Non-small cell lung cancer, nonsquamous
Section editor transclusions Note: these are regimens tested in histology-specific populations, please see the main NSCLC page for other regimens.
61 regimens on this page
93 variants on this page
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Adjuvant therapy
Cisplatin & Pemetrexed
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Kenmotsu et al. 2020 (JIPANG) | 2012-2016 | Phase 3 (E-switch-ic) | CVb | Did not meet primary endpoint of RFS Median RFS: 38.9 vs 37.3 mo (HR 0.98, 95% CI 0.81-1.20) |
Fewer grade 3-4 toxicities |
Preceding treatment
- Complete surgical resection
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
References
- JIPANG: Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T, Goto K, Daga H, Ikeda N, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Tsuboi M. Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jul 1;38(19):2187-2196. Epub 2020 May 14. link to original article contains verified protocol PubMed UMIN000006737
Cisplatin & Vinorelbine
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CVb: Cisplatin & Vinorelbine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Kenmotsu et al. 2020 (JIPANG) | 2012-2016 | Phase 3 (C) | Cisplatin & Pemetrexed | Did not meet primary endpoint of RFS | More grade 3-4 toxicities |
Preceding treatment
- Complete surgical resection
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 4 cycles
References
- JIPANG: Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T, Goto K, Daga H, Ikeda N, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Tsuboi M. Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jul 1;38(19):2187-2196. Epub 2020 May 14. link to original article contains verified protocol PubMed UMIN000006737
Tegafur & uracil monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kato et al. 2004 | 1994-1997 | Phase 3 (E-esc) | Observation | Seems to have superior OS OS60: 88% vs 85% (HR 0.71, 95% CI 0.52-0.98) |
Preceding treatment
Chemotherapy
- Tegafur and uracil (UFT) 250 mg PO once per day
2-year course
References
- Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article contains protocol PubMed
Definitive therapy for locally advanced disease
Cisplatin, Etoposide, RT
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EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Senan et al. 2016 (PROCLAIM) | 2008-2012 | Phase 3 (C) | Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation | Did not meet primary endpoint of OS |
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
Radiotherapy
- Concurrent radiation therapy, 1.8 to 2 Gy fractions x 30 to 33 fractions (total dose: 60 to 66 Gy)
6- to 6.5-week course
Subsequent treatment
- Investigator's choice of: Carboplatin & Paclitaxel or Cisplatin & Etoposide or Cisplatin & Vinorelbine consolidation
References
- PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
- Dataset: Project Data Sphere
Consolidation or maintenance after definitive therapy for inoperable disease
Carboplatin & Paclitaxel (CP)
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Senan et al. 2016 (PROCLAIM) | 2008-2012 | Non-randomized portion of RCT |
Preceding 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
References
- PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
- Dataset: Project Data Sphere
Cisplatin & Etoposide (EP)
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Regimen
Study | Evidence |
---|---|
Senan et al. 2016 (PROCLAIM) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 8
- Etoposide (Vepesid) 50 mg/m2 IV once per day on days 1 to 5
28-day cycle for 2 cycles
References
- PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
- Dataset: Project Data Sphere
Cisplatin & Vinorelbine
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Regimen
Study | Evidence |
---|---|
Senan et al. 2016 (PROCLAIM) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Cisplatin (Platinol) (dose not specified) mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycle for 2 cycles
References
- PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
- Dataset: Project Data Sphere
Advanced or metastatic disease, first-line
ABCP
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ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel
Regimen variant #1, 1200/15/6/175 x 4
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (E-RT-esc) | 1. ACP | Not reported |
2. BCP | Seems to have superior OS Median OS: 19.2 vs 14.7 mo (HR 0.78, 95% CI 0.64-0.96) |
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 1200/15/6/175 x 6
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (E-RT-esc) | 1. ACP | Not reported |
2. BCP | Seems to have superior OS Median OS: 19.2 vs 14.7 mo (HR 0.78, 95% CI 0.64-0.96) |
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
Regimen variant #3, 1200/15/6/200 x 4
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (E-RT-esc) | 1. ACP | Not reported |
2. BCP | Seems to have superior OS Median OS: 19.2 vs 14.7 mo (HR 0.78, 95% CI 0.64-0.96) |
Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #4, 1200/15/6/200 x 6
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (E-RT-esc) | 1. ACP | Not reported |
2. BCP | Seems to have superior OS Median OS: 19.2 vs 14.7 mo (HR 0.78, 95% CI 0.64-0.96) |
Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
References
- IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed NCT02366143
Atezolizumab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Herbst et al. 2020 (IMpower110) | 2015-2018 | Phase 3 (E-switch-ooc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior OS1 Median OS: 20.2 vs 13.1 mo (HR 0.59, 95% CI 0.40-0.89) |
