & Gemcitabine 2. Carboplatin & Paclitaxel 3. Carboplatin & Pemetrexed 4. Cisplatin & Gemcitabine 5. Cisplatin & Pemetrexed |
Superior OS | Superior HRQoL |
Mok et al. 2015 (KEYNOTE-042) | Phase III (E) | 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
- Pembrolizumab (Keytruda) 200 IV once on day 1
21-day cycles
References
- 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
- 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
- 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
- Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract
Advanced or metastatic disease, first-line, 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 | Efficacy |
---|---|---|---|
Socinski et al. 2018 (IMpower150) | Phase III (E) | 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.
Chemotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Variant #2, 1200/15/6/175 x 6
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Socinski et al. 2018 (IMpower150) | Phase III (E) | 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.
Chemotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
Variant #3, 1200/15/6/200 x 4
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Socinski et al. 2018 (IMpower150) | Phase III (E) | 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.
Chemotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Variant #4, 1200/15/6/200 x 6
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Socinski et al. 2018 (IMpower150) | Phase III (E) | 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.
Chemotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
References
- IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed
Carboplatin & Docetaxel
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DCb: Docetaxel & Carboplatin
Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Rodrigues-Pereira et al. 2011 | Phase III (C) | Carboplatin & Pemetrexed | Seems not superior | Inferior survival without treatment-emergent grade 3/4 toxicity |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
References
- 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 & Paclitaxel
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TC: Taxol (Paclitaxel) & Carboplatin
CP: Carbolpatin & Paclitaxel
Variant #1, 6/175
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Zhou et al. 2015 (BEYOND) | Phase III (C) | Carboplatin, Paclitaxel, Bevacizumab | Seems to have inferior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive medications
- Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion
21-day cycle for up to 6 cycles
Variant #2, 6/200
Study | Evidence | Comparator | 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) | Carboplatin, Motesanib, Paclitaxel | Seems not superior |
Kubota et al. 2017 (MONET-A) | Phase III (C) | Carboplatin, Motesanib, Paclitaxel | Might have inferior PFS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 3 or more cycles
References
- ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
- 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
- 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
- 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
- Dataset: Project Data Sphere
- MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article contains protocol PubMed
- 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
- 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 | 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
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Variant #2, 6/175/15 x 6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Socinski et al. 2018 (IMpower150) | Phase III (C) | 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
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
Variant #3, 6/200/15 x 4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Patel et al. 2013 (PointBreak) | Phase III (C) | PemCBev, then PemBev maint. | Seems to have inferior PFS |
Zinner et al. 2015 (PRONOUNCE) | Phase III (C) | See link | See link |
Socinski et al. 2018 (IMpower150) | Phase III (C) | 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
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications per paclitaxel label
- Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycle for 4 cycles
Subsequent treatment
Variant #4, 6/200/15 x 6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Sandler et al. 2006 (ECOG E4599) | Phase III (E) | See link | See link |
Zhou et al. 2015 (BEYOND) | Phase III (E) | Carboplatin & Paclitaxel | Seems to have superior OS |
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
- 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
- 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
- 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
- Dataset: Project Data Sphere
- PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
- 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
- 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 | 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
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for up to 4 cycles
Subsequent treatment
- Pemetrexed maintenance (optional in KEYNOTE-021)
Variant #2, 5/500 x 6
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Rodrigues-Pereira et al. 2011 | Phase III (E) | Carboplatin & Docetaxel | Seems not superior | Superior survival without treatment-emergent grade 3/4 toxicity |
Mok et al. 2015 (KEYNOTE-042) | Phase III (C) | Pembrolizumab | Inferior OS |
Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for up to 6 cycles
Subsequent treatment
- Optional pemetrexed maintenance
Variant #3, 6/500 x 4
Study | Evidence | Comparator | 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
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for up to 4 cycles
Subsequent treatment
Variant #4, 6/500 x 6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mok et al. 2015 (KEYNOTE-042) | Phase III (C) | Pembrolizumab | Inferior OS |
Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Supportive medications
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose prior to Pemetrexed (Alimta)
- Folic acid 1 mg PO once per day
21-day cycle for up to 6 cycles
Subsequent treatment
- Optional pemetrexed maintenance
References
- 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
- 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
- Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract
- 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
- 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
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed
Carboplatin, Pemetrexed, Bevacizumab
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PemCBev: Pemetrexed, Carboplatin, Bevacizumab
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Patel et al. 2013 (PointBreak) | Phase III (E) | PacCBev, then Maintenance Bev | Seems to have superior PFS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications, folic acid, and vitamin supplementation per pemetrexed label
- Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycle for 4 cycles
Subsequent treatment
- Patients with complete response, partial response, or stable disease: Pemetrexed & Bevacizumab maintenance
References
- PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
- 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 | Efficacy |
---|---|---|---|
Park et al. 2017 | Phase III (C) | Cisplatin & Pemetrexed | Inconclusive whether non-inferior |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
References
- 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 | Efficacy |
---|---|---|---|
Wu et al. 2014 (LUX-Lung 6) | Phase III (C) | Afatinib | Inferior PFS |
Tumor specimen was required to be EGFR mutation-positive.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #2, 75/1250 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Paz-Ares et al. 2012 (NExUS) | Phase III (C) | Cisplatin, Gemcitabine, Sorafenib | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 30 minutes once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #3, 80/1250 x 6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Reck et al. 2009 (AVAil) | Phase III (C) | 1. Cisplatin, Gemcitabine, low-dose Bevacizumab | Inferior PFS |
2. Cisplatin, Gemcitabine, standard-dose Bevacizumab | Seems to have inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #4, 80/1250 x 9
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Han et al. 2012 (First-SIGNAL) | Phase III (C) | Gefitinib | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 9 cycles
References
- AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains protocol PubMed
- 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
- 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
- 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
- Dataset: Project Data Sphere
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
Reck et al. 2009 (AVAil) | Phase III (E) | Cisplatin & Gemcitabine | Superior PFS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycle for up to 6 cycles
Subsequent treatment
Variant #2, standard-dose bev
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Reck et al. 2009 (AVAil) | Phase III (E) | Cisplatin & Gemcitabine | Seems to have superior PFS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 6 cycles
Subsequent treatment
References
- AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed
- 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 | Efficacy |
---|---|---|---|
Park et al. 2017 | Phase III (E) | Cisplatin & Docetaxel | Inconclusive whether non-inferior |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
Variant #2, 75/500
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy | 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 | Seems not superior | |
Solomon et al. 2014 (PROFILE 1014) | Phase III (C) | Crizotinib | Inferior PFS | |
Paz-Ares et al. 2015 (INSPIRE) | Phase III (C) | Cisplatin, Pemetrexed, Necitumumab | Seems not superior | |
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Soria et al. 2017 (ASCEND-4) | Phase III (C) | Ceritinib | Inferior PFS | |
Shi et al. 2017 (CONVINCE) | Phase III (C) | See link | See link | |
Gandhi et al. 2018 (KEYNOTE-189) | Phase III (C) | See link | See link |
Note: 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
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (as described in JMDB):
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
- Folic acid 1 mg PO once per day
- In Sequist et al. 2013: Patients "received folic acid, vitamin B12, and dexamethasone, as per package recommendations for Pemetrexed (Alimta)."
