Non-small cell lung cancer, Nonsquamous

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Note: these are regimens tested in histology-specific populations, please see the main NSCLC page for other regimens.

38 regimens on this page
58 variants on this page


Adjuvant therapy

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 III (C) Cisplatin & Pemetrexed Did not meet primary endpoint of RFS More grade 3-4 toxicities

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. 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 III (E-esc) Observation Seems to have superior OS

Preceding treatment

Chemotherapy

2-year course

References

  1. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article contains protocol PubMed

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 III (C) Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation Did not meet primary endpoint of OS

Chemotherapy

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

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
    1. 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

21-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
    1. 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

28-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
    1. Dataset: Project Data Sphere

Cisplatin & Vinorelbine

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Regimen

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

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains verified protocol PubMed NCT00686959
    1. 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 III (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Targeted therapy

Chemotherapy

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 III (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Targeted therapy

Chemotherapy

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 III (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS

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

Immunotherapy

Targeted therapy

Chemotherapy

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 III (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS

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

Immunotherapy

Targeted therapy

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed NCT02366143

Atezolizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Herbst et al. 2020 (IMpower110) 2015-2018 Phase III (E-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed
Superior OS1
(HR 0.59, 95% CI 0.40-0.89)

1Reported efficacy is for TC3/IC3 only i.e., PD-L1 TC>50%.

Immunotherapy

21-day cycles

References

  1. 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 III (C) Carboplatin & Pemetrexed Did not meet primary endpoint of OS Inferior survival without treatment-emergent grade 3/4 toxicity

Chemotherapy

21-day cycle for up to 6 cycles

References

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

Carboplatin & Gemcitabine (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

28-day cycle for 2 cycles

Subsequent treatment

  • Continued CG x 4 versus CG & Gefitinib

References

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

Carboplatin, nab-Paclitaxel, Atezolizumab

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
West et al. 2019 (IMpower130) 2015-2017 Phase III (E-RT-esc) Carboplatin & nab-Paclitaxel Seems to have superior OS

Note: the FDA-recommended dose is specific to the atezolizumab dosing.

Chemotherapy

Immunotherapy

21-day cycle for 4 to 6 cycles

Subsequent treatment

  • Atezolizumab maintenance

References

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

Chemotherapy

Supportive medications

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 III (C) PacCBev Inferior OS
Mok et al. 2009 (IPASS) 2006-2007 Phase III (C) Gefitinib Inferior PFS
Scagliotti et al. 2012 (MONET1) 2007-2010 Phase III (C) TC & Motesanib Did not meet primary endpoint of OS
Kubota et al. 2017 (MONET-A) 2012-2015 Phase III (C) TC & Motesanib Might have inferior PFS

Chemotherapy

21-day cycle for 3 or more cycles

References

  1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed NCT00021060
    1. 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
  2. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed NCT00322452
    1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
    2. Dataset: Project Data Sphere
  3. MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article contains protocol PubMed NCT00460317
  4. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed NCT01364012
  5. MONET-A: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. Epub 2017 Sep 13. link to original article contains verified protocol PubMed JapicCTI-121887
  6. 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 III (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

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

Chemotherapy

Targeted therapy

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 III (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

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

Chemotherapy

Targeted therapy

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 III (C) PemCBev, then PemBev maint. Seems to have inferior PFS
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase III (C) See link See link
Socinski et al. 2018 (IMpower150) 2015-2016 Phase III (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

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

Chemotherapy

Targeted therapy

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 III (E-RT-esc) CP Superior OS
(HR 0.79, 95% CI 0.67-0.92)
Zhou et al. 2015 (BEYOND) 2011-2012 Phase III (E-esc) Carboplatin & Paclitaxel Seems to have superior OS
(HR 0.68, 95% CI 0.50-0.93)
Socinski et al. 2018 (IMpower150) 2015-2016 Phase III (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

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

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

21-day cycles

References

  1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains verified protocol PubMed NCT00021060
    1. 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
  2. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  3. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
  4. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains protocol PubMed NCT01364012
  5. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed NCT02366143

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 III (C) Carboplatin, Pemetrexed, Camrelizumab Inferior PFS
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase III (C) 1. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab
2. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab
Inferior OS

Note: this was the lower bound of cycles in CameL.