1Reported efficacy is for TC3/IC3 only i.e., PD-L1 TC>50%.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains verified protocol PubMed NCT02409342
Carboplatin & Docetaxel
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DCb: Docetaxel & Carboplatin
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Rodrigues-Pereira et al. 2011 (H3E-CR-S380) | 2007-2009 | Phase 3 (C) | Carboplatin & Pemetrexed | Did not meet primary endpoint of OS | Inferior survival without treatment-emergent grade 3/4 toxicity |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
References
- H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed NCT00520676
Carboplatin & Gemcitabine (GCb)
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CG: Carboplatin & Gemcitabine
Regimen
Study | Evidence |
---|---|
Jian et al. 2017 | Non-randomized portion of RCT |
Note: the manuscript does not specify whether gemcitabine is given more than once per cycle.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once on day 1
28-day cycle for 2 cycles
Subsequent treatment
- Continued CG x 4 versus CG & Gefitinib
References
- Jian H, Li W, Ma Z, Huang J, Feng J, Song Y, Gao B, Zhu H, Tao M, Bai C, Ma S, Pan H, Qin S, Hua D, Yu Y, Lu S. Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status. Sci Rep. 2017 Aug 16;7(1):8483. link to original article link to PMC article contains verified protocol PubMed
Carboplatin, nab-Paclitaxel, Atezolizumab
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
West et al. 2019 (IMpower130) | 2015-2017 | Phase 3 (E-RT-esc) | Carboplatin & nab-Paclitaxel | Seems to have superior OS Median OS: 18.6 vs 13.9 mo (HR 0.79, 95% CI 0.64-0.98) |
Note: the FDA-recommended dose is specific to the atezolizumab dosing.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycle for 4 to 6 cycles
Subsequent treatment
- Atezolizumab maintenance
References
- IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article contains protocol PubMed NCT02367781
Carboplatin & Paclitaxel (CP)
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TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel
Regimen variant #1, 6/175
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zhou et al. 2015 (BEYOND) | 2011-2012 | Phase 3 (C) | Carboplatin, Paclitaxel, Bevacizumab | Seems to have inferior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive medications
- Corticosteroids could be used as premedication for Paclitaxel (Taxol) infusion
21-day cycle for up to 6 cycles
Regimen variant #2, 6/200
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sandler et al. 2006 (ECOG E4599) | 2001-2004 | Phase 3 (C) | PacCBev | Inferior OS |
Mok et al. 2009 (IPASS) | 2006-2007 | Phase 3 (C) | Gefitinib | Inferior PFS |
Scagliotti et al. 2012 (MONET1) | 2007-2010 | Phase 3 (C) | TC & Motesanib | Did not meet primary endpoint of OS |
Kubota et al. 2017 (MONET-A) | 2012-2015 | Phase 3 (C) | TC & Motesanib | Might have inferior PFS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for 3 or more cycles
References
- ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed NCT00021060
- Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
- IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed NCT00322452
- Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
- Dataset: Project Data Sphere
- MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article contains protocol PubMed NCT00460317
- BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed NCT01364012
- MONET-A: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. Epub 2017 Sep 13. link to original article contains verified protocol PubMed JapicCTI-121887
- M14-359: NCT02264990
Carboplatin & Paclitaxel (CP) & Bevacizumab
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PacCBev: Paclitaxel, Carboplatin, Bevacizumab
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel
CbTB: Carboplatin, Taxol (Paclitaxel), Bevacizumab
Regimen variant #1, 6/175/15 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (C) | 1. ACP | Not reported |
2. ABCP | Seems to have inferior OS |
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 6/175/15 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (C) | 1. ACP | Not reported |
2. ABCP | Seems to have inferior OS |
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
Regimen variant #3, 6/200/15 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Patel et al. 2013 (PointBreak) | 2008-2012 | Phase 3 (C) | PemCBev, then PemBev maint. | Did not meet primary endpoint of OS |
Zinner et al. 2015 (PRONOUNCE) | 2009-2013 | Phase 3 (C) | See link | See link |
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (C) | 1. ACP | Not reported |
2. ABCP | Seems to have inferior OS |
Note: the total number of cycles given in IMpower150 was determined prior to randomization.
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications per paclitaxel label
- Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #4, 6/200/15 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sandler et al. 2006 (ECOG E4599) | 2001-2004 | Phase 3 (E-RT-esc) | CP | Superior OS Median OS: 12.3 vs 10.3 mo (HR 0.79, 95% CI 0.67-0.92) |
Zhou et al. 2015 (BEYOND) | 2011-2012 | Phase 3 (E-esc) | Carboplatin & Paclitaxel | Superior OS Median OS: 24.3 vs 17.7 mo (HR 0.68, 95% CI 0.50-0.93) |
Socinski et al. 2018 (IMpower150) | 2015-2016 | Phase 3 (C) | 1. ACP | Not reported |
2. ABCP | Seems to have inferior OS | |||
Sugawara et al. 2021 (TASUKI-52) | 2017-2019 | Phase 3 (C) | CP, Bevacizumab, Nivolumab | Inferior PFS |
Note: the total number of cycles given in IMpower150 was determined prior to randomization.
