Non-small cell lung cancer
Just 8 days left to fill out a survey on how we can make HemOnc.org better and more useful. |
Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer. If this is your first time visiting, we suggest you read the tutorial.
Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.
Section editor | |
---|---|
Travis Osterman, DO, MS Nashville, TN Twitter: TravisOsterman |
Note: biomarker-specific regimens have been moved to dedicated pages:
118 regimens on this page
227 variants on this page
|
Guidelines
ASCO
Current
- 2017: Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update PubMed
Former
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
- 2016: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
- 2015: 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. PubMed
- 2014: 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. PubMed
- 2014: 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: Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. PubMed
NCCN
Adjuvant therapy
Carboplatin & Paclitaxel
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Strauss et al. 2008 (CALGB 9633) | Phase III | 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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2015 | Phase III | Cisplatin & Gemcitabine | Seems not superior |
Wakelee et al. 2017 (E1505) | Phase III | Cisplatin, Docetaxel, Bevacizumab Cisplatin, Gemcitabine, Bevacizumab Cisplatin, Pemetrexed, Bevacizumab Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
Preceding treatment
- Barlesi et al. 2015: Complete R0 resection, within 8 weeks
- 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 (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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 | Phase III | 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
- 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
Cisplatin & Gemcitabine
back to top |
Regimen #1, 75/1200 x 4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wakelee et al. 2017 (E1505) | Phase III | Cisplatin, Docetaxel, Bevacizumab Cisplatin, Gemcitabine, Bevacizumab Cisplatin, Pemetrexed, Bevacizumab Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
Preceding treatment
- Complete surgical resection, within 6 to 12 weeks
Chemotherapy
- 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
Regimen #2, 75/1250 x 3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2015 | Phase III | 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
- 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
back to top |
CPx: Cisplatin & Pemetrexed
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kreuter et al. 2013 (TREAT) | Randomized Phase II | Cisplatin & Vinorelbine | Seems not superior (*) |
Wakelee et al. 2017 (E1505) | Phase III | Cisplatin, Docetaxel, Bevacizumab Cisplatin, Gemcitabine, Bevacizumab Cisplatin, Pemetrexed, Bevacizumab Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
In TREAT, intended for pathologically confirmed NSCLC stages (according to the TNM staging system version 6) IB, IIA, IIB or T3N1. Efficacy reported for TREAT based on 2016 update.
Preceding treatment
- TREAT: Complete surgical resection, within 4 to 6 weeks
- 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
- 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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 | Phase III | 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
- 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 contains verified protocol PubMed
Cisplatin & Vindesine
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 | Phase III | 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
- 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 contains verified protocol PubMed
Cisplatin & Vinorelbine
back to top |
CVb: Cisplatin & Vinorelbine
Regimen #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 | 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
Regimen #2, cisplatin 75 mg/m2, q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wakelee et al. 2017 (E1505) | Phase III (C) | Cisplatin, Docetaxel, Bevacizumab Cisplatin, Gemcitabine, Bevacizumab Cisplatin, Pemetrexed, Bevacizumab Cisplatin, Vinorelbine, Bevacizumab |
Seems not superior |
Zhong et al. 2017 (ADJUVANT/CTONG1104) | Phase III (C) | Gefinitib | Inferior DFS |
Patients enrolled in ADJUVANT/CTONG1104 had EGFR-mutated lung cancer.
Preceding treatment
- Complete surgical resection, within 6 to 12 weeks
Chemotherapy
- 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
Regimen #3, cisplatin 100 mg/m2, q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 | 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
- Arriagada et al. 2004: 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
- 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 content property of HemOnc.org
- 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
- Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed
- 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
- 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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Arriagada et al. 2004 | Phase III | Cisplatin & Etoposide | Seems to have inferior OS |
Cisplatin & Vinblastine | Seems to have inferior OS | ||
Cisplatin & Vindesine | Seems to have inferior OS | ||
Cisplatin & Vinorelbine | Seems to have inferior OS | ||
Winton et al. 2006 (JBR.10) | Phase III | Cisplatin & Vinorelbine | Seems to have inferior OS |
Douillard et al. 2006 (ANITA) | Phase III | Cisplatin & Vinorelbine | Seems to have inferior OS |
Strauss et al. 2008 (CALGB 9633) | Phase III | 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.
References
- 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
- 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
- Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27. link to original article PubMed
- 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
Induction chemotherapy for locally advanced disease
Carboplatin & Paclitaxel
back to top |
Regimen
Study | Evidence |
---|---|
Belani et al. 2005 | Phase II |
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
- RT x 63 Gy
References
- 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
Cisplatin & Vinblastine
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Curran et al. 2011 (RTOG 9410) | Phase III | 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
- 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 total course of chemotherapy
Subsequent treatment
- RT x 63 Gy
References
- 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
Definitive therapy for locally advanced disease
Carboplatin, Paclitaxel, RT
back to top |
PC & RT: Paclitaxel, Carboplatin, Radiation Therapy
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Belani et al. 2005 | Phase II | ||
Bradley et al. 2015 (RTOG 0617) | Phase III (C) | Carboplatin, Paclitaxel, Cetuximab, concurrent RT | Seems not superior |
Carboplatin, Paclitaxel, high-dose RT Carboplatin, Paclitaxel, Cetuximab, high-dose RT |
Superior OS | ||
Liang et al. 2017 | Phase III | EP & RT | Might have inferior OS |
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, as follows:
- Belani et al. 2005: 1.8 Gy fractions x 25 fractions given 5 days per week, then 2 Gy fractions x 9 fractions given 5 days per week. Total dose: 63 Gy over a 7 week course of treatment.
- RTOG 0617: 2 Gy fractions x 30 fractions given 5 days per week (total dose: 60 Gy)
21-day cycle for 2 cycles
Treatment in some protocols followed by carboplatin & paclitaxel consolidation.