21-day cycle for 4 to 6 cycles
Subsequent treatment
- PARAMOUNT: Placebo versus pemetrexed maintenance
- CONVINCE, KEYNOTE-024, ASCEND-4, KEYNOTE-189: Pemetrexed maintenance (optional in CONVINCE & KEYNOTE-024)
References
- PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed
- HRQoL analaysis: 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed
Cisplatin, Pemetrexed, Bevacizumab
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Regimen
Study | Evidence |
---|---|
Barlesi et al. 2013 (AVAPERL) | Non-randomized portion of RCT |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 2 hours once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV over 90 minutes once on day 1
- If well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes
Supportive medications
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
- Folic acid 350 to 1000 mcg PO once per day, given throughout therapy
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1, 1, 2 of each cycle
21-day cycle for 4 cycles
Subsequent treatment
- Patients with complete response (CR), partial response (PR), or stable disease (SD): Bevacizumab versus Pemetrexed & Bevacizumab maintenance
References
- AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
- 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 | Efficacy |
---|---|---|---|
Gandhi et al. 2018 (KEYNOTE-189) | Phase III (E) | See link | See link |
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.
Chemoimmunotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given third
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given second
- Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy
Supportive medications
- "Premedication with folic acid, vitamin B12, and corticosteroids was administered according to local guidelines."
21-day cycle for 4 cycles
Subsequent treatment
References
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed
Gefitinib monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mok et al. 2009 (IPASS) | Phase III (E) | Carboplatin & Paclitaxel | Superior PFS |
Han et al. 2012 (First-SIGNAL) | Phase III (E) | Cisplatin & Gemcitabine | Seems not superior |
Yang et al. 2014 | Phase III (E) | Cisplatin & Pemetrexed, then Gefitinib maint. | Seems not superior |
Chemotherapy
- Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
References
- IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed
- 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
- Dataset: Project Data Sphere
- First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed
- 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
Advanced or metastatic disease, first-line, squamous
Carboplatin & nab-Paclitaxel
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Paz-Ares et al. 2018 (KEYNOTE-407) | Phase III (C) | Carboplatin, nab-Paclitaxel, Pembrolizumab x 4, then Pembrolizumab maint. | Inferior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
21-day cycle for 4 cycles
References
- 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 | Efficacy |
---|---|---|---|
Paz-Ares et al. 2018 (KEYNOTE-407) | Phase III (E) | See link | See link |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
- Pembrolizumab (Keytruda) 200 mg IV once on day 1, given first
21-day cycle for 4 cycles
Subsequent treatment
References
- 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: Carbolpatin & Paclitaxel
Variant #1, 5/200
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mok et al. 2015 (KEYNOTE-042) | Phase III (C) | Pembrolizumab | Inferior OS |
Patients enrolled in this arm of KEYNOTE-042 had squamous histology.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 4 to 6 cycles
Variant #2, 6/175
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Govindan et al. 2017 (CA184-104) | Phase III (C) | Carboplatin, Paclitaxel, Ipilimumab | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive medications
- Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion.
21-day cycle for up to 6 cycles
Variant #3, 6/200
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mok et al. 2015 (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
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 4 cycles (KEYNOTE-407) or up to 6 cycles (KEYNOTE-042)
References
- 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
- Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract
- 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, Ipilimumab
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Govindan et al. 2017 (CA184-104) | Phase III (E) | Carboplatin & Paclitaxel | Seems not superior |
Note: this is the "phased" approach to this regimen.
Chemoimmunotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
- Ipilimumab (Yervoy) as follows:
- Cycles 3 to 6: 10 mg/kg IV once on day 1
Supportive medications
- Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion or for toxicity management.
21-day cycle for up to 6 cycles
Subsequent treatment
References
- 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 | Efficacy |
---|---|---|---|
Paz-Ares et al. 2018 (KEYNOTE-407) | Phase III (E) | See link | See link |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
- Pembrolizumab (Keytruda) 200 mg IV once on day 1, given first
21-day cycle for 4 cycles
Subsequent treatment
References
- 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
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shukuya et al. 2015 (WJOG5208L) | Phase III (C) | Docetaxel & Nedaplatin | Seems to have inferior OS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for 4 to 6 cycles
References
- 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
Cisplatin & Gemcitabine
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GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Thatcher et al. 2015 (SQUIRE) | Phase III (C) | Cisplatin, Gemcitabine, Necitumumab | Seems to have inferior OS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 30 minutes once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycle for up to 6 cycles
References
- 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
- Dataset: Project Data Sphere
Cisplatin, Gemcitabine, Necitumumab
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Thatcher et al. 2015 (SQUIRE) | Phase III (E) | Cisplatin & Gemcitabine | Seems to have superior OS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 2 hours once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1 & 8
- Necitumumab (Portrazza) 800 mg IV over at least 50 minutes once per day on days 1 & 8
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
- 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
- Dataset: Project Data Sphere
Advanced or metastatic disease, first-line, elderly or poor performance status
Best supportive care
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gridelli et al. 1999 (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 |
Seems not superior |
No active antineoplastic treatment.
References
- 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
- 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 | Efficacy | Toxicity |
---|---|---|---|---|
Biesma et al. 2011 (NVALT-3) | Phase III (C) | CP | Seems not superior | Similar QoL |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 4 cycles
References
- 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 | Efficacy | Toxicity |
---|---|---|---|---|
Biesma et al. 2011 (NVALT-3) | Phase III (C) | CG | Seems not superior | Similar QoL |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
Variant #2, 6/90
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Quoix et al. 2011 (IFCT-0501) | Phase III (E) | 1. Gemcitabine | Superior OS |
2. Vinorelbine | Superior OS |
Study involved only patients 70 to 89 years old
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
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 | Efficacy |
---|---|---|---|
Lilenbaum et al. 2008 | Phase III (C) | Erlotinib | Seems to have superior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for up to 4 cycles
Variant #4, 6/225
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Langer et al. 2008 | Phase III (C) | Carboplatin & PPX | Seems to have superior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
21-day cycles
References
- 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
- 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
- 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
- IFCT-0501: Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, Dauba J, Debieuvre D, Souquet PJ, Bigay-Game L, Dansin E, Poudenx M, Molinier O, Vaylet F, Moro-Sibilot D, Herman D, Bennouna J, Tredaniel J, Ducoloné A, Lebitasy MP, Baudrin L, Laporte S, Milleron B; Intergroupe Francophone de Cancérologie Thoracique. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88. Epub 2011 Aug 8. link to original article contains verified protocol PubMed
Carboplatin & Pemetrexed
