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Open Access 01-12-2017 | Minireview

Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer?

Authors: Jordi Remon, Benjamin Besse, Jean-Charles Soria

Published in: BMC Medicine | Issue 1/2017

Abstract

Immune checkpoint inhibitors have significantly modified the therapeutic landscape of advanced non-small cell lung cancer in second-line settings, with a more recent advancement in first-line settings. Given the superior outcome with pembrolizumab as an upfront strategy, PD-L1 status should now be considered a new reflex biomarker to guide first-line treatment in patients with advanced non-small cell lung cancer. Improved responses have also been reported with the combination of immune checkpoint inhibitors and chemotherapy as the first-line treatment; however, this strategy has not yet been validated by phase III trial data and its interplay with PD-L1 status still requires clarification.

Herein, we review the contradictory results of recent phase III trials with immune checkpoint inhibitors in the first-line setting, the potential reasons for such discrepancies, and some of the remaining points of discussion related to the positioning of immune checkpoint inhibitors in the first-line therapy of non-small cell lung cancer.

Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5:2892–911.PubMedPubMedCentral

Dearden S, Stevens J, Wu Y-L, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24:2371–6. doi:10.1093/annonc/mdt205.CrossRefPubMedPubMedCentral

Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, Kerr K, Popat S, Reck M, Senan S, Simo GV, Vansteenkiste J, Peters S, ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v1–v27. doi:10.1093/annonc/mdw326.CrossRefPubMed

Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61. doi:10.1016/j.ccell.2015.03.001.CrossRefPubMedPubMedCentral

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. doi:10.1038/nrc3239.CrossRefPubMedPubMedCentral

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. doi:10.1016/j.cell.2011.02.013.CrossRefPubMed

Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064–74. doi:10.1158/1078-0432.CCR-13-3271.CrossRefPubMedPubMedCentral

Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792. doi:10.1038/cddis.2015.162.CrossRefPubMedPubMedCentral

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35. doi:10.1056/NEJMoa1504627.CrossRefPubMedPubMedCentral

10.

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39. doi:10.1056/NEJMoa1507643.CrossRefPubMed

11.

Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50. doi:10.1016/S0140-6736(15)01281-7.CrossRefPubMed

12.

Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, OAK Study Group, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–65. doi:10.1016/S0140-6736(16)32517-X.CrossRefPubMed

13.

Pillai RN, Behera M, Owonikoko TK, Kamphorst AO, Pakkala S, Belani CP, et al. Evaluation of toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer. J Thorac Oncol. 2016;11:OA03.06.

14.

Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33:2004–12. doi:10.1200/JCO.2014.58.3708.CrossRefPubMedPubMedCentral

15.

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, KEYNOTE-024 Investigators, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33. doi:10.1056/NEJMoa1606774.CrossRefPubMed

16.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8. doi:10.1126/science.aaa1348.CrossRefPubMedPubMedCentral

17.

Brahmer J, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Health-related quality of life for pembrolizumab vs chemotherapy in advanced NSCLC with PD-L1 TPS ≥50%: data from KEYNOTE-024. J Clin Oncol. 2016;34:Abstr 7153.

18.

Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–51. doi:10.1200/JCO.2007.15.0375.CrossRefPubMed

19.

Fukuoka M, Wu Y-L, Thongprasert S, Sunpaweravong P, Leong S-S, Sriuranpong V, et al. 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;29:2866–74. doi:10.1200/JCO.2010.33.4235.CrossRefPubMed

20.

Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, PROFILE 1014 Investigators, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77. doi:10.1056/NEJMoa1408440.CrossRefPubMed

21.

Miyauchi E, Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, North-East Japan Study Group, et al. Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002). Jpn J Clin Oncol. 2015;45:670–6. doi:10.1093/jjco/hyv054.CrossRefPubMed

22.

Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Spanish Lung Cancer Group, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–67. doi:10.1056/NEJMoa0904554.CrossRefPubMed

23.

Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976–83. doi:10.1016/S1470-2045(16)30053-5.CrossRefPubMed

24.

Moro-Sibilot D, Smit E, de Castro Carpeño J, Lesniewski-Kmak K, Aerts JG, Villatoro R, et al. Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: analysis from the European FRAME study. Lung Cancer. 2015;90:427–32. doi:10.1016/j.lungcan.2015.11.011.CrossRefPubMed

25.

Peters S, Bexelius C, Munk V, Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. 2016;45:139–62. doi:10.1016/j.ctrv.2016.03.009.CrossRefPubMed

26.