References
- 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
- 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
- Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017 Apr 1;28(4):777-783. link to original article contains verified protocol PubMed
Carboplatin & RT
back to top |
Carboplatin & RT: Carboplatin & 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: 60 Gy, details not available in abstract
References
- 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, Etoposide, RT
back to top |
EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Senan et al. 2016 (PROCLAIM) | Phase III | Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation | Seems not superior |
Liang et al. 2017 | Phase III | 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, 2 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy), given 5 days per week, started on day 1
28-day cycle for 2 cycles
Treatment followed by cisplatin & etoposide consolidation or cisplatin & vinorelbine consolidation or carboplatin & paclitaxel consolidation (investigator's choice).
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Curran et al. 2011 (RTOG 9410) | Phase III | Cisplatin, Vinblastine, RT | Seems not superior |
Cisplatin & Vinblastine, then RT | Might have superior OS |
Chemoradiotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1, 8, 29, 36
- Etoposide (Vepesid) 50 mg PO BID on days 1 to 5, 8 to 12, 29 to 33, 36 to 40
- Concurrent radiation therapy, 1.2 Gy fractions (total dose: 69.6 Gy), given twice per day for 5 days per week, starting on day 1
5-week course
Regimen #3
Study | Evidence |
---|---|
Albain et al. 2002 (SWOG 9019) | Phase II |
Chemoradiotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1, 8, 29, 36
- Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5, 29 to 33
- Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions (total dose: 45 Gy), given 5 days per week, to start within 24 hours of chemotherapy
- Patients were reimaged 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 Gy per day x 8 fractions for a total of 61 Gy administered overall
5-week course
References
- 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
- 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
- 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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Curran et al. 2011 (RTOG 9410) | Phase III | Cisplatin, Etoposide, RT | Seems not superior |
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
- 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
back to top |
RT: Radiation Therapy
Regimen #1, 45 Gy + 18 Gy boost (63 Gy total)
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Belani et al. 2005 | Phase II | ||
Curran et al. 2011 (RTOG 9410) | Phase III | See link | See link |
Preceding treatment
- Belani et al. 2005: Carboplatin & Paclitaxel x 2
- RTOG 9410: Cisplatin & Vinblastine x 5 wk
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
Regimen #2, 60 Gy
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Atagi et al. 2012 (JCOG0301) | Phase III (C) | Carboplatin & RT | Seems to have inferior OS |
Radiotherapy
- 60 Gy, details not available in abstract
References
- 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
- 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
- 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 after definitive therapy
Carboplatin & Paclitaxel
back to top |
Regimen
Study | Evidence |
---|---|
Belani et al. 2005 | 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
- Belani et al. 2005 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
- 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
- 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
- Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
Cisplatin & Etoposide
back to top |
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
- Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
Cisplatin & Vinorelbine
back to top |
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
- Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed
Durvalumab monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Antonia et al. 2017 (PACIFIC) | Phase III | Placebo | Superior PFS |
Preceding treatment
- "Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."
Immunotherapy
- Durvalumab (Imfinzi) 10 mg/kg IV once every 2 weeks
Up to 12-month course
References
- Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. Epub 2017 Sep 8. link to original article contains verified protocol PubMed
Placebo
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Antonia et al. 2017 (PACIFIC) | Phase III | Durvalumab | Inferior PFS |
Preceding treatment
- "Two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 to 66 Gy), in which the mean dose to the lung was less than 20 Gy, the V20 (the volume of lung parenchyma that received 20 Gy or more) was less than 35%, or both."
Treatment
Up to 12-month course
References
- 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
Advanced or metastatic disease, first-line
Carboplatin & Docetaxel
back to top |
DCb: Docetaxel & Carboplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fossella et al. 2003 (TAX 326) | Phase III | Cisplatin & Docetaxel | Not reported |
Cisplatin & Vinorelbine | Seems not superior | ||
Booton et al. 2006 (BTOG1) | Phase III | MIC MVP |
Seems not superior |
Rossell et al. 2012 (EURTAC) | Phase III | Erlotinib | Inferior PFS |
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 cycles
References
- Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
- 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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Klastersky et al. 1990 (EORTC 07861) | Phase III | Carboplatin & 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
- Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, et al. 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
back to top |
GC: Gemcitabine and Carboplatin
GCb: Gemcitabine and Carboplatin
Regimen #1, 5/1000 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Grønberg et al. 2009 | Phase III | 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
Regimen #2, 5/1000 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Danson et al. 2003 | Phase III (E) | MIC MVP |
Seems not superior |
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
Regimen #3, 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
Regimen #4, 5/1250 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wu et al. 2013 (FASTACT-2) | Phase III (C) | Carboplatin & Gemcitabine/Erlotinib | Seems to have inferior OS |
Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.
Chemotherapy
- 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
Regimen #5, 6/1250 ("GCb6")
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Ferry et al. 2017 (BTOG2) | Phase III | GC50 | Seems to have superior OS | |
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
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
back to top |
TC: Taxol (Paclitaxel) and Carboplatin
Regimen #1, 5/200
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Mok et al. 2009 (IPASS) | Phase III | Gefitinib | Inferior PFS | |
Reck et al. 2016 (KEYNOTE-024) | Phase III | 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
Patients in KEYNOTE-024 with nonsquamous histology could optionally proceed, after 4 to 6 cycles, to pemetrexed switch maintenance.