Biomarker eligibility criteria
- SWOG S0819: EGFR FISH positive
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 6: AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
- Paclitaxel (Taxol) as follows:
- Cycles 1 to 6: 200 mg/m2 IV over 3 hours once on day 1, given first
Targeted therapy
- Bevacizumab (Avastin) as follows:
- Cycles 1 to 6: 15 mg/kg IV once on day 1, given third, starting 60 minutes after the completion of carboplatin
- Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later
- Cycle 7 onwards: 15 mg/kg IV once on day 1
- Cycles 1 to 6: 15 mg/kg IV once on day 1, given third, starting 60 minutes after the completion of carboplatin
21-day cycles
References
- ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed NCT00021060
- Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains verified protocol PubMed
- PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
- Dataset: Project Data Sphere
- PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
- BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed NCT01364012
- IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed NCT02366143
- TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article contains verified protocol PubMed NCT03117049
Carboplatin & Paclitaxel (CP), Bevacizumab, Nivolumab
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Regimen variant #4, 6/200/15 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sugawara et al. 2021 (TASUKI-52) | 2017-2019 | Phase 3 (E-esc) | CP & Bevacizumab | Superior PFS Median PFS: 12.1 vs 8.1 mo (HR 0.56, 96.4% CI 0.43-0.71) |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 6: AUC 6 once on day 1
- Paclitaxel (Taxol) as follows:
- Cycles 1 to 6: 200 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Immunotherapy
- Nivolumab (Opdivo) 360 mg IV once on day 1
21-day cycles
References
- TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article contains verified protocol PubMed NCT03117049
Carboplatin & Pemetrexed
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CP: Carboplatin & Pemetrexed
Carbo-Pem: Carboplatin & Pemetrexed
Example orders
Regimen variant #1, 5/500 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Langer et al. 2016 (KEYNOTE-021) | 2014-2016 | Randomized Phase II (C) | See link | See link |
Zhou et al. 2020 (CameL) | 2017-2018 | Phase 3 (C) | Carboplatin, Pemetrexed, Camrelizumab | Inferior PFS |
Paz-Ares et al. 2021 (CheckMate 9LA) | 2017-2019 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab 2. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab |
Inferior OS |
Note: this was the lower bound of cycles in CameL.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
- Folic acid (Folate) 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
Subsequent treatment
- Optional Pemetrexed maintenance
Regimen variant #2, 5/500 x 4, then maintenance pem
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gandhi et al. 2018 (KEYNOTE-189) | 2016-2017 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Pembrolizumab 2. Cisplatin, Pemetrexed, Pembrolizumab |
Inferior OS |
Yang et al. 2020 (CIBI308C302) | 2018-2019 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Sintilimab 2. Cisplatin, Pemetrexed, Sintilimab |
Inferior PFS |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
- Folic acid (Folate) 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 cycles
Regimen variant #2, 5/500 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Rodrigues-Pereira et al. 2011 (H3E-CR-S380) | 2007-2009 | Phase 3 (E-switch-ic) | Carboplatin & Docetaxel | Did not meet primary endpoint of OS | Superior survival without treatment-emergent grade 3/4 toxicity |
Mok et al. 2019 (KEYNOTE-042) | 2014-2017 | Phase 3 (C) | Pembrolizumab | Inferior OS | |
Zhou et al. 2020 (CameL) | 2017-2018 | Phase 3 (C) | Carboplatin, Pemetrexed, Camrelizumab | Inferior PFS |
Note: Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC. This was the upper bound of cycles in CameL.
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
- Folic acid (Folate) 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 6 cycles
Subsequent treatment
- Optional pemetrexed maintenance
Regimen variant #3, 6/500 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zinner et al. 2015 (PRONOUNCE) | 2009-2013 | Phase 3 (E-switch-ooc) | See link | See link |
Paz-Ares et al. 2021 (CheckMate 9LA) | 2017-2019 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab 2. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab |
Inferior OS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV over 15 to 60 minutes once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (Ardizzoni et al. 2012 contained more details):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
- Folic acid (Folate) 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
Subsequent treatment
- Pemetrexed maintenance (optional in CheckMate 9LA)
Regimen variant #4, 6/500 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mok et al. 2019 (KEYNOTE-042) | 2014-2017 | Phase 3 (C) | Pembrolizumab | Inferior OS |
Herbst et al. 2020 (IMpower110) | 2015-2018 | Phase 3 (C) | Atezolizumab | Inferior OS1 |
1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.