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Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Zukin et al. 2013 (INCA-Lung001) | Phase III (E) | Pemetrexed | Superior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of Pemetrexed (Alimta), to be given throughout pemetrexed therapy
21-day cycle for up to 4 cycles
References
- INCA-Lung001: Zukin M, Barrios CH, Rodrigues Pereira J, De Albuquerque Ribeiro R, de Mendonça Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, de Lima Araujo LH, Da Rocha Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. Epub 2013 Jun 17. link to original article contains verified protocol PubMed
Carboplatin, Pemetrexed, Bevacizumab
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Spigel et al. 2018 | Randomized Phase II (E) | 1. Pemetrexed 2. Pemetrexed & Bevacizumab |
PFS: 4.8 mo |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications, folic acid, and vitamin supplementation per standard guidelines
- Antiemetics per standard guidelines
21-day cycle for 4 cycles
Subsequent treatment
References
- Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed
Docetaxel monotherapy
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Example orders
Variant #1, 25 mg/m2, 3 out of 4 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Tsukada et al. 2014 (JCOG0207) | Phase III (C) | Cisplatin & Docetaxel | Seems not superior |
Chemotherapy
- Docetaxel (Taxotere) 25 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Variant #2, 36 mg/m2, 3 out of 4 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hainsworth et al. 2007 | Phase III (C) | Docetaxel & Gemcitabine | Seems not superior |
Chemotherapy
- Docetaxel (Taxotere) 36 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Variant #3, 38 mg/m2, 2 out of 3 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Karampeazis et al. 2011 | Phase III (E) | Vinorelbine | Might have superior OS |
Chemotherapy
- Docetaxel (Taxotere) 38 mg/m2 IV over 60 minutes once per day on days 1 & 8
21-day cycle for up to 6 cycles
Variant #4, 60 mg/m2 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kudoh et al. 2006 (WJTOG 9904) | Phase III (E) | Vinorelbine | Seems not superior |
Abe et al. 2015 (JCOG0803/WJOG4307L) | Phase III (C) | Cisplatin & Docetaxel | Seems not superior |
This is the PMDA-approved dose.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1
21-day cycle for up to 4 cycles (WJTOG 9904) or indefinitely
References
- 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
- 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
- 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
- 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
- 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 | Efficacy |
---|---|---|---|
O'Brien et al. 2008 | Phase III (C) | Paclitaxel Poliglumex | Seems not superior |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for up to 6 cycles
Variant #2, 1150 mg/m2, 2 out of 3 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Quoix et al. 2011 (IFCT-0501) | Phase III (C) | Carboplatin & Paclitaxel | Inferior OS |
Study involved only patients 70 to 89 years old
Chemotherapy
- Gemcitabine (Gemzar) 1150 mg/m2 IV once per day on days 1 & 8
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 | Efficacy |
---|---|---|---|
Gridelli et al. 2003 (MILES) | Phase III (E) | 1. Gemcitabine & Vinorelbine | Seems not superior |
2. Vinorelbine | Seems not superior | ||
Reynolds et al. 2009 (USO-03012) | Phase III (C) | Carboplatin & Gemcitabine | Seems not superior |
Morabito et al. 2013 (CAPPA-2) | Phase III (C) | Cisplatin & Gemcitabine | Seems to have inferior OS |
Gridelli et al. 2018 (MILES-3/MILES-4) | Phase III (C) | Cisplatin & Gemcitabine | Seems not superior |
MILES studies involved only patients at least 70 years old. CAPPA-2 allowed patients aged 18-70 with ECOG PS = 2.
Chemotherapy
- Gemcitabine (Gemzar) 1200 mg/m2 IV once per day on days 1 & 8
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
- 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
- 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
- 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
- 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
- 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
- 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
- MILES-3/MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed
Gemcitabine & Paclitaxel
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GT: Gemcitabine & Taxol (Paclitaxel)
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Comella et al. 2004 (SICOG 9909) | Phase III (E) | 1. Gemcitabine 2. Paclitaxel |
Seems to have superior OS |
3. GV | Not reported |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
References
- SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains protocol PubMed
Gemcitabine & Vinorelbine
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GV: Gemcitabine & Vinorelbine
VG: Vinorelbine & Gemcitabine
Variant #1, 1000/25
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gridelli et al. 2003 (MILES) | Phase III (E) | 1. Gemcitabine | Seems not superior |
2. Vinorelbine | Seems not superior |
This study involved only patients at least 70 years old
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
Supportive medications
- "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."
21-day cycle for up to 6 cycles
Variant #2, 1200/30
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Frasci et al. 2000 | Phase III (E) | Vinorelbine | Superior OS |
This study involved only patients at least 70 years old
Chemotherapy
- Gemcitabine (Gemzar) 1200 mg/m2 IV once per day on days 1 & 8
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
References
- 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
- 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
- SICOG 9909: Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, Maiorino L, Guida M, Panza N, Mancarella S, Cioffi R. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004 Aug 2;91(3):489-97. link to original article link to PMC article contains protocol PubMed
Pemetrexed monotherapy
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Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Zukin et al. 2013 (INCA-Lung001) | Phase III (C) | Carboplatin & Pemetrexed | Inferior OS |
Gridelli et al. 2018 (MILES-4) | Phase III (C) | 1. Cisplatin & Gemcitabine 2. Cisplatin & Pemetrexed |
Seems not superior |
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
21-day cycle for up to 4 cycles (INCA-Lung001) or 6 cycles (MILES-4)
References
- 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
- 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
- MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains verified protocol PubMed
Pemetrexed & Bevacizumab
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Spigel et al. 2018 | Randomized Phase II (E) | 1. Pemetrexed 2. Carboplatin, Pemetrexed, Bevacizumab |
PFS: 4.0 mo |
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications, folic acid, and vitamin supplementation per standard guidelines
- Antiemetics per standard guidelines
21-day cycles
References
- Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA 3rd, Greco FA. Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2. Cancer. 2018 May 1;124(9):1982-1991. Epub 2018 Feb 16. link to original article contains verified protocol PubMed
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Lee et al. 2012 (TOPICAL) | Phase III (C) | Erlotinib | Seems not superior |
No active antineoplastic treatment. Placed here because one or more randomized clinical trials included a placebo arm in this disease context.
References
- TOPICAL: Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, Marshall E, Woll PJ, Hatton M, Lal R, Jones R, Toy E, Chao D, Middleton G, Bulley S, Ngai Y, Rudd R, Hackshaw A, Boshoff C. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1161-70. Epub 2012 Oct 16. link to original article link to PMC article PubMed
Vinorelbine monotherapy
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Variant #1, 25 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kudoh et al. 2006 (WJTOG 9904) | Phase III (C) | Docetaxel | Seems not superior |
Karampeazis et al. 2011 | Phase III (E) | 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
- Vinorelbine (Navelbine) 25 mg/m2 IV over 30 minutes once per day on days 1 & 8
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 | Efficacy |
---|---|---|---|
Gridelli et al. 1999 (ELVIS) | Phase III (E) | Best supportive care | Seems to have superior OS |
Gridelli et al. 2003 (MILES) | Phase III (C) | 1. Gemcitabine | Seems not superior |
2. Gemcitabine & Vinorelbine | Seems not superior |
Study involved only patients at least 70 years old
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
Supportive medications
- (varies depending on reference):
- Elderly Lung Cancer Vinorelbine Italian Study Group, 1999: Metoclopramide (Reglan) 20 mg IV bolus prior to Vinorelbine (Navelbine)
- Gridelli et al. 2003: "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."