Regimen #2, 6/175
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Lynch et al. 2012 | Randomized Phase II | Carboplatin, Paclitaxel, Ipilimumab | Seems to have inferior PFS |
Govindan et al. 2017 | Phase III | 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
Regimen #3, 6/200
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Johnson et al. 2004 | Randomized Phase II | PacCBev | Seems to have inferior TTP | |
Ohe et al. 2006 | Phase III | Cisplatin & Gemcitabine | Seems not superior | |
Cisplatin & Irinotecan | Seems not superior | |||
Cisplatin & Vinorelbine | Seems not superior | |||
Sandler et al. 2006 (ECOG 4599) | Phase III | PacCBev, then Maintenance Bev | Inferior OS | |
Lilenbaum et al. 2008 | Phase III | Erlotinib | Seems to have superior OS | |
Mok et al. 2009 (IPASS) | Phase III | Gefitinib | Inferior PFS | |
Maemondo et al. 2010 | Phase III | Gefitinib | Inferior PFS | |
Socinski et al. 2012 | Phase III | Carboplatin & nabPaclitaxel | Inferior ORR | |
Langer et al. 2014 | Phase III | Carboplatin, Figitumumab, Paclitaxel | Might have superior OS | |
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Ramalingam et al. 2016 | Randomized Phase II (C) | Carboplatin, Paclitaxel, Veliparib | Seems not superior | |
Herbst et al. 2017 (SWOG S0819) | Phase III (C) | Carboplatin, Paclitaxel, Cetuximab | Seems not superior |
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
Patients in KEYNOTE-024 with nonsquamous histology could optionally proceed, after 4 to 6 cycles, to pemetrexed switch maintenance.
Regimen #4, 6/225
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schiller et al. 2002 | Phase III | Cisplatin & Docetaxel | Seems not superior |
Cisplatin & Gemcitabine | Seems not superior | ||
Cisplatin & Paclitaxel | Seems not superior | ||
Lilenbaum et al. 2005 (CALGB 9730) | Phase III | Paclitaxel | Superior FFS |
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 cycles
References
- 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
- 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
- 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
- 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
- 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
- Subset 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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, nanoparticle albumin-bound
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Socinski et al. 2012 | Phase III | 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
- Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. Epub 2012 Apr 30. link to original article contains verified protocol PubMed
Carboplatin, Paclitaxel, Bevacizumab
back to top |
PacCBev: Paclitaxel, Carboplatin, Bevacizumab
Regimen #1, limited duration
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Patel et al. 2013 (PointBreak) | Phase III | PemCBev, then PemBev maint. | Seems to have inferior PFS |
Zinner et al. 2015 (PRONOUNCE) | Phase III | Carboplatin & Pemetrexed, then Pemetrexed maint. | Seems not superior |
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
Patients with complete response, partial response, or stable disease proceeded to bevacizumab maintenance therapy.
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Johnson et al. 2004 | Randomized Phase II (E) | Carboplatin & Paclitaxel | Seems to have superior TTP |
Sandler et al. 2006 (ECOG 4599) | Phase III (E) | Carboplatin & Paclitaxel | Superior OS |
Herbst et al. 2017 (SWOG S0819) | Phase III (C) | Carboplatin, Paclitaxel, Bevacizumab, Cetuximab | Seems not superior |
Patients in SWOG S0819 were EGFR FISH positive.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
- Bevacizumab (Avastin) 15 mg/kg IV on day 1, given third, starting 60 minutes after the completion of carboplatin
- Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later
21-day cycle for up to 6 cycles, or until progression of disease, or unacceptable toxicity
After 6 cycles, patients in ECOG 4599 who had stable disease or response continued to bevacizumab maintenance therapy.
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
- 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
- Subset 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
- 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
- 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
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Lynch et al. 2012 | Randomized Phase II | Carboplatin & Paclitaxel | Seems to have superior PFS |
Govindan et al. 2017 | Phase III | 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
Patients without progressive disease proceeded to receive maintenance ipilimumab therapy.
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
- Govindan R, Szczesna A, Ahn MJ, Schneider CP, Gonzalez Mella PF, Barlesi F, Han B, Ganea DE, Von Pawel J, Vladimirov V, Fadeeva N, Lee KH, Kurata T, Zhang L, Tamura T, Postmus PE, Jassem J, O'Byrne K, Kopit J, Li M, Tschaika M, Reck M. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol. 2017 Oct 20;35(30):3449-3457. Epub 2017 Aug 30. link to original article contains verified protocol PubMed
Carboplatin & Pemetrexed
back to top |
Example orders
Regimen #1, 5/500
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Zukin et al. 2013 | Phase III | Pemetrexed | Superior OS | |
Reck et al. 2016 (KEYNOTE-024) | Phase III | Pembrolizumab | Inferior OS | Inferior HRQoL |
Langer et al. 2016 (KEYNOTE-021) | Randomized Phase II | Carboplatin, Pemetrexed, Pembrolizumab, then pembrolizumab maintenance +/- pemetrexed maintenance | Inferior ORR | |
Soria et al. 2017 (ASCEND-4) | Phase III | Ceritinib | Inferior PFS |
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 BID on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for 4 to 6 cycles, or until progressive disease, unacceptable toxicity, or patient refusal
Treatment in KEYNOTE-024, KEYNOTE-021 and AURA3 followed by optional pemetrexed maintenance. Patients in ASCEND-4 proceeded to pemetrexed maintenance after 4 cycles.
Regimen #2, 6/500
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Grønberg et al. 2009 | Phase III | Carboplatin & Gemcitabine | Seems not superior | |
Zinner et al. 2015 (PRONOUNCE) | Phase III | PacCBev, then Bevacizumab maint. | Seems not superior | |
Reck et al. 2016 (KEYNOTE-024) | Phase III | 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 cycles
Patients in PRONOUNCE proceeded to pemetrexed maintenance after 4 cycles. Treatment in KEYNOTE-024 followed, after 4 to 6 cycles, by 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
- Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. link to original article does not contain specific protocol PubMed
- 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
- 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
- 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
- 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
- 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
Carboplatin, Pemetrexed, Bevacizumab
back to top |
PemCBev: Pemetrexed, Carboplatin, Bevacizumab
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Patel et al. 2013 (PointBreak) | Phase III | 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
Patients with complete response, partial response, or stable disease proceeded to bevacizumab & pemetrexed maintenance therapy.