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 (Folate) 1 mg PO once per day
21-day cycle for up to 6 cycles
Subsequent treatment
- KEYNOTE-042: Optional pemetrexed maintenance
- IMpower110: pemetrexed maintenance
Regimen variant #5, 6/500 indefinitely
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Edelman et al. 2017 (CALGB 30801) | 2010-2013 | Phase 3 (C) | CP & Celecoxib | Did not meet primary endpoint of PFS |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
References
- H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed NCT00520676
- PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
- KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed NCT02039674
- CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains verified protocol PubMed NCT01041781
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
- Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
- Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
- KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed NCT02220894
- MYSTIC: Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. link to original article contains verified protocol in supplement link to PMC article PubMed NCT02453282
- IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains verified protocol PubMed NCT02409342
- CIBI308C302: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article PubMed NCT03607539
- IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article PubMed NCT02657434
- CameL: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Zhang T, Shi W, Zou J; CameL Study Group. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2021 Mar;9(3):305-314. Epub 2020 Dec 18. link to original article contains protocol PubMed NCT03134872
- CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains verified protocol PubMed NCT03215706
- RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article PubMed NCT03663205
- M14-359: NCT02264990
Carboplatin, Pemetrexed, Atezolizumab
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APP: Atezolizumab, Platinum (Carboplatin), Pemetrexed
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nishio et al. 2020 (IMpower132) | 2016-2017 | Phase 3 (E-esc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior PFS1 Median PFS: 8 mo vs 5 mo (HR 0.60, 95% CI 0.49-0.72) |
1IMpower132 did not meet the co-primary endpoint of OS
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4 up to 6: AUC 6 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article contains verified protocol PubMed NCT02657434
- APPLE: JapicCTI-194565
Carboplatin, Pemetrexed, Bevacizumab
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PemCBev: Pemetrexed, Carboplatin, Bevacizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Patel et al. 2013 (PointBreak) | 2008-2012 | Phase 3 (E-switch-ic) | PacCBev, then Maintenance Bev | Did not meet primary endpoint of OS |
Seto et al. 2019 (COMPASS) | 2010-2015 | Non-randomized portion of RCT |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications, Folic acid (Folate), and vitamin supplementation per pemetrexed label
- Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycle for 4 cycles
Subsequent treatment
- PointBreak, patients without progression: Pemetrexed & Bevacizumab maintenance
- COMPASS, patients without progression: Bevacizumab versus Pemetrexed & Bevacizumab maintenance
References
- PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
- Dataset: Project Data Sphere
- COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article contains protocol PubMed UMIN000004194
Carboplatin, Pemetrexed, Ipilimumab, Nivolumab
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Regimen variant #1, AUC 5
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al. 2021 (CheckMate 9LA) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior OS Median OS: 14.1 vs 10.7 mo (HR 0.69, 96.71% CI 0.55-0.87) |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 & 2: AUC 5 IV once on day 1
- Pemetrexed (Alimta) as follows:
- Cycles 1 & 2: 500 mg/m2 IV once on day 1
Immunotherapy
- Ipilimumab (Yervoy) as follows:
- Odd cycles: 1 mg/kg IV once on day 1
- Nivolumab (Opdivo) 360 mg IV once on day 1, given first
21-day cycles
Regimen variant #2, AUC 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al. 2021 (CheckMate 9LA) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior OS Median OS: 14.1 vs 10.7 mo (HR 0.69, 96.71% CI 0.55-0.87) |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 & 2: AUC 6 IV once on day 1
- Pemetrexed (Alimta) as follows:
- Cycles 1 & 2: 500 mg/m2 IV once on day 1
Immunotherapy
- Ipilimumab (Yervoy) as follows:
- Odd cycles: 1 mg/kg IV once on day 1
- Nivolumab (Opdivo) 360 mg IV once on day 1, given first
21-day cycles
References
- CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains verified protocol PubMed NCT03215706
Carboplatin, Pemetrexed, Pembrolizumab
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Langer et al. 2016 (KEYNOTE-021) | 2014-2016 | Randomized Phase II (E-esc) | See link | See link |
Gandhi et al. 2018 (KEYNOTE-189) | 2016-2017 | Phase III (E-esc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior OS1 Median OS: 22 vs 10.6 mo (HR 0.56, 95% CI 0.46-0.69) |
1Reported efficacy is based on the 2021 update.