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Subsequent treatment

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 III (C) 1. Carboplatin, Pemetrexed, Pembrolizumab
2. Cisplatin, Pemetrexed, Pembrolizumab
Inferior OS
Yang et al. 2020 (CIBI308C302) 2018-2019 Phase III (C) 1. Carboplatin, Pemetrexed, Sintilimab
2. Cisplatin, Pemetrexed, Sintilimab
Inferior PFS

Chemotherapy

Supportive medications

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 III (E-switch-ic) Carboplatin & Docetaxel Did not meet primary endpoint of OS Superior survival without treatment-emergent grade 3/4 toxicity
Mok et al. 2019 (KEYNOTE-042) 2014-2017 Phase III (C) Pembrolizumab Inferior OS
Zhou et al. 2020 (CameL) 2017-2018 Phase III (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

Supportive medications

21-day cycle for up to 6 cycles

Subsequent treatment

Regimen variant #3, 6/500 x 4

Study Years of enrollment Evidence Comparator Comparative Efficacy
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase III (E-switch-ooc) See link See link
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase III (C) 1. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab
2. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab
Inferior OS

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Subsequent treatment

Regimen variant #4, 6/500 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042) 2014-2017 Phase III (C) Pembrolizumab Inferior OS
Herbst et al. 2020 (IMpower110) 2015-2018 Phase III (C) Atezolizumab Inferior OS1

1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Subsequent treatment

Regimen variant #5, 6/500 indefinitely

Study Years of enrollment Evidence Comparator Comparative Efficacy
Edelman et al. 2017 (CALGB 30801) 2010-2013 Phase III (C) CP & Celecoxib Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

References

  1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains protocol PubMed
  2. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
  3. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed NCT02039674
  4. 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
  5. 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
    1. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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 III (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

Immunotherapy

21-day cycles

References

  1. 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

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 III (E-switch-ic) PacCBev, then Maintenance Bev Seems to have superior PFS
Seto et al. 2019 (COMPASS) 2010-2015 Non-randomized portion of RCT

Chemotherapy

Targeted therapy

Supportive medications

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

21-day cycle for 4 cycles

Subsequent treatment

References

  1. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  2. 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 III (E-RT-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed
Superior OS

Chemotherapy

Immunotherapy

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 III (E-RT-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed
Superior OS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. 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 OS

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

Chemotherapy

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

21-day cycles

References

  1. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary appendix PubMed NCT02039674
  2. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
    1. 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
  3. 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 III (C) Cisplatin & Pemetrexed Inconclusive whether non-inferior PFS

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. 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 III (C) GC & Sorafenib Did not meet primary endpoint of OS

Chemotherapy

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 III (C) 1. GC & Bevacizumab; low-dose Inferior PFS
2. GC & Bevacizumab; standard-dose Seems to have inferior PFS

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #3, 80/1250 x 9

Study Years of enrollment Evidence Comparator Comparative Efficacy
Han et al. 2012 (First-SIGNAL) 2005-2007 Phase III (C) Gefitinib Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 9 cycles

References

  1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains protocol PubMed NCT00806923
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
  2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed NCT00455936
  3. NExUS: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non–small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. Epub 2012 Jul 30. link to original article contains protocol PubMed NCT00449033
    1. 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 III (E-RT-esc) Cisplatin & Gemcitabine Superior PFS

Chemotherapy

Targeted therapy

21-day cycle for up to 6 cycles

Subsequent treatment

Regimen variant #2, standard-dose bev

Study Years of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) 2005-2006 Phase III (E-RT-esc) Cisplatin & Gemcitabine Seems to have superior PFS

Chemotherapy

Targeted therapy

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed NCT00806923
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed

Cisplatin & Pemetrexed

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

Regimen variant #1, 70/500

Study Years of enrollment Evidence Comparator Comparative Efficacy
Park et al. 2017 (TRAIL) 2011-2013 Phase III (E-switch-ic) Cisplatin & Docetaxel Inconclusive whether non-inferior PFS

Chemotherapy

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 III (C) GC Did not meet primary endpoint of OS
Paz-Ares et al. 2015 (INSPIRE) 2009-2011 Phase III (C) Pem-Cis & Necitumumab Did not meet primary endpoint of OS
Reck et al. 2016 (KEYNOTE-024) 2014-2015 Phase III (C) Pembrolizumab Inferior OS Inferior HRQoL
Rizvi et al. 2020 (MYSTIC) 2015-2016 Phase III (C) Durvalumab Might have inferior OS
Durvalumab & Tremelimumab Did not meet primary endpoints of PFS/OS
Herbst et al. 2020 (IMpower110) 2015-2018 Phase III (C) Atezolizumab Inferior OS1
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase III (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

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

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 III (C) 1. Carboplatin, Pemetrexed, Pembrolizumab
2. Cisplatin, Pemetrexed, Pembrolizumab
Inferior OS
Yang et al. 2020 (CIBI308C302) 2018-2019 Phase III (C) 1. Carboplatin, Pemetrexed, Sintilimab
2. Cisplatin, Pemetrexed, Sintilimab
Inferior PFS

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

Chemotherapy

Supportive medications

21-day cycles

References

  1. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed NCT00789373
    1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  2. 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
  3. 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
  4. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains verified protocol PubMed NCT02142738
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
  5. 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
  6. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
    1. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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 III (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