References
- Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed
Carboplatin, Pemetrexed, Pembrolizumab
Source: Carboplatin, Pemetrexed, Pembrolizumab in advanced or metastatic non-small cell lung cancer
Regimen
Cisplatin & Docetaxel
back to top |
DC: Docetaxel & Cisplatin
Regimen #1, 75/75
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schiller et al. 2002 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Cisplatin & Gemcitabine | Seems not superior | ||
Cisplatin & Paclitaxel | Seems not superior | ||
Fossella et al. 2003 (TAX 326) | Phase III | Carboplatin & Docetaxel | Not reported |
Cisplatin & Vinorelbine | Seems to have superior OS | ||
Rossell et al. 2012 (EURTAC) | Phase III | 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 cycles
Regimen #2, 80/60
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mitsudomi et al. 2016 (WJTOG3405) | Phase III | Gefitinib | Inferior PFS |
Patients 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
References
- 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
- Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
- 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
- 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
Cisplatin & Etoposide
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cardenal et al. 1999 | Phase III | 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
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Klastersky et al. 1990 (EORTC 07861) | Phase III | Carboplatin & Etoposide | Might have superior ORR |
Chemotherapy
- Cisplatin (Platinol) 120 mg/m2 IV once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
3- to 4-week cycles
References
- Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J, et al. 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
- 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
Cisplatin & Gemcitabine
back to top |
GC: Gemcitabine & Cisplatin GP: Gemcitabine & Platinol (Cisplatin)
Regimen #1, 75/1000
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wu et al. 2014 (LUX-Lung 6) | Phase III | 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
Regimen #2, 75/1250 q3wk
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Rossell et al. 2012 (EURTAC) | Phase III | Erlotinib | Inferior PFS | |
Thatcher et al. 2015 (SQUIRE) | Phase III | Cisplatin, Gemcitabine, Necitumumab | Seems to have inferior OS | |
Wu et al. 2015 (ENSURE) | Phase III | Erlotinib | Inferior PFS | |
Reck et al. 2016 (KEYNOTE-024) | Phase III | Pembrolizumab | Inferior OS | Inferior HRQoL |
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 cycles
Patients in ENSURE received up to 4 cycles. Patients in KEYNOTE-024 received 4 to 6 cycles.
Regimen #3, 75/1250 q4wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wu et al. 2013 (FASTACT-2) | Phase III (E) | 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
Regimen #4, 80/1000
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ohe et al. 2006 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Cisplatin & Irinotecan | Seems not superior | ||
Cisplatin & Vinorelbine | 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 cycles
Regimen #5, 80/1250 ("GC80")
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pérol et al. 2012 | Non-randomized portion of RCT | ||
Ferry et al. 2017 (BTOG2) | Phase III | GC50 | Seems to have superior OS |
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
Treatment in Pérol et al. 2012 followed by erlotinib switch maintenance versus gemcitabine maintenance versus observation.
Regimen #6, 100/1000
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schiller et al. 2002 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Cisplatin & Docetaxel | Seems not superior | ||
Cisplatin & Paclitaxel | Superior PFS | ||
Scagliotti et al. 2008 | Phase III | Cisplatin & Pemetrexed | Seems non-inferior |
Note: the subgroup of Scagliotti et al. 2008 with adenocarcinoma seemed to have superior OS with this regimen.
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
Regimen #7, 100/1250
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cardenal et al. 1999 | Phase III | Cisplatin & Etoposide | Superior TTP |
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 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Cisplatin, Gemcitabine, Necitumumab
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Thatcher et al. 2015 (SQUIRE) | Phase III | Cisplatin & Gemcitabine | Seems to have superior OS |
Patients had stage IV squamous non-small-cell lung cancer
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, before gemcitabine
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
Patients who were free of disease progression proceeded to maintenance necitumumab.
References
- Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. link to original article contains verified protocol PubMed
Cisplatin & Irinotecan
back to top |
IP: Irinotecan and Platinol (Cisplatin)
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ohe et al. 2006 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Cisplatin & Gemcitabine | Seems not superior | ||
Cisplatin & Vinorelbine | 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 cycles
References
- 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
Cisplatin & Paclitaxel
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Schiller et al. 2002 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Cisplatin & Docetaxel | Seems not superior | ||
Cisplatin & Gemcitabine | Inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 2, after paclitaxel
- Paclitaxel (Taxol) 135 mg/m2 IV continuous infusion over 24 hours once on day 1
21-day cycles
References
- 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
Cisplatin & Pemetrexed
back to top |
Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Scagliotti et al. 2008 | Phase III | Cisplatin & Gemcitabine | Seems non-inferior | |
Paz-Ares et al. 2012 (PARAMOUNT) | Non-randomized portion of RCT | |||
Sequist et al. 2013 (LUX-Lung 3) | Phase III (C) | Afatinib | Inferior PFS | |
Solomon et al. 2014 (PROFILE 1014) | Phase III (C) | Crizotinib | Inferior PFS | |
Paz-Ares et al. 2015 (INSPIRE) | Phase III (C) | Cisplatin, Pemetrexed, Necitumumab | Seems not superior | |
Reck et al. 2016 (KEYNOTE-024) | Phase III (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Soria et al. 2017 (ASCEND-4) | Phase III (C) | Ceritinib | Inferior PFS |
Note: the subgroup of Scagliotti et al. 2008 with adenocarcinoma seemed to have inferior OS with this regimen. Patients in LUX-Lung 3 had activating mutations in EGFR. Patients in PROFILE 1014 had ALK-rearranged NSCLC. Patients in ASCEND-4 had ALK-rearranged NSCLC.