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 5 IV over 15 to 60 minutes once on day 1, given third
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given second
Immunotherapy
- Pembrolizumab (Keytruda) as follows:
- Cycles 1 to 35: 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy
Supportive medications
- "Premedication with folic acid, vitamin B12, and corticosteroids was administered according to local guidelines."
21-day cycles
References
- KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary appendix PubMed NCT02039674
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
- Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
- Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
- KEYLYNK-006: NCT03976323
Cisplatin & Docetaxel (DC)
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DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Park et al. 2017 (TRAIL) | 2011-2013 | Phase 3 (C) | Cisplatin & Pemetrexed | Inconclusive whether non-inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
References
- TRAIL: Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains protocol PubMed NCT01282151
Cisplatin & Gemcitabine (GC)
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GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)
Regimen variant #1, 75/1250
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al. 2012 (NExUS) | 2007-2009 | Phase 3 (C) | GC & Sorafenib | Did not meet primary endpoint of OS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 30 minutes once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycle for up to 6 cycles
Regimen variant #2, 80/1250 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Reck et al. 2009 (AVAil) | 2005-2006 | Phase 3 (C) | 1. GC & Bevacizumab; low-dose | Inferior PFS |
2. GC & Bevacizumab; standard-dose | Seems to have inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
Regimen variant #3, 80/1250 x 9
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Han et al. 2012 (First-SIGNAL) | 2005-2007 | Phase 3 (C) | Gefitinib | Did not meet primary endpoint of 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 up to 9 cycles
References
- AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains protocol PubMed NCT00806923
- Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
- First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed NCT00455936
- NExUS: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non–small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. Epub 2012 Jul 30. link to original article contains protocol PubMed NCT00449033
- Dataset: Project Data Sphere
Cisplatin & Gemcitabine (GC) & Bevacizumab
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Regimen variant #1, low-dose bev
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Reck et al. 2009 (AVAil) | 2005-2006 | Phase 3 (E-RT-esc) | Cisplatin & Gemcitabine | Superior PFS1 (HR 0.75, 95% CI 0.64-.87) |
1Reported efficacy is based on the 2010 update.
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) as follows:
- Cycles 1 to 6: 1250 mg/m2 IV once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, standard-dose bev
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Reck et al. 2009 (AVAil) | 2005-2006 | Phase 3 (E-RT-esc) | Cisplatin & Gemcitabine | Seems to have superior PFS1 (HR 0.85, 95% CI 0.73-1.00) |
1Reported efficacy is based on the 2010 update.
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 80 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) as follows:
- Cycles 1 to 6: 1250 mg/m2 IV once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed NCT00806923
- Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
Cisplatin & Pemetrexed
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Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed
Regimen variant #1, 70/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Park et al. 2017 (TRAIL) | 2011-2013 | Phase 3 (E-switch-ic) | Cisplatin & Docetaxel | Inconclusive whether non-inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycle for up to 4 cycles
Regimen variant #2, 75/500
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Paz-Ares et al. 2012 (PARAMOUNT) | 2008-2010 | Non-randomized portion of RCT | |||
Wu et al. 2014 (JMIL) | 2009-2010 | Phase 3 (C) | GC | Did not meet primary endpoint of OS | |
Paz-Ares et al. 2015 (INSPIRE) | 2009-2011 | Phase 3 (C) | Pem-Cis & Necitumumab | Did not meet primary endpoint of OS | |
Reck et al. 2016 (KEYNOTE-024) | 2014-2015 | Phase 3 (C) | Pembrolizumab | Inferior OS | Inferior HRQoL |
Rizvi et al. 2020 (MYSTIC) | 2015-2016 | Phase 3 (C) | Durvalumab | Might have inferior OS | |
Durvalumab & Tremelimumab | Did not meet primary endpoints of PFS/OS | ||||
Herbst et al. 2020 (IMpower110) | 2015-2018 | Phase 3 (C) | Atezolizumab | Inferior OS1 | |
Paz-Ares et al. 2021 (CheckMate 9LA) | 2017-2019 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab 2. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab |
Inferior OS |
1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.
Note: Selection of platinum agent in IMpower110, KEYNOTE-189, and MYSTIC was per investigator choice.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (as described in JMDB):
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
- Folic acid (Folate) 1 mg PO once per day
- In Sequist et al. 2013: Patients "received Folic acid (Folate), 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
- IMpower110: Pemetrexed maintenance
- KEYNOTE-024, MYSTIC, CheckMate 9LA: Optional Pemetrexed maintenance
Regimen variant #3, 75/500 x 4, then maintenance pem
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gandhi et al. 2018 (KEYNOTE-189) | 2016-2017 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Pembrolizumab 2. Cisplatin, Pemetrexed, Pembrolizumab |
Inferior OS |
Yang et al. 2020 (CIBI308C302) | 2018-2019 | Phase 3 (C) | 1. Carboplatin, Pemetrexed, Sintilimab 2. Cisplatin, Pemetrexed, Sintilimab |
Inferior PFS |
Note: Selection of platinum agent in KEYNOTE-189 was per investigator choice.