21-day cycle for up to 6 cycles
References
- 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
- 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
- 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
- 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
- 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
Chemotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed
Bevacizumab monotherapy
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Variant #1, 7.5 mg/kg
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Reck et al. 2009 (AVAil) | Non-randomized portion of RCT | ||
Barlesi et al. 2013 (AVAPERL) | Phase III (C) | Bevacizumab & Pemetrexed maintenance | Inferior PFS |
Preceding treatment
- AVAil: Cisplatin, Gemcitabine, Bevacizumab x 6
- AVAPERL: Cisplatin, Pemetrexed, Bevacizumab x 4
Chemotherapy
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
Variant #2, 15 mg/kg
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Sandler et al. 2006 (ECOG E4599) | Phase III (E) | See link | See link | |
Reck et al. 2009 (AVAil) | Non-randomized portion of RCT | |||
Johnson et al. 2013 (ATLAS-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
- ECOG E4599: PacCBev x 6
- AVAil: Cisplatin, Gemcitabine, Bevacizumab x 6
- ATLAS: Carboplatin, Docetaxel, Bevacizumab x 4 or Carboplatin, Gemcitabine, Bevacizumab x 4 or PacCBev x 4 or Cisplatin, Docetaxel, Bevacizumab x 4 or Cisplatin, Gemcitabine, Bevacizumab x 4 or Cisplatin, Vinorelbine, Bevacizumab x 4
- PointBreak and PRONOUNCE: PacCBev x 4
- IMpower150: BCP x 4 or BCP x 6
Chemotherapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Dataset: Project Data Sphere
- PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed
- 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 | Efficacy |
---|---|---|---|
Brodowicz et al. 2006 | Phase III (E) | Observation | Superior TTP |
Pérol et al. 2012 | Phase III (E) | 1. Erlotinib | Not reported |
2. Observation | Superior PFS |
Preceding treatment
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycles
References
- Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, Cucevic B, Gyurkovits K, Ulsperger E, Jassem J, Grgic M, Saip P, Szilasi M, Wiltschke C, Wagnerova M, Oskina N, Soldatenkova V, Zielinski C, Wenczl M; Central European Cooperative Oncology Group 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
- 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
- Ipilimumab (Yervoy) 10 mg/kg IV once on day 1
12-week cycles
References
- 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
- 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
- Necitumumab (Portrazza) 800 mg IV over at least 50 minutes once per day on days 1 & 8
21-day cycles
References
- 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
- Dataset: Project Data Sphere
Observation
back to top |
Regimen
Study | Evidence | Comparator | 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
- 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 | Efficacy |
---|---|---|---|
Paz-Ares et al. 2018 (KEYNOTE-407) | Phase III (E) | See link | See link |
Preceding treatment
Chemotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (including induction)
References
- 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 | Efficacy |
---|---|---|---|
Ciuleanu et al. 2009 (JMEN) | Phase III (E) | Placebo | Seems to have superior OS |
Paz-Ares et al. 2012 (PARAMOUNT) | Phase III (E) | Placebo | Superior PFS |
Zinner et al. 2015 (PRONOUNCE) | Phase III (E) | See link | See link |
Reck et al. 2016 (KEYNOTE-024) | Non-randomized portion of RCT | ||
Langer et al. 2016 (KEYNOTE-021) | Non-randomized portion of RCT | ||
Mok et al. 2015 (KEYNOTE-042) | Non-randomized portion of RCT | ||
Shi et al. 2017 (CONVINCE) | Phase III (C) | See link | See link |
Gandhi et al. 2018 (KEYNOTE-189) | Non-randomized portion of RCT |
Preceding treatment
- JMEN: Platinum-based chemotherapy x 4
- PARAMOUNT: Cisplatin & Pemetrexed x 4; maintenance therapy started 21 to 42 days after cycle 4 day 1 of induction chemotherapy
- PRONOUNCE & KEYNOTE-021 (control arm): Carboplatin & Pemetrexed x 4
- KEYNOTE-024: Carboplatin & Paclitaxel or Carboplatin & Pemetrexed or Cisplatin & Pemetrexed
- KEYNOTE-042: Carboplatin & Pemetrexed x 6
- CONVINCE: Cisplatin & Pemetrexed x 4
- KEYNOTE-189 (control arm): Carboplatin & Pemetrexed x 4 or Cisplatin & Pemetrexed x 4
- KEYNOTE-021 & KEYNOTE-189 (experimental arm): Pemetrexed & Pembrolizumab maintenance x 2 y
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Supportive medications
- Folic acid
- Cyanocobalamin (Vitamin B12)
- Dexamethasone (Decadron)
- "Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."
21-day cycles
References
- 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
- 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
- HRQoL analaysis: 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
- 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
- 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
- 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
- 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
- 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
- Abstract: Tony Mok, Yi-Long Wu, Patricia A, Watson, Jin Zhang, Reshma A. Rangwala, and Gilberto Lopes. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015 33:15_suppl, TPS8105-TPS8105 link to abstract
- 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
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed
Pemetrexed & Bevacizumab
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Variant #1, 500/7.5
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2013 (AVAPERL) | Phase III (E) | Bevacizumab maintenance | Superior PFS |
Preceding treatment
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
Supportive medications
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
- Folic acid 350 to 1000 mcg PO once per day, given throughout therapy
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1, 1, 2 of each cycle
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
- PointBreak: PemCBev (AUC 6) x 4
- Spigel et al. 2018: PemCBev (AUC 5) x 4
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications, folic acid, and vitamin supplementation per pemetrexed label
- Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycles
References
- 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
- 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
- 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
- Dataset: Project Data Sphere
- 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
Pembrolizumab & Pemetrexed maintenance therapy for advanced or metastatic non-small cell lung cancer
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Johnson et al. 2008 (NCCTG 97-24-51) | Phase III (C) | CAI | Seems not superior |
Ciuleanu et al. 2009 (JMEN) | Phase III (E) | Pemetrexed | Seems to have inferior OS |
Lee et al. 2009 | Phase III (C) | Thalidomide | Seems not superior |
Cappuzzo et al. 2010 (SATURN) | Phase III (C) | Erlotinib | Inferior PFS |
Koch et al. 2011 (CYCLUS) | Phase III (C) | Celecoxib | Seems not superior |
Gaafar et al. 2011 (EORTC 08021) | Phase III (C) | Gefitinib | Seems not superior |
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 | Seems not superior |
Giaccone et al. 2015 | Phase III (C) | Belagenpumatucel-L | Seems not superior |
Cicènas et al. 2016 (IUNO) | Phase III (C) | See link | See link |
Baggstrom et al. 2017 (CALGB 30607) | Phase III (C) | Sunitinib | Inferior PFS |
No further antineoplastic treatment after first-line therapy. Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks.
Preceding treatment
- JMEN, SATURN, EORTC 08021, INFORM, IUNO: 4 cycles of platinum-doublet therapy
- Lee et al. 2009: Carboplatin & Gemcitabine x 4
- PARAMOUNT: Cisplatin & Pemetrexed x 4
- Giaccone et al. 2015: Platinum-based chemotherapy
Subsequent treatment
- IUNO: Erlotinib, after PD or intolerance
References
- NCCTG 97-24-51: Johnson EA, Marks RS, Mandrekar SJ, Hillman SL, Hauge MD, Bauman MD, Wos EJ, Moore DF, Kugler JW, Windschitl HE, Graham DL, Bernath AM Jr, Fitch TR, Soori GS, Jett JR, Adjei AA, Perez EA. Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Lung Cancer. 2008 May;60(2):200-7. Epub 2007 Nov 28. link to original article PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- HRQoL analaysis: 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
- 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
- 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
- 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
- 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
- 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
- CALGB 30607: Baggstrom MQ, Socinski MA, Wang XF, Gu L, Stinchcombe TE, Edelman MJ, Baker S Jr, Feliciano J, Novotny P, Hahn O, Crawford JA, Vokes EE. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study-CALGB 30607 (Alliance). J Thorac Oncol. 2017 May;12(5):843-849. Epub 2017 Feb 1. link to original article PubMed
Advanced or metastatic disease, subsequent lines of therapy
Afatinib monotherapy
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Variant #1, 30 mg/day
FDA-recommended dose |
This is the FDA-recommended dose for patients with "severe renal impairment".
