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Current Clinical Pharmacology

Editor-in-Chief

ISSN (Print): 1574-8847
ISSN (Online): 2212-3938

Review Article

The New Immunotherapy Combinations in the Treatment of Advanced Non-Small Cell Lung Cancer: Reality and Perspectives

Author(s): Danilo Rocco, Luigi D. Gravara and Cesare Gridelli*

Volume 15, Issue 1, 2020

Page: [11 - 19] Pages: 9

DOI: 10.2174/1574884714666190809124555

Abstract

Background: In the recent years, immunotherapeutics and specifically immunecheckpoints inhibitors have marked a significant shift in the diagnostic and therapeutic algorithm of Non-Small Cell Lung Cancer (NSCLC), allowing us to use immunotherapeutics alone or combined with chemotherapy for a great subset of patients. However, new interesting approaches are being presently investigated, markedly immunotherapy combinations, that is, the use of two or more immunotherapeutics combined.

Methods: In particular, the combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has already provided groundbreaking positive results in the advanced NSCLC and other combinations are currently under investigation.

Results: Therefore, this paper aims to provide a comprehensive state-of-the-art review about immunotherapy combination, along with suggestions about future directions. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov.

Conclusion: Nivolumab plus ipilimumab represent the most promising immunotherapy combination for the treatment of advanced NSCLC patients; safety, tolerability and efficacy of new immunotherapeutics (in monotherapy and in immunotherapy combinations) must be further assessed in future studies.

Keywords: NSCLC, immunotherapy, combination therapy, immune modulators, TMB, LAG-3, OX40, IDO1.