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 4: 75 mg/m2 IV once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Supportive medications
- (as described in JMDB):
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, first dose prior to Pemetrexed (Alimta)
- Folic acid (Folate) 1 mg PO once per day
- In Sequist et al. 2013: Patients "received Folic acid (Folate), vitamin B12, and dexamethasone, as per package recommendations for Pemetrexed (Alimta)."
21-day cycles
References
- PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed NCT00789373
- HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
- 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
- JMIL: Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M. Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2014 Sep;85(3):401-7. Epub 2014 Jul 17. link to original article PubMed NCT01005680
- INSPIRE: Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA; INSPIRE investigators. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015 Mar;16(3):328-37. Epub 2015 Feb 18. link to original article PubMed NCT00982111
- KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed NCT02142738
- 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
- Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
- TRAIL: Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains protocol PubMed NCT01282151
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
- Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
- Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
- MYSTIC: Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. link to original article contains verified protocol in supplement link to PMC article PubMed NCT02453282
- IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains verified protocol PubMed NCT02409342
- CIBI308C302: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article PubMed NCT03607539
- IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article PubMed NCT02657434
- CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains verified protocol PubMed NCT03215706
- RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article PubMed NCT03663205
- M14-359: NCT02264990
Cisplatin, Pemetrexed, Atezolizumab
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APP: Atezolizumab, Platinum (Cisplatin), Pemetrexed
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nishio et al. 2020 (IMpower132) | 2016-2017 | Phase 3 (E-esc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior PFS1 Median PFS: 8 mo vs 5 mo (HR 0.60, 95% CI 0.49-0.72) |
1IMpower132 did not meet the co-primary endpoint of OS
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 4 up to 6: 75 mg/m2 IV once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article contains verified protocol PubMed NCT02657434
Cisplatin, Pemetrexed, Bevacizumab
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Regimen
Study | Evidence |
---|---|
Barlesi et al. 2013 (AVAPERL) | Non-randomized portion of RCT |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 2 hours once on day 1
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 7.5 mg/kg IV over 90 minutes once on day 1
- If well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes
Supportive medications
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 3 cycles (i.e. every 9 weeks), given throughout therapy
- Folic acid (Folate) 350 to 1000 mcg PO once per day, given throughout therapy
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
21-day cycle for 4 cycles
Subsequent treatment
- Patients with complete response (CR), partial response (PR), or stable disease (SD): Bevacizumab versus Pemetrexed & Bevacizumab maintenance
References
- AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed NCT00961415
- Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
Cisplatin, Pemetrexed, Ipilimumab, Nivolumab
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al. 2021 (CheckMate 9LA) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior OS Median OS: 14.1 vs 10.7 mo (HR 0.69, 96.71% CI 0.55-0.87) |
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 & 2: 75 mg/m2 IV once on day 1
- Pemetrexed (Alimta) as follows:
- Cycles 1 & 2: 500 mg/m2 IV once on day 1
Immunotherapy
- Ipilimumab (Yervoy) as follows:
- Odd cycles: 1 mg/kg IV once on day 1
- Nivolumab (Opdivo) 360 mg IV once on day 1, given first
21-day cycles
References
- CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains verified protocol PubMed NCT03215706
Cisplatin, Pemetrexed, Pembrolizumab
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gandhi et al. 2018 (KEYNOTE-189) | 2016-2017 | Phase 3 (E-RT-esc) | 1. Carboplatin & Pemetrexed 2. Cisplatin & Pemetrexed |
Superior OS1 Median OS: 22 vs 10.6 mo (HR 0.56, 95% CI 0.46-0.69) |
1Reported efficacy is based on the 2021 update.
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 4: 75 mg/m2 IV once on day 1, given second
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given first
Immunotherapy
- Pembrolizumab (Keytruda) as follows:
- Cycles 1 to 35: 200 mg IV over 30 minutes once on day 1, at least 30 minutes prior to chemotherapy
Supportive medications
- "Premedication with folic acid, vitamin B12, and corticosteroids was administered according to local guidelines."
21-day cycles
References
- KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
- Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
- Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
- KEYLYNK-006: NCT03976323
Gefitinib monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Han et al. 2012 (First-SIGNAL) | 2005-2007 | Phase 3 (E-switch-ooc) | Cisplatin & Gemcitabine | Did not meet primary endpoint of OS |
Mok et al. 2009 (IPASS) | 2006-2007 | Phase 3 (E-RT-switch-ooc) | Carboplatin & Paclitaxel | Might have superior OS1 Median OS: 18.8 vs 17.4 mo (HR 0.90, 95% CI 0.79-1.02) |
Yang et al. 2014 (H3E-CR-S131) | 2009-2012 | Phase 3 (E-de-esc) | Cisplatin & Pemetrexed, then Gefitinib maint. | Did not meet primary endpoint of PFS |
1Reported efficacy is based on the 2011 update.