Chemotherapy
- Afatinib (Gilotrif) 30 mg PO once per day
Continued indefinitely
Variant #2, 40 mg/day
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Soria et al. 2015 (LUX-Lung 8) | Phase III (E) | Erlotinib | Superior OS |
Chemotherapy
- Afatinib (Gilotrif) 40 mg PO once per day, given 1 hour before eating food
Continued indefinitely
Variant #3, 50 mg/day
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Miller et al. 2012 (LUX-Lung 1) | Phase III (E) | Placebo | Superior PFS |
Katakami et al. 2013 (LUX-Lung 4) | Phase II | ORR: 8% (95% CI: 3-18) |
In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.
Chemotherapy
- Afatinib (Gilotrif) 50 mg PO once per day, given 1 hour before eating food
Continued indefinitely
References
- LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
- HRQoL analysis: Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. link to original article PubMed
- LUX-Lung 4: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: A phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
- 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
Afatinib & Paclitaxel
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schuler et al. 2015 (LUX-Lung 5) | Phase III (E) | Single-agent chemotherapy | Superior PFS |
Chemotherapy
References
- LUX-Lung 5: Schuler M, Yang JC, Park K, Kim JH, Bennouna J, Chen YM, Chouaid C, De Marinis F, Feng JF, Grossi F, Kim DW, Liu X, Lu S, Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand VK, Planchard D; LUX-Lung 5 Investigators. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016 Mar;27(3):417-23. Epub 2015 Dec 8. link to original article link to PMC article PubMed
Amrubicin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Yoshioka et al. 2017 | Phase III (E) | Docetaxel | Seems not superior |
Chemotherapy
- Amrubicin (Calsed) 35 mg/m2 IV over 5 minutes once per day on days 1 to 3
21-day cycles
References
- Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains verified protocol PubMed
Atezolizumab monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fehrenbacher et al. 2016 (POPLAR) | Randomized Phase II (E) | Docetaxel | Seems to have superior OS |
Rittmeyer et al. 2017 (OAK) | Phase III (E) | Docetaxel | Superior OS |
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains protocol PubMed
- OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. link to original article PubMed
Cabozantinib monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Neal et al. 2016 (ECOG-ACRIN 1512) | Randomized Phase II (E) | 1. Cabozantinib & Erlotinib | Not reported |
2. Erlotinib | Superior PFS |
Chemotherapy
- Cabozantinib (Cometriq) 60 mg PO once per day
Continued indefinitely
References
- ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN 1512 Investigators. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed
Cabozantinib & Erlotinib
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Neal et al. 2016 (ECOG-ACRIN 1512) | Randomized Phase II (E) | 1. Cabozantinib | Not reported |
2. Erlotinib | Superior PFS |
Chemotherapy
- Cabozantinib (Cometriq) 40 mg PO once per day
- Erlotinib (Tarceva) 150 mg PO once per day
Continued indefinitely
References
- ECOG-ACRIN 1512: Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, Gerstner GJ, Lerner RE, Rubin JL, Owonikoko TK, Stella PJ, Steen PD, Khalid AA, Ramalingam SS; ECOG-ACRIN 1512 Investigators. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1661-1671. Epub 2016 Nov 4. link to original article contains protocol link to PMC article PubMed
Carboplatin & Pemetrexed
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Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ardizzoni et al. 2012 (GOIRC 02-2006) | Randomized Phase II (E) | Pemetrexed | Seems not superior |
Mok et al. 2016 (AURA3) | Phase III (C) | Osimertinib | Inferior PFS |
Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for 4 to 6 cycles, or until progressive disease, unacceptable toxicity, or patient refusal
Subsequent treatment
- AURA3: Optional pemetrexed maintenance
References
- 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
- 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
Cisplatin & Pemetrexed
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Soria et al. 2015 (IMPRESS) | Phase III (C) | Cisplatin, Pemetrexed, Gefitinib | Seems not superior |
Mok et al. 2016 (AURA3) | Phase III (C) | Osimertinib | Inferior PFS |
Patients enrolled in IMPRESS were EGFR mutation positive and had progression after first-line gefitinib. Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Supportive medications
- (as described in Scagliotti et al. 2008):
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
- Folic acid 1 mg PO once per day
- In Sequist et al. 2013: Patients "received folic acid, vitamin B12, and dexamethasone, as per package recommendations for Pemetrexed (Alimta)."
21-day cycle for 4 to 6 cycles
Subsequent treatment
- AURA3: Patients without disease progression could optionally proceed to pemetrexed maintenance after 4 cycles
References
- IMPRESS: Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):990-8. Epub 2015 Jul 6. link to original article contains verified protocol PubMed
- Update: Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Shi X, Rukazenkov Y, Haddad V, Thress KS, Soria JC. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses. J Clin Oncol. 2017 Dec 20;35(36):4027-4034. Epub 2017 Oct 2. link to original article PubMed
- AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains verified protocol PubMed
Docetaxel monotherapy
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Example orders
Variant #1, 35 mg/m2, 3 out of 4 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schuette et al. 2005 | Phase III (E) | Docetaxel 75 mg/m2, every 3 wks | Might have superior OS |
Chen et al. 2006 | Phase III (E) | 1. Docetaxel 40 mg/m2, 2 out of 3 wks | Seems not superior |
2. Docetaxel 75 mg/m2, every 3 wks | Seems not superior | ||
Garassino et al. 2013 (TAILOR-NSCLC) | Phase III (C) | Erlotinib | Seems to have superior OS |
Note that there is another trial named TAILOR in colorectal cancer, so this one has been dubbed TAILOR-NSCLC.
Chemotherapy
- Docetaxel (Taxotere) 35 mg/m2 IV once per day on days 1, 8, 15
Supportive medications
- Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel
28-day cycles
Variant #2, 50 mg/m2 q2wk, limited duration
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pallis et al. 2010 | Phase III (C) | Carboplatin & Docetaxel | Seems not superior |
These patients had previously been treated with a platinum-free regimen.