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
- PARAMOUNT: Placebo versus pemetrexed maintenance
- KEYNOTE-024: Patients without disease progression could optionally proceed to pemetrexed maintenance after 4 cycles
- ASCEND-4: Pemetrexed maintenance
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Cisplatin, Pemetrexed, Bevacizumab
back to top |
Regimen
Study | Evidence |
---|---|
Barlesi et al. 2013 (AVAPERL) | Phase II |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 2 hours once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1; administered over 90 minutes for the first dose, and if well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes
Supportive medications
- 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 BID on days -1, 1, 2 of each cycle
21-day cycle for 4 cycles
Patients with complete response (CR), partial response (PR), or stable disease (SD) were randomized to bevacizumab maintenance versus bevacizumab & pemetrexed maintenance.
References
- Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
Cisplatin & Vinorelbine
back to top |
NP: Navelbine (Vinorelbine) & Platinol (Cisplatin) CV: Cisplation & Vinorelbine
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ohe et al. 2006 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Cisplatin & Gemcitabine | Seems not superior | ||
Cisplatin & Irinotecan | Seems not superior | ||
Pirker et al. 2009 (FLEX) | Phase III | Cisplatin, Vinorelbine, Cetuximab | Seems to have inferior 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
21-day cycle for up to 6 cycles (FLEX) or until progression (Ohe et al. 2006)
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pujol et al. 2005 | Phase III | Docetaxel & Gemcitabine | Seems not superior |
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
Regimen #3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fossella et al. 2003 (TAX 326) | Phase III | Carboplatin & Docetaxel | Seems not superior |
Cisplatin & Docetaxel | Seems to have inferior OS |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 25 mg/m2 IV once on day 1
28-day cycles
References
- Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol. 2003 Aug 15;21(16):3016-24. Epub 2003 Jul 1. link to original article contains protocol PubMed
- 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
- Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains verified protocol PubMed
Cisplatin, Vinorelbine, Cetuximab
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pirker et al. 2009 (FLEX) | Phase III | 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 over 1 hour once per week
21-day cycle for up to 6 cycles
Cetuximab was then to continue until progression or intolerable toxicity.
References
- Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. link to original article contains protocol PubMed
Gefitinib monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mok et al. 2009 (IPASS) | Phase III | Carboplatin & Paclitaxel | Superior PFS |
Chemotherapy
- Gefitinib (Iressa) 250 mg PO once per day
Given until progression of objective disease or unacceptable toxicity
References
- 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
Gemcitabine & Vinorelbine
back to top |
VG: Vinorelbine & Gemcitabine
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Tan et al. 2005 (GLOB 2) | Phase III | 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
References
- 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
Nivolumab monotherapy
back to top |
Regimen
Study | Evidence | ORR | Comparator | Efficacy |
---|---|---|---|---|
Carbone et al. 2017 (CheckMate 026) | Phase III | 26% (95% CI 20 - 33) | Platinum doublet | Seems not superior |
Note: control arm patients in CheckMate 026 received investigator's choice of platinum doublet; the most commonly used regimen was carboplatin & paclitaxel.
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
References
- Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. link to original articlecontains verified protocol PubMed
Pembrolizumab monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Reck et al. 2016 (KEYNOTE-024) | Phase III | Carboplatin & Gemcitabine Carboplatin & Paclitaxel Carboplatin & Pemetrexed Cisplatin & Gemcitabine Cisplatin & Pemetrexed |
Superior OS | Superior HRQoL |
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. First-line therapy, PD-L1 expressed on at least 50% of tumor cells, no EGFR/ALK mutations. ORR was 45% (95% CI: 37-53).
Immunotherapy
- Pembrolizumab (Keytruda) 200 IV once on day 1
21-day cycles for up to 35 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
- 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
Advanced or metastatic disease, first-line, elderly or poor performance status
Best supportive care
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Elderly Lung Cancer Vinorelbine Italian Study Group, 1999 | Phase III | Vinorelbine | Seems to have inferior OS |
No active antineoplastic treatment. This trial did NOT include a placebo.
References
- The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999 Jan 6;91(1):66-72. link to original article contains verified protocol PubMed
Carboplatin & Paclitaxel
back to top |
TC: Taxol (Paclitaxel) and Carboplatin
Regimen #1, 6/200
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Lilenbaum et al. 2008 | Phase III | 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
Regimen #2, paclitaxel 3 out of 4 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Quoix et al. 2011 (IFCT-0501) | Phase III | Gemcitabine | Superior OS |
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
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
- 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
back to top |
Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Zukin et al. 2013 | Phase III | 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 BID 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
- 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
Gemcitabine monotherapy
back to top |
Regimen #1, 1150 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Quoix et al. 2011 (IFCT-0501) | Phase III | 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
Regimen #2, 1200 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gridelli et al. 2003 (MILES) | Phase III | Gemcitabine & Vinorelbine | Seems not superior |
Vinorelbine | Seems not superior |
Study involved only patients at least 70 years old
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 up to 6 cycles
References
- 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
- 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
Gemcitabine & Vinorelbine
back to top |
VG: Vinorelbine & Gemcitabine
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gridelli et al. 2003 (MILES) | Phase III | Gemcitabine | Seems not superior |
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
References
- 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
Pemetrexed monotherapy
back to top |
Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Zukin et al. 2013 | Phase III | Carboplatin & Pemetrexed | Inferior OS |
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
'21-day cycle for up to 4 cycles
References
- 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
Placebo
back to top |
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
- 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
back to top |
Regimen #1, 25 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Quoix et al. 2011 (IFCT-0501) | Phase III | Carboplatin & Paclitaxel | Inferior OS |
Study involved only patients 70 to 89 years old
Chemotherapy
- Vinorelbine (Navelbine) 25 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
Regimen #2, 30 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Elderly Lung Cancer Vinorelbine Italian Study Group, 1999 | Phase III | Best supportive care | Seems to have superior OS |
Gridelli et al. 2003 (MILES) | Phase III | Gemcitabine | Seems not superior |
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
- 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
- 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
- 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
Bevacizumab monotherapy
back to top |
Regimen #1
Study | Evidence |
---|---|
Sandler et al. 2006 (ECOG 4599) | Non-randomized portion of RCT |
Patel et al. 2013 (PointBreak) | Non-randomized portion of RCT |
Zinner et al. 2015 (PRONOUNCE) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2013 (AVAPERL (MO22089)) | Phase III | Bevacizumab & Pemetrexed maintenance | Inferior PFS |
Preceding treatment
Chemotherapy
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
References
- 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
- Subset 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
- 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
- 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
- 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
Erlotinib monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cappuzzo et al. 2010 (SATURN) | Phase III | Placebo | Superior PFS |
Pérol et al. 2012 | Phase III | Gemcitabine | Not reported |
Observation | Superior PFS | ||
Cicènas et al. 2016 (IUNO) | Phase III | See link | See link |
Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks.