Franceschini D, Franzese C, Navarria P, Ascolese AM, De Rose F, Del Vecchio M, Santoro A, Scorsetti M. Radiotherapy and immunotherapy: can this combination change the prognosis of patients with melanoma brain metastases? Cancer Treat Rev. 2016;50:1–8. doi:10.1016/j.ctrv.2016.08.003.CrossRefPubMed

27.

Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, KEYNOTE-001 Investigators, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28. doi:10.1056/NEJMoa1501824.CrossRefPubMed

28.

Salloum RG, Smith TJ, Jensen GA, Lafata JE. Using claims-based measures to predict performance status score in patients with lung cancer. Cancer. 2011;117:1038–48. doi:10.1002/cncr.25677.CrossRefPubMed

29.

Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, Biomarkers France Contributors, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387:1415–26. doi:10.1016/S0140-6736(16)00004-0.CrossRefPubMed

30.

Khan SA, Pruitt SL, Xuan L, Gerber DE. Prevalence of autoimmune disease among patients with lung cancer: implications for immunotherapy treatment options. JAMA Oncol. 2016;2:1507–8. doi:10.1001/jamaoncol.2016.2238.CrossRefPubMed

31.

Socinski M, Creelan B, Horn L, Reck M, Paz-Ares L, Steins M, et al. NSCLC, metastatic CheckMate 026: a phase 3 trial of nivolumab vs investigator’s choice of platinum-based doublet chemotherapy as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)-positive NSCLC. Ann Oncol. 2016;27:LBA7_PR. doi: 10.1093/annonc/mdw435.39.

32.

Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2016. Ahead of print. doi:10.1158/1078-0432.CCR-16-1741.

33.

Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:2980–7. doi:10.1200/JCO.2016.66.9929.CrossRefPubMed

34.

Champiat S, Ferté C, Lebel-Binay S, Eggermont A, Soria JC. Exomics and immunogenics: bridging mutational load and immune checkpoints efficacy. Oncoimmunology. 2014;3:e27817. doi:10.4161/onci.27817.CrossRefPubMedPubMedCentral

35.

Leroi N, Lallemand F, Coucke P, Noel A, Martinive P. Impacts of ionizing radiation on the different compartments of the tumor microenvironment. Front Pharmacol. 2016;7:78. doi:10.3389/fphar.2016.00078.CrossRefPubMedPubMedCentral

36.

Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102:115–23. doi:10.1038/sj.bjc.6605465.CrossRefPubMed

37.

Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 2015;75:5034–45. doi:10.1158/0008-5472.CAN-14-3098.CrossRefPubMed

38.

Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B, et al. The up-regulation of PD-L1 promotes the resistant response in non-small cell lung cancer patients with neo-adjuvant chemotherapy. Cancer Sci. 2016;107:1563–71. doi:10.1111/cas.13072.CrossRefPubMedPubMedCentral

39.

Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, KEYNOTE-021 Investigators, et al. 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;17:1497–508. doi:10.1016/S1470-2045(16)30498-3.CrossRefPubMed

40.

Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, et al. 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;31:4349–57.CrossRefPubMedPubMedCentral

41.

Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275–80. doi:10.1073/pnas.0915174107.CrossRefPubMedPubMedCentral

42.

Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18:31–41. doi:10.1016/S1470-2045(16)30624-6.CrossRefPubMed

43.

Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–73. doi:10.1016/S0140-6736(14)60845-X.CrossRefPubMed

44.

Reck M, Kaiser R, Mellemgaard A, Douillard J-Y, Orlov S, Krzakowski M, LUME-Lung 1 Study Group, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143–55. doi:10.1016/S1470-2045(13)70586-2.CrossRefPubMed

45.

Cherny N, Sullivan R, Torode J, Saar M, Eniu A. ESMO European Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in Europe. Ann Oncol. 2016;27:1423–43. doi:10.1093/annonc/mdw213.CrossRefPubMed

46.

Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, de Vries EGE, Piccart MJ. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. 2015;26:1547–73. doi:10.1093/annonc/mdv249.CrossRefPubMed

47.

Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, et al. ESMO - Magnitude of Clinical Benefit Scale V.1.0 questions and answers. ESMO Open. 2016;1:e000100. doi:10.1136/esmoopen-2016-000100.CrossRefPubMedPubMedCentral

Title: Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer?
Authors: Jordi Remon
Benjamin Besse
Jean-Charles Soria
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-017-0819-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer?

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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