Chemotherapy
- Docetaxel (Taxotere) 50 mg/m2 IV once per day on days 1 & 15
28-day cycle for up to 6 cycles
Variant #3, 60 mg/m2 q3wk, limited duration
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III (C) | Docetaxel & Vandetanib | Inferior PFS |
This is the PMDA-approved dose. While statistically inferior, the median PFS difference was only 0.8 months.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Variant #4, 60 mg/m2 q3wk, indefinite
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Maruyama et al. 2008 (V-15-32) | Phase III (C) | Gefitinib | Inconclusive whether non-inferior |
Takeda et al. 2009 (JCOG 0104) | Phase III (C) | Docetaxel & Gemcitabine | Seems not superior |
Kawaguchi et al. 2014 (DELTA) | Phase III (C) | Erlotinib | Might have superior PFS |
Garon et al. 2014 (REVEL) | Phase III (C) | Docetaxel & Ramucirumab | Seems to have inferior OS |
Yoshioka et al. 2017 | Phase III (C) | Amrubicin | Seems not superior |
Nokihara et al. 2017 | Phase III (C) | S-1 | Non-inferior OS |
This is the PMDA-approved dose, the dose used for East Asian patients in REVEL, and the dose used in Japanese patients in Nokihara et al. 2017.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV over at least 60 minutes once on day 1
21-day cycles
Variant #5, 75 mg/m2 q3wk, limited duration
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III (C) | Docetaxel & Vandetanib | Inferior PFS |
While statistically inferior, the median PFS difference was only 0.8 months.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Variant #6, 75 mg/m2 q3wk, indefinite
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shepherd et al. 2000 | Phase III (E) | Best supportive care | Seems to have superior OS |
Fossella et al. 2000 (TAX 320) | Phase III (E) | 1. Docetaxel 100 mg/m2 | Seems not superior |
2. Ifosfamide 3. Vinorelbine |
Seems not superior | ||
Hanna et al. 2004 (JMEI) | Phase III (C) | Pemetrexed | Inconclusive whether non-inferior |
Gridelli et al. 2004 (DISTAL 01) | Phase III (C) | Docetaxel 33.3 mg/m2, 6 out of 8 wks | Seems not superior |
Schuette et al. 2005 | Phase III (C) | Docetaxel 35 mg/m2, 3 out of 4 wks | Might have inferior OS |
Camps et al. 2005 | Phase III (C) | Docetaxel 36 mg/m2, 6 out of 8 wks | Seems not superior |
Chen et al. 2006 | Phase III (C) | 1. Docetaxel 35 mg/m2, 3 out of 4 wks | Seems not superior |
2. Docetaxel 40 mg/m2, 2 out of 3 wks | Seems not superior | ||
Ramlau et al. 2006 | Phase III (C) | Topotecan | Might have superior OS |
Paz-Ares et al. 2008 | Phase III (C) | Paclitaxel poliglumex | Seems not superior |
Kim et al. 2008 (INTEREST) | Phase III (C) | Gefitinib | Seems non-inferior |
Fidias et al. 2008 | Phase III (C) | Docetaxel consolidation | Might have inferior OS |
Lee et al. 2010 (ISTANA) | Phase III (C) | Gefitinib | Seems to have inferior PFS |
Krzakowski et al. 2010 | Phase III (C) | Vinflunine | Non-inferior PFS |
Ramlau et al. 2012 (EFC10261) | Phase III (C) | Docetaxel & ziv-Aflibercept | Seems not superior |
Shaw et al. 2013 (PROFILE 1007) | Phase III (C) | Crizotinib | Inferior PFS |
Garassino et al. 2013 (TAILOR-NSCLC) | Phase III (C) | Erlotinib | Seems to have superior OS |
Reck et al. 2014 (LUME-Lung 1) | Phase III (C) | Docetaxel & Nintedanib | Inferior PFS |
Garon et al. 2014 (REVEL) | Phase III (C) | Docetaxel & Ramucirumab | Seems to have inferior OS |
Blumenschein et al. 2015 | Randomized Phase II (C) | Trametinib | Seems not superior |
Brahmer et al. 2015 (CheckMate 017) | Phase III (C) | Nivolumab | Inferior OS |
Borghaei et al. 2015 (CheckMate 057) | Phase III (C) | Nivolumab | Inferior OS |
Herbst et al. 2015 (KEYNOTE-010) | Phase II/III (C) | Pembrolizumab | Inferior OS |
Fehrenbacher et al. 2016 (POPLAR) | Randomized Phase II (C) | Atezolizumab | Seems to have inferior OS |
Rittmeyer et al. 2016 (OAK) | Phase III (C) | Atezolizumab | Inferior OS |
Jänne et al. 2017 (SELECT-1) | Phase III (C) | Docetaxel & Selumetinib | Seems not superior |
Shaw et al. 2017 (ASCEND-5) | Phase III (C) | Ceritinib | Inferior PFS |
Katakami et al. 2017 (E7389-G000-302) | Phase III (C) | Eribulin | Seems not superior |
Nokihara et al. 2017 | Phase III (C) | S-1 | Non-inferior OS |
Barlesi et al. 2018 (JAVELIN Lung 200) | Phase III (C) | Avelumab | Seems not superior |
Patients in Blumenschein et al. 2015 and SELECT-1 had KRAS-mutated NSCLC. Patients in ASCEND-5 had ALK-rearranged NSCLC progressed after crizotinib. Note that there is another trial named TAILOR in colorectal cancer, so this one has been dubbed TAILOR-NSCLC.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
Supportive medications
- Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day the day before, the day of, and the day after docetaxel
- Per Chem et al. 2006: Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel
21-day cycles
Variant #7, 100 mg/m2 q3wk
Study | Evidence |
---|---|
Fossella et al. 1995 | Phase II |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
References
- Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, Murphy WK, Lippman S, Benner S, Glisson B, Chasen M, Hong WK, Raber M. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol. 1995 Mar;13(3):645-51. link to original article contains protocol PubMed
- Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. link to original article contains protocol PubMed
- TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; The TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains verified protocol PubMed
- JMEI: Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains verified protocol PubMed
- 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
- 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
- Camps C, Massuti B, Jiménez A, Maestu I, Gómez RG, Isla D, González JL, Almenar D, Blasco A, Rosell R, Carrato A, Viñolas N, Batista N, Girón CG, Galán A, López M, Blanco R, Provencio M, Diz P, Felip E; Spanish Lung Cancer Group. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol. 2006 Mar;17(3):467-72. Epub 2005 Dec 21. link to original article contains protocol PubMed
- Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest. 2006 Apr;129(4):1031-8. link to original article contains verified protocol PubMed
- Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, Dharan B, Grotzinger KM, Ross G, Dane G, Shepherd FA. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006 Jun 20;24(18):2800-7. Epub 2006 May 8. link to original article contains protocol PubMed
- 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
- V-15-32: Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Inoue A, Tomii K, Harada M, Masuda N, Jiang H, Itoh Y, Ichinose Y, Saijo N, Fukuoka M. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008 Sep 10;26(26):4244-52. link to original article contains verified protocol PubMed
- HRQoL analysis: Sekine I, Ichinose Y, Nishiwaki Y, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, Takeda K, Itoh Y, Tamura T, Saijo N, Fukuoka M. Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel. Ann Oncol. 2009 Sep;20(9):1483-8. Epub 2009 Mar 12. link to original article PubMed
- INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains protocol PubMed
- Dataset: Project Data Sphere
- Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, Hristova-Kazmierski M, Treat J, Obasaju CK, Marciniak M, Gill J, Schiller JH. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1;27(4):591-8. Epub 2008 Dec 15. link to original articlecontains verified protocol PubMed
- 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
- ISTANA: Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. link to original article contains protocol PubMed
- 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
- 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
- Dataset: Project Data Sphere
- 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
- EFC10261: Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Le-Guennec S, Rey A, Miller V, Thatcher N, Scagliotti G. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10;30(29):3640-7. Epub 2012 Sep 10. link to original article contains protocol PubMed
- Dataset: Project Data Sphere
- PROFILE 1007: Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed
- 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
- TAILOR-NSCLC: 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
- LUME-Lung 1: Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55. 2. Epub 2014 Jan 9. link to original article PubMed