Preceding treatment
- SATURN and IUNO: 4 cycles of platinum-doublet therapy
- Pérol et al. 2012: Cisplatin & Gemcitabine x 4
Chemotherapy
- Erlotinib (Tarceva) 150 mg PO once per day
Continued until progression or intolerance
References
- 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
- 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
- Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. link to original article contains verified protocol PubMed
Gemcitabine monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pérol et al. 2012 | Phase III | Erlotinib | Not reported |
Observation | Superior PFS |
Preceding treatment
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycles until progression
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
Ipilimumab monotherapy
back to top |
Regimen
Study | Evidence |
---|---|
Lynch et al. 2012 | Non-randomized portion of RCT |
Govindan et al. 2017 | 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
- 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
back to top |
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
- Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74. link to original article contains verified protocol PubMed
Observation
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Pérol et al. 2012 | Phase III | Erlotinib | Inferior PFS |
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
Pemetrexed monotherapy
back to top |
Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Paz-Ares et al. 2012 (PARAMOUNT) | Phase III | Placebo | Superior PFS |
Zinner et al. 2015 (PRONOUNCE) | Non-randomized portion of RCT | ||
Reck et al. 2016 (KEYNOTE-024) | Non-randomized portion of RCT | ||
Langer et al. 2016 (KEYNOTE-021) | Non-randomized portion of RCT |
Preceding treatment
- PARAMOUNT: Cisplatin & Pemetrexed x 4; maintenance therapy started 21 to 42 days after cycle 4 day 1 of induction chemotherapy
- PRONOUNCE: Carboplatin & Pemetrexed x 4
- KEYNOTE-024: Carboplatin & Paclitaxel or Carboplatin & Pemetrexed or Cisplatin & Pemetrexed
- KEYNOTE-021: Carboplatin & Pemetrexed x 4 versus Carboplatin, Pemetrexed, Pembrolizumab x 4
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Supportive medications
- Folic acid, Cyanocobalamin (Vitamin B12), prophylactic 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, given until progression of disease, unacceptable toxicity, or physician/patient choice
References
- 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
- 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
- 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
- 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
- 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
Pemetrexed & Bevacizumab
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Barlesi et al. 2013 (AVAPERL (MO22089)) | Phase III | 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 BID on days -1, 1, 2 of each cycle
21-day cycles
Regimen #2
Study | Evidence |
---|---|
Patel et al. 2013 (PointBreak) | Non-randomized portion of RCT |
Preceding treatment
- PemCBev 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
- 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
- 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
Pemetrexed & Pembrolizumab
Pembrolizumab & Pemetrexed maintenance therapy for advanced or metastatic non-small cell lung cancer
Placebo
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cappuzzo et al. 2010 (SATURN) | Phase III | Erlotinib | Inferior PFS |
Paz-Ares et al. 2012 (PARAMOUNT) | Phase III | Pemetrexed | Inferior PFS |
Giaccone et al. 2015 | Phase III | Belagenpumatucel-L | Seems not superior |
Cicènas et al. 2016 (IUNO) | Phase III | See link | See link |
No further antineoplastic treatment after first-line therapy. Note: while SATURN was technically a positive study for erlotinib, the median PFS gain was 1.2 weeks.
Preceding treatment
- SATURN and IUNO: 4 cycles of platinum-doublet therapy
- PARAMOUNT: Cisplatin & Pemetrexed x 4
- Giaccone et al. 2015: Platinum-based chemotherapy
Subsequent treatment
- IUNO: Erlotinib, after PD or intolerance
References
- 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
- 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
- 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
- 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
- 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 SD article contains verified protocol PubMed
Advanced or metastatic disease, subsequent lines of therapy
Afatinib monotherapy
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Soria et al. 2015 (LUX-Lung 8) | Phase III | Erlotinib | Superior OS |
Chemotherapy
- Afatinib (Gilotrif) 40 mg PO once per day, given 1 hour before eating food (Yang et al. 2012: "no food intake immediately before or after afatinib")
- In LUX-Lung 3, patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.
Given until progressive disease, unacceptable toxicity, or withdrawal of consent
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Miller et al. 2012 (LUX-Lung 1) | Phase III | 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
Given until progressive disease, unacceptable toxicity, or withdrawal of consent
References
- 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
- 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
- Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. Epub 2015 Jul 5. link to original article contains protocol PubMed
Amrubicin monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Yoshioka et al. 2017 | Phase III | 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fehrenbacher et al. 2016 (POPLAR) | Randomized Phase II | Docetaxel | Seems to have superior OS |
Rittmeyer et al. 2017 (OAK) | Phase III | Docetaxel | Superior OS |
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- 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
- 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 origial article PubMed
Cabozantinib monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Neal et al. 2016 (ECOG-ACRIN 1512) | Randomized Phase II | Cabozantinib & Erlotinib | Not reported |
Erlotinib | Superior PFS |
Chemotherapy
- Cabozantinib (Cometriq) 60 mg PO once per day
Continued until progression or intolerance
References
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Neal et al. 2016 (ECOG-ACRIN 1512) | Randomized Phase II | Cabozantinib | Not reported |
Erlotinib | Superior PFS |
Chemotherapy
- Cabozantinib (Cometriq) 40 mg PO once per day
- Erlotinib (Tarceva) 150 mg PO once per day
Continued until progression or intolerance
References
- 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
back to top |
Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Ardizzoni et al. 2012 (GOIRC 02-2006) | Randomized Phase II | Pemetrexed | Seems not superior |
Mok et al. 2016 (AURA3) | Phase III | 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 BID on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycle for 4 to 6 cycles, or until progressive disease, unacceptable toxicity, or patient refusal
Treatment in AURA3 followed by optional pemetrexed maintenance.