Targeted therapy
- Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
References
- IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed NCT00322452
- Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
- Dataset: Project Data Sphere
- First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed NCT00455936
- H3E-CR-S131: Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, Kim DW, Tsai CM, Barraclough H, Altug S, Orlando M, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer. 2014 Sep;50(13):2219-30. Epub 2014 Jun 18. link to original article PubMed NCT01017874
- Update: Yang JC, Srimuninnimit V, Ahn MJ, Lin CC, Kim SW, Tsai CM, Mok T, Orlando M, Puri T, Wang X, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol. 2016 Mar;11(3):370-9. Epub 2015 Dec 25. link to original article PubMed
Maintenance after first-line therapy
Atezolizumab & Bevacizumab
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence |
---|---|---|
Socinski et al. 2018 (IMpower150) | 2015-2016 | Non-randomized portion of RCT |
Note: this is the FDA-recommended dose for atezolizumab.
Preceding treatment
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV over 60 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed NCT02366143
Bevacizumab monotherapy
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Regimen variant #1, 7.5 mg/kg
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Barlesi et al. 2013 (AVAPERL) | 2009-2010 | Phase 3 (C) | Pemetrexed & Bevacizumab | Inferior PFS |
Preceding treatment
Targeted therapy
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, 15 mg/kg
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Patel et al. 2013 (PointBreak) | 2008-2012 | Non-randomized portion of RCT | ||
Zinner et al. 2015 (PRONOUNCE) | 2009-2013 | Phase 3 (C) | See link | See link |
Ramalingam et al. 2019 (ECOG-ACRIN E5508) | 2010-2015 | Phase 3 (C) | 1. Pemetrexed 2. Pemetrexed & Bevacizumab |
Did not meet primary endpoint of OS |
Seto et al. 2019 (COMPASS) | 2010-2015 | Phase 3 (C) | Pemetrexed & Bevacizumab | Might have inferior OS |
Preceding treatment
- PacCBev x 4
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed NCT00961415
- Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
- PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
- Dataset: Project Data Sphere
- PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
- ECOG-ACRIN E5508: Ramalingam SS, Dahlberg SE, Belani CP, Saltzman JN, Pennell NA, Nambudiri GS, McCann JC, Winegarden JD, Kassem MA, Mohamed MK, Rothman JM, Lyss AP, Horn L, Stinchcombe TE, Schiller JH. Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508. J Clin Oncol. 2019 Sep 10;37(26):2360-2367. Epub 2019 Jul 30. link to original article link to PMC article contains verified protocol PubMed NCT01107626
- COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article contains protocol PubMed UMIN000004194
Pemetrexed monotherapy
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al. 2012 (PARAMOUNT) | 2008-2010 | Phase 3 (E-RT-esc) | Placebo | Superior PFS |
Zinner et al. 2015 (PRONOUNCE) | 2009-2013 | Phase 3 (E-switch-ooc) | See link | See link |
Langer et al. 2016 (KEYNOTE-021) | 2014-2016 | 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 & KEYNOTE-021 (control arm): Carboplatin & Pemetrexed x 4
- KEYNOTE-021: Pemetrexed & Pembrolizumab maintenance x 2 y
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Supportive medications
- Folic acid (Folate)
- Cyanocobalamin (Vitamin B12)
- Dexamethasone (Decadron)
- "Investigators followed current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines for use of colony-stimulating factors and erythropoiesis-stimulating agents."
21-day cycles
References
- PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed NCT00789373
- HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
- Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
- PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
- KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed NCT02039674
Pemetrexed & Bevacizumab
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Regimen variant #1, 500/7.5
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Barlesi et al. 2013 (AVAPERL) | 2009-2010 | Phase 3 (E-esc) | Bevacizumab maintenance | Superior PFS |
Preceding treatment
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Targeted therapy
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
Supportive medications
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, given throughout therapy
- Folic acid (Folate) 350 to 1000 mcg PO once per day, given throughout therapy
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
21-day cycles
Regimen variant #2, 500/15
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Patel et al. 2013 (PointBreak) | 2008-2012 | Non-randomized portion of RCT | ||
Seto et al. 2019 (COMPASS) | 2010-2015 | Phase 3 (E-esc) | Bevacizumab | Might have superior OS |
Preceding treatment
- PemCBev (AUC 6) x 4
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
Supportive medications
- Premedications, Folic acid (Folate), and vitamin supplementation per pemetrexed label
- Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines
21-day cycles
References
- AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed NCT00961415
- Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
- PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
- Dataset: Project Data Sphere
- COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article contains protocol PubMed UMIN000004194
Pemetrexed & Pembrolizumab
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Langer et al. 2016 (KEYNOTE-021) | 2014-2016 | Randomized Phase II (E-esc) | See link | See link |
Note: the pemetrexed portion of the protocol was optional in KEYNOTE-021.