- 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
- 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
- Blumenschein GR Jr, Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn MJ, Hanna NH, Kim JH, Mazieres J, Kim SW, Baas P, Rappold E, Redhu S, Puski A, Wu FS, Jänne PA. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2015 May;26(5):894-901. Epub 2015 Feb 26. link to original article link to PMC article contains verified protocol PubMed
- CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article PubMed
- Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
- CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed
- Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
- KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains protocol PubMed
- POPLAR: Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Epub 2016 Mar 9. link to original article contains protocol PubMed
- OAK: Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Epub 2016 Dec 13. link to original article contains protocol PubMed
- Yoshioka H, Katakami N, Okamoto H, Iwamoto Y, Seto T, Takahashi T, Sunaga N, Kudoh S, Chikamori K, Harada M, Tanaka H, Saito H, Saka H, Takeda K, Nogami N, Masuda N, Harada T, Kitagawa H, Horio H, Yamanaka T, Fukuoka M, Yamamoto N, Nakagawa K. A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer. Ann Oncol. 2017 Feb 1;28(2):285-291. link to original article contains verified protocol PubMed
- SELECT-1: Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, Orlov S, Blackhall F, Wolf J, Garrido P, Poltoratskiy A, Mariani G, Ghiorghiu D, Kilgour E, Smith P, Kohlmann A, Carlile DJ, Lawrence D, Bowen K, Vansteenkiste J. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: The SELECT-1 randomized clinical trial. JAMA. 2017 May 9;317(18):1844-1853. link to original article contains verified protocol PubMed
- ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original articlecontains protocolPubMed
- E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed
- Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article contains verified protocol PubMed
- JAVELIN Lung 200: Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, Özgüroğlu M, Szczesna A, Polychronis A, Uslu R, Krzakowski M, Lee JS, Calabrò L, Arén Frontera O, Ellers-Lenz B, Bajars M, Ruisi M, Park K. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1468-79. Epub 2018 Sep 21. link to original article contains protocol PubMed
Docetaxel & Ramucirumab
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Variant #1, 60 mg/m2 docetaxel
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Garon et al. 2014 (REVEL) | Phase III (E) | Docetaxel | Seems to have superior OS |
Note: This is the PMDA-approved dose and the dose recommended for East Asians. The FDA only provides recommendations for ramucirumab dosing.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
- Ramucirumab (Cyramza) 10 mg/kg IV once on day 1
Supportive medications
- Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.
21-day cycles
Variant #2, 75 mg/m2 docetaxel
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Garon et al. 2014 (REVEL) | Phase III (E) | Docetaxel | Seems to have superior OS |
Note: The FDA only provides recommendations for ramucirumab dosing.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Ramucirumab (Cyramza) 10 mg/kg IV once on day 1
Supportive medications
- Colony-stimulating factors and erythroid-stimulating factor use per investigator discretion.
21-day cycles
References
- REVEL: Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. link to original article contains verified protocol PubMed
Docetaxel & Vandetanib
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Variant #1, 60 mg/m2 docetaxel
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III (E) | Docetaxel | Superior PFS |
This is the PMDA-approved dose of docetaxel. While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
- Vandetanib (Caprelsa) 100 mg PO once per day
21-day cycle for up to 6 cycles (*)
Variant #2, 75 mg/m2 docetaxel
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III (E) | Docetaxel | Superior PFS |
While statistically superior, the median PFS difference was only 0.8 months. Vandetanib is continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Vandetanib (Caprelsa) 100 mg PO once per day
21-day cycle for up to 6 cycles (see note)
References
- 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 | Efficacy |
---|---|---|---|
Kris et al. 2003 (IDEAL2) | Randomized Phase II (E) | Gefitinib 500 mg/day | Seems not superior |
Thatcher et al. 2005 (ISEL) | Phase III (E) | Placebo | Might have superior OS |
Kim et al. 2008 (INTEREST) | Phase III (E) | Docetaxel | Seems non-inferior |
Lee et al. 2010 (ISTANA) | Phase III (E) | Docetaxel | Seems to have superior PFS |
Han et al. 2011 | Randomized Phase II (C) | Gefitinib & Simvastatin | Seems not superior |
Sun et al. 2012 (KCSG-LU08-01) | Phase III (E) | Pemetrexed | Superior PFS |
Shi et al. 2013 (ICOGEN) | Phase III (C) | Icotinib | Seems non-inferior |
Urata et al. 2016 (WJOG 5108L) | Phase III (C) | Erlotinib | Inconclusive whether non-inferior |
Chemotherapy
- Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
References
- IDEAL2: Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003 Oct 22;290(16):2149-58. link to original article PubMed
- ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article PubMed
- INTEREST: Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008 Nov 22;372(9652):1809-18. link to original article contains verified protocol PubMed
- Dataset: Project Data Sphere
- ISTANA: Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010 Feb 15;16(4):1307-14. Epub 2010 Feb 9. link to original article contains protocol PubMed
- Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. link to orinigal article contains protocol PubMed
- 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
- ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article PubMed
- WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article contains verified protocol PubMed
Gemcitabine monotherapy
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Variant #1, 1000 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Crinò et al. 1999 | Phase II | ||
Katakami et al. 2017 (E7389-G000-302) | Phase III (C) | Eribulin | Seems not superior |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Variant #2, 1250 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Katakami et al. 2017 (E7389-G000-302) | Phase III (C) | Eribulin | Seems not superior |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycles
References
- 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
- E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed
Icotinib monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shi et al. 2013 (ICOGEN) | Phase III (E) | Gefitinib | Seems non-inferior |
Note: this drug is only approved in China.
Chemotherapy
- Icotinib (Conmana) 125 mg PO TID
Continued indefinitely
References
- ICOGEN: Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013 Sep;14(10):953-61. Epub 2013 Aug 13. link to original article contains protocol PubMed
Nivolumab monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy | ORR |
---|---|---|---|---|
Rizvi et al. 2015 (CheckMate 063) | Phase II | 14% (95% CI 9 - 22) | ||
Brahmer et al. 2015 (CheckMate 017) | Phase III (E) | Docetaxel | Superior OS | 20% (95% CI 14 - 28) |
Borghaei et al. 2015 (CheckMate 057) | Phase III (E) | Docetaxel | Superior OS | 19% (95% CI 15 - 24) |
Patients in CheckMate 017 had squamous histology. Patients in CheckMate 057 had non-squamous histology.
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
References
- CheckMate 063: Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Feb 19. link to original article contains verified protocol PubMed
- CheckMate 017: Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. Epub 2015 May 31. link to original article link to PMC article PubMed
- CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed
Pembrolizumab monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy | ORR |
---|---|---|---|---|
Garon et al. 2015 (KEYNOTE-001) | Phase 1, >20 pts in dosing cohort | |||
Herbst et al. 2015 (KEYNOTE-010) | Phase II/III (E) | Docetaxel | Superior OS | 2 mg/kg: 18% (95% CI 14 - 23) 10 mg/kg: 19% (95% CI 15 - 23) |
Note: patients had previously received chemotherapy.