References
- 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
- 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
back to top |
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
- 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
- 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
back to top |
Example orders
Regimen #1, 35 mg/m2, 3 out of 4 weeks
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Chen et al. 2006 | Phase III | Docetaxel 40 mg/m2, 2 out of 3 wks | Seems not superior |
Docetaxel 75 mg/m2, every 3 wks | Seems not superior | ||
Garassino et al. 2013 (TAILOR) | Phase III (C) | Erlotinib | Seems to have superior OS |
Chemotherapy
- 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
Regimen #2, 60 mg/m2 q3wk, limited duration
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III (C) | Docetaxel & Vandetanib | Inferior PFS |
This is the PMDA-approved dose. While statistically inferior, the median PFS difference was only 0.8 months.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen #3, 60 mg/m2 q3wk, indefinite
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
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 |
This is the PMDA-approved dose, and the dose used for East Asian patients in REVEL.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV over at least 60 minutes once on day 1
21-day cycles
Regimen #4, 75 mg/m2 q3wk, limited duration
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III (C) | Docetaxel & Vandetanib | Inferior PFS |
While statistically inferior, the median PFS difference was only 0.8 months.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen #5, 75 mg/m2 q3wk, indefinite
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fossella et al. 2000 (TAX 320) | Phase III | Docetaxel 100 mg/m2 | Seems not superior |
Ifosfamide Vinorelbine |
Seems not superior | ||
Hanna et al. 2004 | Phase III | Pemetrexed | Inconclusive whether non-inferior |
Chen et al. 2006 | Phase III | Docetaxel 35 mg/m2, 3 out of 4 wks | Seems not superior |
Docetaxel 40 mg/m2, 2 out of 3 wks | Seems not superior | ||
Kim et al. 2008 (INTEREST) | Phase III (C) | Gefitinib | Seems non-inferior |
Fidias et al. 2008 | Phase III | Docetaxel consolidation | Might have inferior OS |
Shaw et al. 2013 | Phase III (C) | Crizotinib | Inferior PFS |
Garassino et al. 2013 (TAILOR) | Phase III (C) | Erlotinib | Seems to have superior OS |
Reck et al. 2014 (LUME-Lung 1) | Phase III (C) | Docetaxel & Nintedanib | Inferior PFS |
Garon et al. 2014 (REVEL) | Phase III (C) | Docetaxel & Ramucirumab | Seems to have inferior OS |
Blumenschein et al. 2015 | Randomized Phase II (C) | Trametinib | Seems not superior |
Brahmer et al. 2015 (CheckMate 017) | Phase III (C) | Nivolumab | Inferior OS |
Borghaei et al. 2015 (CheckMate 057) | Phase III (C) | Nivolumab | Inferior OS |
Herbst et al. 2015 (KEYNOTE-010) | Phase II/III (C) | Pembrolizumab | Inferior OS |
Fehrenbacher et al. 2016 (POPLAR) | Randomized Phase II (C) | Atezolizumab | Seems to have inferior OS |
Rittmeyer et al. 2016 (OAK) | Phase III (C) | Atezolizumab | Inferior OS |
Jänne et al. 2017 (SELECT-1) | Phase III (C) | Docetaxel & Selumetinib | Seems not superior |
Shaw et al. 2017 (ASCEND-5) | Phase III (C) | Ceritinib | Inferior PFS |
Patients in Blumenschein et al. 2015 and SELECT-1 had KRAS-mutated NSCLC. Patients in ASCEND-5 had ALK-rearranged NSCLC progressed after crizotinib.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
Supportive medications
- Per Hanna et al. 2004: Dexamethasone (Decadron) 8 mg PO BID the day before, the day of, and the day after docetaxel
- Per Chem et al. 2006: Dexamethasone (Decadron) 8 mg PO once 12 hours before docetaxel, 10 mg IV once 30 minutes before docetaxel, and 8 mg PO 12 hours after docetaxel
21-day cycles
References
- 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. 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. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original articlecontains verified protocol PubMed
- Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 origial 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
- 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
- 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
Docetaxel & Ramucirumab
back to top |
Regimen #1, 60 mg/m2 docetaxel
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Garon et al. 2014 (REVEL) | Phase III | Docetaxel | Seems to have superior OS |
This is the PMDA-approved dose and the dose recommended for East Asians.