Preceding treatment
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to pemetrexed
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1, given second
Supportive medications
- Folic acid (Folate) according to local guidelines
- Cyanocobalamin (Vitamin B12) according to local guidelines
- Corticosteroids according to local guidelines
21-day cycle for up to 2 years (35 cycles total, including induction)
Subsequent treatment
- Optional Pemetrexed maintenance
References
- KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary appendix PubMed NCT02039674
Advanced or metastatic disease, subsequent lines of therapy
Note: this section includes regimens that were tested in second-line and beyond.
Docetaxel monotherapy
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Regimen variant #1, 75 mg/m2 q3wk, limited duration
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gerber et al. 2018 (SUNRISE) | 2013-2016 | Phase 3 (C) | Docetaxel & Bavituximab | Did not meet primary endpoint of OS |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen variant #2, 75 mg/m2 q3wk, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Borghaei et al. 2015 (CheckMate 057) | 2012-2015 | Phase 3 (C) | Nivolumab | Inferior OS |
Cortot et al. 2020 (ULTIMATE) | 2013-2014 | Phase 3 (C) | Paclitaxel & Bevacizumab | Inferior PFS |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
References
- CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed NCT01673867
- 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
- HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article PubMed
- Pooled update: Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wójcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, García MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Mar 1;39(7):723-733. Epub 2021 Jan 15. link to original article PubMed
- SUNRISE: Gerber DE, Horn L, Boyer M, Sanborn R, Natale R, Palmero R, Bidoli P, Bondarenko I, Germonpre P, Ghizdavescu D, Kotsakis A, Lena H, Losonczy G, Park K, Su WC, Tang M, Lai J, Kallinteris NL, Shan JS, Reck M, Spigel DR. Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer. Ann Oncol. 2018 Jul 1;29(7):1548-1553. link to original article contains verified protocol link to PMC article PubMed NCT01999673
- ULTIMATE: Cortot AB, Audigier-Valette C, Molinier O, Le Moulec S, Barlesi F, Zalcman G, Dumont P, Pouessel D, Poulet C, Fontaine-Delaruelle C, Hiret S, Dixmier A, Renault PA, Becht C, Raffy O, Dayen C, Mazieres J, Pichon E, Langlais A, Morin F, Moro-Sibilot D, Besse B. Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study. Eur J Cancer. 2020 May;131:27-36. Epub 2020 Apr 8. link to original article contains protocol PubMed NCT01763671
Gefitinib monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Urata et al. 2016 (WJOG 5108L) | 2009-2012 | Phase 3 (C) | Erlotinib | Inconclusive whether non-inferior PFS |
Targeted therapy
- Gefitinib (Iressa) 250 mg PO once per day
Continued indefinitely
References
- WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article contains verified protocol PubMed UMIN000002014
Nintedanib & Pemetrexed
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hanna et al. 2016 (LUME-Lung 2) | 2008-2011 | Phase 3 (E-esc) | Pemetrexed | Seems to have superior PFS |
Targeted therapy
- Nintedanib (Vargatef) 200 mg PO twice per day on days 2 to 21
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV once on day 1
21-day cycles
References
- LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed NCT00806819
Nivolumab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Borghaei et al. 2015 (CheckMate 057) | 2012-2015 | Phase 3 (E-RT-switch-ooc) | Docetaxel | Superior OS |
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
References
- CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article PubMed NCT01673867
- 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
- HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article PubMed
Pemetrexed monotherapy
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hanna et al. 2016 (LUME-Lung 2) | 2008-2011 | Phase 3 (C) | Nintedanib & Pemetrexed | Seems to have inferior PFS |
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Supportive medications
- (per Ardizzoni et al. 2012):
- Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of Pemetrexed (Alimta)
- Folic acid (Folate) 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
- JMEI used Folic acid (Folate) 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 (Alimta), to be given throughout pemetrexed therapy
21-day cycles
References
- LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed NCT00806819
Sorafenib monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al. 2015 (MISSION) | 2009-NR | Phase 3 (E-esc) | 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).
Targeted therapy
- Sorafenib (Nexavar) 400 mg PO twice per day
Continued indefinitely
References
- MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article contains verified protocol PubMed NCT00863746