Immunotherapy

21-day cycles

References

  1. 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

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

21-day cycle for 4 cycles

Subsequent treatment

References

  1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed NCT00961415
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed

Cisplatin, Pemetrexed, 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 III (E-RT-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed
Superior OS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. 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 III (E-RT-esc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed
Superior OS

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

Chemotherapy

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

21-day cycles

References

  1. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains verified protocol PubMed NCT02578680
    1. 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
  2. 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 III (E-switch-ooc) Cisplatin & Gemcitabine Did not meet primary endpoint of OS
Mok et al. 2009 (IPASS) 2006-2007 Phase III (E-RT-switch-ooc) Carboplatin & Paclitaxel Superior PFS
Yang et al. 2014 (H3E-CR-S131) 2009-2012 Phase III (E-de-esc) Cisplatin & Pemetrexed, then Gefitinib maint. Did not meet primary endpoint of PFS

Targeted therapy

Continued indefinitely

References

  1. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains verified protocol PubMed NCT00322452
    1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
    2. Dataset: Project Data Sphere
  2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains protocol PubMed NCT00455936
  3. H3E-CR-S131: Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, Kim DW, Tsai CM, Barraclough H, Altug S, Orlando M, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer. 2014 Sep;50(13):2219-30. Epub 2014 Jun 18. link to original article PubMed NCT01017874
    1. Update: Yang JC, Srimuninnimit V, Ahn MJ, Lin CC, Kim SW, Tsai CM, Mok T, Orlando M, Puri T, Wang X, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol. 2016 Mar;11(3):370-9. Epub 2015 Dec 25. link to original article PubMed

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

Targeted therapy

21-day cycles

References

  1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains verified protocol PubMed NCT02366143

Bevacizumab monotherapy

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Regimen variant #1, 7.5 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) 2005-2006 Non-randomized portion of RCT
Barlesi et al. 2013 (AVAPERL) 2009-2010 Phase III (C) Pemetrexed & Bevacizumab Inferior PFS

Preceding treatment

Targeted therapy

21-day cycles

Regimen variant #2, 15 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) 2005-2006 Non-randomized portion of RCT
Patel et al. 2013 (PointBreak) 2008-2012 Non-randomized portion of RCT
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase III (C) See link See link
Ramalingam et al. 2019 (ECOG-ACRIN E5508) 2010-2015 Phase III (C) 1. Pemetrexed
2. Pemetrexed & Bevacizumab
Did not meet primary endpoint of OS
Seto et al. 2019 (COMPASS) 2010-2015 Phase III (C) Pemetrexed & Bevacizumab Might have inferior OS

Preceding treatment

Targeted therapy

21-day cycles

References

  1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains verified protocol PubMed NCT00806923
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
  2. 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
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
  3. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  4. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains verified protocol PubMed NCT00948675
  5. 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
  6. 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 III (E-RT-esc) Placebo Superior PFS
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase III (E-switch-ooc) See link See link
Langer et al. 2016 (KEYNOTE-021) 2014-2016 Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Supportive medications

21-day cycles

References

  1. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains verified protocol PubMed NCT00789373
    1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
  2. 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
  3. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol PubMed 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 III (E-esc) Bevacizumab maintenance Superior PFS

Preceding treatment

Chemotherapy

Targeted therapy

Supportive medications

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 III (E-esc) Bevacizumab Might have superior OS

Preceding treatment

Chemotherapy

Targeted therapy

Supportive medications

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

21-day cycles

References

  1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains verified protocol PubMed NCT00961415
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed
  2. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. link to original article contains verified protocol link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  3. 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

Chemotherapy

Supportive medications

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

Subsequent treatment

References

  1. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary 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 III (C) Docetaxel & Bavituximab Did not meet primary endpoint of OS

Chemotherapy

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 III (C) Nivolumab Inferior OS
Cortot et al. 2020 (ULTIMATE) 2013-2014 Phase III (C) Paclitaxel & Bevacizumab Inferior PFS

Chemotherapy

21-day cycles

References

  1. 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
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
    2. 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
    3. 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
  2. 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
  3. 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 III (C) Erlotinib Inconclusive whether non-inferior PFS

Targeted therapy

Continued indefinitely

References

  1. 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 III (E-esc) Pemetrexed Seems to have superior PFS

Targeted therapy

Chemotherapy

21-day cycles

References

  1. 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 III (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

  1. 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
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article PubMed
    2. 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 III (C) Nintedanib & Pemetrexed Seems to have inferior PFS

Chemotherapy

Supportive medications

21-day cycles

References

  1. 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 III (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

Continued indefinitely

References

  1. MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article contains verified protocol PubMed NCT00863746