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
Regimen #2, 75 mg/m2 docetaxel
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Garon et al. 2014 (REVEL) | Phase III | Docetaxel | Seems to have superior OS |
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
- 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
back to top |
Regimen #1, 60 mg/m2 docetaxel
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III | 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 (*)
Regimen #2, 75 mg/m2 docetaxel
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Herbst et al. 2010 (ZODIAC) | Phase III | 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 (*)
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
Erlotinib monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shepherd et al. 2005 (NCIC CTG BR.21) | Phase III | Placebo | Superior OS |
Ramalingam et al. 2012 | Randomized Phase II | Dacomitinib | Seems to have inferior PFS |
Garassino et al. 2013 (TAILOR) | Phase III | Docetaxel | Seems to have inferior OS |
Ramalingam et al. 2014 (ARCHER 1009) | Phase III | Dacomitinib | Seems not superior |
Scagliotti et al. 2015 | Phase III | Erlotinib & Figitumumab | Seems not superior |
Soria et al. 2015 (LUX-Lung 8) | Phase III | Afatinib | Inferior OS |
Urata et al. 2016 (WJOG 5108L) | Phase III | Gefitinib | Inconclusive whether non-inferior |
Smit et al. 2016 (CurrentS) | Phase III | High-dose Erlotinib | Seems not superior |
Cicènas et al. 2016 (IUNO) | Phase III | See link | See link |
Neal et al. 2016 (ECOG-ACRIN 1512) | Randomized Phase II | Cabozantinib | Inferior PFS |
Cabozantinib & Erlotinib | Inferior PFS | ||
Spigel et al. 2016 (METLung) | Phase III | Erlotinib & Onartuzumab | Might have superior OS |
Preceding treatment
- IUNO: Placebo
Chemotherapy
- Erlotinib (Tarceva) 150 mg PO once per day
Continued until progression or intolerance
References
- 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
- Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012 Sep 20;30(27):3337-44. link to original article link to PMC article PubMed
- 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
- Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15.link to original article PubMed
- Scagliotti GV, Bondarenko I, Blackhall F, Barlesi F, Hsia TC, Jassem J, Milanowski J, Popat S, Sanchez-Torres JM, Novello S, Benner RJ, Green S, Molpus K, Soria JC, Shepherd FA. Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer. Ann Oncol. 2015 Mar;26(3):497-504. Epub 2014 Nov 13. link to original article PubMed
- 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
- 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
- Smit EF, Wu YL, Gervais R, Zhou C, Felip E, Feng J, Guclu SZ, Hoiczyk M, Dorokhova E, Freudensprung U, Grange S, Perez-Moreno PD, Mitchell L, Reck M. A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS). Lung Cancer. 2016 Sep;99:94-101. Epub 2016 Jun 27. link to SD article PubMed
- 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 SD article contains verified protocol PubMed
- 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
- Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol. 2017 Feb;35(4):412-420. Epub 2016 Dec 12. link to original article contains verified protocol PubMed
Gefitinib monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kris et al. 2003 (IDEAL2) | Randomized Phase II | Gefitinib 500 mg/day | Seems not superior |
Kim et al. 2008 (INTEREST) | Phase III | Docetaxel | Seems non-inferior |
Han et al. 2011 | Randomized Phase II | Gefitinib & Simvastatin | Seems not superior |
Shi et al. 2013 (ICOGEN) | Phase III | Icotinib | Seems non-inferior |
Urata et al. 2016 (WJOG 5108L) | Phase III | Erlotinib | Inconclusive whether non-inferior |
Chemotherapy
- Gefitinib (Iressa) 250 mg PO once per day
Given until progression of objective disease or unacceptable toxicity
References
- 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
- 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
- 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
- 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
- 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
Nivolumab monotherapy
back to top |
Regimen
Study | Evidence | ORR | Comparator | Efficacy |
---|---|---|---|---|
Rizvi et al. 2015 (CheckMate 063) | Phase II | 14% (95% CI 9 - 22) | ||
Brahmer et al. 2015 (CheckMate 017) | Phase III | 20% (95% CI 14 - 28) | Docetaxel | Superior OS |
Borghaei et al. 2015 (CheckMate 057) | Phase III | 19% (95% CI 15 - 24) | Docetaxel | Superior OS |
Patients in CheckMate 017 had squamous histology. Patients in CheckMate 057 had non-squamous histology.
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
References
- 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
- 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
- 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
back to top |
Regimen
Study | Evidence | ORR | Comparator | Efficacy | Pt Population |
---|---|---|---|---|---|
Herbst et al. 2015 (KEYNOTE-010) | Phase II/III | 2 mg/kg: 18% (95% CI 14 - 23)
10 mg/kg: 19% (95% CI 15 - 23) |
Docetaxel | Superior OS | Chemo exposed |
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
- 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
back to top |
Example orders
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hanna et al. 2004 | Phase III | Docetaxel | Inconclusive whether non-inferior |
Ardizzoni et al. 2012 (GOIRC 02-2006) | Randomized Phase II | Carboplatin & Pemetrexed | Seems not superior |
Shaw et al. 2013 | Phase III (C) | Crizotinib | Inferior PFS |
Kim et al. 2013 | Phase III (C) | Pemetrexed & Cetuximab | Seems not superior |
Hanna et al. 2016 (LUME-Lung 2) | Phase III (C) | Nintedanib & Pemetrexed | Seems to have inferior PFS |
Shaw et al. 2017 (ASCEND-5) | Phase III (C) | Ceritinib | Inferior PFS |
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 BID on the day before, the day of, and day after each dose of pemetrexed
- Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
- Hanna et al. 2004 used folic acid 1 mg PO once per day
- Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy
21-day cycles
Ardizzoni et al. 2012 treated patients for up to 4 cycles or until progressive disease, unacceptable toxicity, or patient refusal.
References
- Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, 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
- 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
- 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
- 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
- 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
- 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
Placebo
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shepherd et al. 2005 (NCIC CTG BR.21) | Phase III | Erlotinib | Inferior OS |
Lee et al. 2012 (ZEPHYR) | Phase III | Vandetanib | Seems not superior |
Miller et al. 2012 (LUX-Lung 1) | Phase III | Afatinib | Inferior PFS |
Ellis et al. 2014 (NCIC CTG BR.26) | Phase III | Dacomitinib | Seems not superior |
Paz-Ares et al. 2015 (MISSION) | Phase III | 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
- 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
- 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
- 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
- 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
- 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
Sorafenib monotherapy
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Paz-Ares et al. 2015 (MISSION) | Phase III | 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 BID
Continued until progression
References
- 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
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fossella et al. 2000 (TAX 320) | Phase III | Docetaxel 100 mg/m2 | Seems not superior |
Docetaxel 75 mg/m2 | Seems not superior |
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV over 5 to 10 minutes once per week
Supportive medications
- 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 (Kytril) (dose/schedule/route not specified) prn nausea
Continued until progression
References
- 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. 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. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209. link to original articlecontains verified protocol PubMed