Immunotherapy
- Pembrolizumab (Keytruda) 2 mg/kg or 10 mg/kg IV once on day 1
21-day cycles
References
- 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
- KEYNOTE-010: Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. Epub 2015 Dec 19. link to original article contains protocol PubMed
Pemetrexed monotherapy
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Example orders
Regimen
FDA-recommended dose |
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hanna et al. 2004 (JMEI) | Phase III (E) | Docetaxel | Inconclusive whether non-inferior |
Cullen et al. 2008 | Phase III (C) | High-dose pemetrexed | Seems not superior |
de Boer et al. 2011 (ZEAL) | Phase III (C) | Pemetrexed & Vandetanib | Seems not superior |
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 | Seems not superior |
Karampeazis et al. 2013 | Phase III (E) | Erlotinib | Seems not superior |
Shaw et al. 2013 (PROFILE 1007) | Phase III (C) | Crizotinib | Inferior PFS |
Kim et al. 2013 | Phase III (C) | Pemetrexed & Cetuximab | Seems not superior |
Hanna et al. 2016 (LUME-Lung 2) | Phase III (C) | Nintedanib & Pemetrexed | Seems to have inferior PFS |
Shaw et al. 2017 (ASCEND-5) | Phase III (C) | Ceritinib | Inferior PFS |
Katakami et al. 2017 (E7389-G000-302) | Phase III (C) | Eribulin | Seems not superior |
Note: Kim et al. 2013 also evaluated docetaxel versus docetaxel & cetuximab, but did not report the efficacy of this comparison; see paper for details. Patients in ASCEND-5 had ALK-rearranged NSCLC that had progressed on crizotinib.
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Supportive medications
- (per Ardizzoni et al. 2012):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- JMEI used folic acid 1 mg PO once per day
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycles
GOIRC 02-2006 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.
References
- JMEI: Hanna N, Shepherd FA, Fossella FV, Rodrigues Pereira J, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. link to original article contains protocol PubMed
- 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 in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008 May;19(5):939-45. Epub 2008 Feb 17. link to original article contains protocol PubMed
- ZEAL: de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2011 Mar 10;29(8):1067-74. Epub 2011 Jan 31. link to original article contains protocol PubMed
- 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
- 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
- Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, Agelaki S, Vamvakas L, Samonis G, Mavroudis D, Georgoulias V. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013 Aug 1;119(15):2754-64. Epub 2013 May 9. link to original article contains verified protocol PubMed
- PROFILE 1007: Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Epub 2013 Jun 1. link to original article link to supplementary appendix contains verified protocol PubMed
- 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
- Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, Robert F, Reynolds C, Katz T, Chittoor S, Simms L, Saxman S. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013 Dec;14(13):1326-36. Epub 2013 Nov 12. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article contains protocol PubMed
- LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed
- ASCEND-5: Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. Epub 2017 Jun 9. link to original articlecontains protocolPubMed
- E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shepherd et al. 2005 (NCIC CTG BR.21) | Phase III (C) | Erlotinib | Inferior OS |
Thatcher et al. 2005 (ISEL) | Phase III (C) | Gefitinib | Might have inferior OS |
Lee et al. 2012 (ZEPHYR) | Phase III (C) | Vandetanib | Seems not superior |
Miller et al. 2012 (LUX-Lung 1) | Phase III (C) | Afatinib | Inferior PFS |
Ellis et al. 2014 (NCIC CTG BR.26) | Phase III (C) | Dacomitinib | Seems not superior |
Paz-Ares et al. 2015 (MISSION) | Phase III (C) | Sorafenib | Inferior PFS |
No active antineoplastic treatment. Placed here because one or more randomized clinical trials included a placebo arm in this disease context.
References
- NCIC CTG BR.21: Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. link to original article contains protocol PubMed
- ISEL: Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37. link to original article PubMed
- ZEPHYR: Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng RP, Chen YM, Emerson L, Langmuir P, Manegold C. Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012 Apr 1;30(10):1114-21. Epub 2012 Feb 27. link to original article PubMed
- LUX-Lung 1: Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
- HRQoL analysis: Hirsh V, Cadranel J, Cong XJ, Fairclough D, Finnern HW, Lorence RM, Miller VA, Palmer M, Yang JC. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1). J Thorac Oncol. 2013 Feb;8(2):229-37. link to original article PubMed
- NCIC CTG BR.26: Ellis PM, Shepherd FA, Millward M, Perrone F, Seymour L, Liu G, Sun S, Cho BC, Morabito A, Leighl NB, Stockler MR, Lee CW, Wierzbicki R, Cohen V, Blais N, Sangha RS, Favaretto AG, Kang JH, Tsao MS, Wilson CF, Goldberg Z, Ding K, Goss GD, Bradbury PA; NCIC CTG; Australasian Lung Cancer Trials Group; NCI Naples Clinical Trials Unit. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1379-88. Epub 2014 Oct 15. link to original article PubMed
- MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article contains verified protocol PubMed
S-1 monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Nokihara et al. 2017 | Phase III (E) | Docetaxel | Non-inferior OS |
Chemotherapy
- Tegafur, gimeracil, oteracil (S-1) as follows:
- BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 28
- BSA at least 1.25 m2 and less than 1.5 m2: 50 mg PO twice per day on days 1 to 28
- BSA 1.5 m2 or more: 60 mg PO twice per day on days 1 to 28
42-day cycles
References
- Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Morita S, Tamura T. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol. 2017 Nov 1;28(11):2698-2706. link to original article link to PMC article PubMed
Sorafenib monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Paz-Ares et al. 2015 (MISSION) | Phase III (E) | Placebo | Superior PFS |
Note: although the primary endpoint (OS) was negative overall, the authors note that the subgroup of patients with known EGFR mutations treated with sorafenib had significantly superior survival (p=0.002).
Chemotherapy
- Sorafenib (Nexavar) 400 mg PO twice per day
Continued indefinitely
References
- MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article contains verified protocol PubMed
Vinorelbine monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fossella et al. 2000 (TAX 320) | Phase III (C) | 1. Docetaxel 100 mg/m2 | Seems not superior |
2. Docetaxel 75 mg/m2 | Seems not superior | ||
Katakami et al. 2017 (E7389-G000-302) | Phase III (C) | Eribulin | Seems not superior |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV over 5 to 10 minutes once per week
Supportive medications
- Per TAX 320:
- Patients who had either grade 4 neutropenia lasting at least 5 days or both fever and grade 3 or 4 neutropenia could receive G-CSF (dose/schedule/duration not specified)
- Metoclopramide (Reglan) (dose/schedule/route not specified) used first for nausea
- Nausea despite metoclopramide was treated with a 5-HT3 antagonist such as Ondansetron (Zofran) or Granisetron (dose/schedule/route not specified) prn nausea
Continued indefinitely
References
- TAX 320: Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L; The TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original article contains verified protocol PubMed
- E7389-G000-302: Katakami N, Felip E, Spigel DR, Kim JH, Olivo M, Guo M, Nokihara H, Yang JC, Iannotti N, Satouchi M, Barlesi F. A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. Ann Oncol. 2017 Sep 1;28(9):2241-2247. link to original article link to PMC article contains verified protocol PubMed
Investigational agents
Drugs with some degree of promising activity in clinical trials.