Graphical Abstract
[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Prac-tice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29(Supplement_4): iv192-37.
[3]
Rocco D, Della Gravara L, Avellino A, et al. Immunotherapy as a targeted therapy in non-small cell lung cancer. Transl Cancer Res in press
[http://dx.doi.org/10.21037/tcr.2018.10.10]
[4]
Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561.
[http://dx.doi.org/10.3389/fphar.2017.00561] [PMID: 28878676]
[5]
Xu-Monette ZY, Zhang M, Li J, Young KH. PD-1/PD-L1 blockade: Have we found the key to unleash the antitumor immune response? Front Immunol 2017; 8: 1597.
[http://dx.doi.org/10.3389/fimmu.2017.01597] [PMID: 29255458]
[6]
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 2005; 54(4): 307-14.
[http://dx.doi.org/10.1007/s00262-004-0593-x] [PMID: 15599732]
[7]
Hui Y, Boyle TA, Zhou C, et al. PD-L1 expression in lung cancer. J Thorac Oncol 2016.
[http://dx.doi.org/10.1016/j.jtho.2016.04.014]
[8]
Meyers DE, Bryan PM, Banerji S, Morris DG. Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer. Curr Oncol 2018; 25(4): e324-34.
[http://dx.doi.org/10.3747/co.25.3976] [PMID: 30111979]
[9]
Juneja VR, McGuire KA, Manguso RT, et al. PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 2017; 214(4): 895-904.
[http://dx.doi.org/10.1084/jem.20160801] [PMID: 28302645]
[10]
Jain P, Jain C, Velcheti V. Role of immune-checkpoint inhibitors in lung cancer. Ther Adv Respir Dis 2018; 121753465817750075
[http://dx.doi.org/10.1177/1753465817750075] [PMID: 29385894]
[11]
Assi HI, Kamphorst AO, Moukalled NM, Ramalingam SS. Immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer 2018; 124(2): 248-61.
[http://dx.doi.org/10.1002/cncr.31105] [PMID: 29211297]
[12]
Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer 2017; 8(3): 410-6.
[http://dx.doi.org/10.7150/jca.17144] [PMID: 28261342]
[13]
McDermott J, Jimeno A. Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer. Drugs Today (Barc) 2015; 51(1): 7-20.
[http://dx.doi.org/10.1358/dot.2015.51.1.2250387] [PMID: 25685857]
[14]
Lee HT, Lee JY, Lim H, et al. Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep 2017; 7(1): 5532.
[http://dx.doi.org/10.1038/s41598-017-06002-8] [PMID: 28717238]
[15]
Buchbinder Elizabeth I. Desai Anupam. CTLA-4 and PD-1 Pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016.
[http://dx.doi.org/10.1097/COC.0000000000000239]
[16]
Chae YK, Arya A, Iams W, et al. Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer 2018; 6(1): 39.
[http://dx.doi.org/10.1186/s40425-018-0349-3] [PMID: 29769148]
[17]
Engelhardt JJ, Sullivan TJ, Allison JP. CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol 2006; 177(2): 1052-61.
[http://dx.doi.org/10.4049/jimmunol.177.2.1052] [PMID: 16818761]
[18]
Paulsen EE, Kilvaer TK, Rakaee M, et al. CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases. Cancer Immunol Immunother 2017; 66(11): 1449-61.
[http://dx.doi.org/10.1007/s00262-017-2039-2] [PMID: 28707078]
[19]
Granier C, De Guillebon E, Blanc C, et al. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open 2017; 2(2)e000213
[http://dx.doi.org/10.1136/esmoopen-2017-000213] [PMID: 28761757]
[20]
Grosso JF, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun 2013; 13: 5.
[PMID: 23390376]
[21]
He Y, Yu H, Rozeboom L, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol 2017; 12(5): 814-23.
[http://dx.doi.org/10.1016/j.jtho.2017.01.019] [PMID: 28132868]
[22]
Hald SM, Rakaee M, Martinez I, et al. LAG-3 in Non-small-cell lung cancer: Expression in primary tumors and metastatic lymph nodes is associated with improved survival. Clin Lung Cancer 2018; 19(3): 249-59.
[http://dx.doi.org/10.1016/j.cllc.2017.12.001] [PMID: 29396238]
[23]
Goldberg MV, Drake CG. LAG-3 in Cancer immunotherapy. Curr Top Microbiol Immunol 2011; 344: 269-78.
[http://dx.doi.org/10.1007/82_2010_114] [PMID: 21086108]
[24]
Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 2017; 276(1): 97-111.
[http://dx.doi.org/10.1111/imr.12520] [PMID: 28258697]
[25]
Du W, Yang M, Turner A, et al. TIM-3 as a Target for cancer immunotherapy and mechanisms of action. Int J Mol Sci 2017; 18(3): 645.
[http://dx.doi.org/10.3390/ijms18030645] [PMID: 28300768]
[26]
Leitner J, Klauser C, Pickl WF, et al. B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur J Immunol 2009; 39(7): 1754-64.
[http://dx.doi.org/10.1002/eji.200839028] [PMID: 19544488]
[27]
Castellanos JR, Purvis IJ, Labak CM, et al. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol 2017; 6(4): 66-75.
[PMID: 28695059]
[28]
Altan M, Pelekanou V, Schalper KA, et al. B7-H3 Expression in NSCLC and its association with B7-H4, PD-L1 and tumor-infiltrating lymphocytes. Clin Cancer Res 2017; 23(17): 5202-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-3107] [PMID: 28539467]
[29]
Lee YH, Martin-Orozco N, Zheng P, et al. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res 2017; 27(8): 1034-45.
[http://dx.doi.org/10.1038/cr.2017.90] [PMID: 28685773]
[30]
Picarda E, Ohaegbulam KC, Zang X. Molecular pathways: Targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res 2016; 22(14): 3425-31.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2428] [PMID: 27208063]
[31]
Lines JL, Sempere LF, Broughton T, Wang L, Noelle R. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2014; 2(6): 510-7.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0072] [PMID: 24894088]
[32]
Villarroel-Espindola F, Yu X, Datar I, et al. Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clin Cancer Res 2018; 24(7): 1562-73.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-2542] [PMID: 29203588]
[33]
Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-The more the better? Eur J Cancer 2017; 74: 55-72.
[http://dx.doi.org/10.1016/j.ejca.2017.01.001] [PMID: 28335888]
[34]
Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology 2011; 132(3): 315-25.
[http://dx.doi.org/10.1111/j.1365-2567.2010.03398.x] [PMID: 21214544]
[35]
Al Omar SY, Marshall E, Middleton D, Christmas SE. Increased killer immunoglobulin-like receptor expression and functional defects in natural killer cells in lung cancer. Immunology 2011; 133(1): 94-104.
[http://dx.doi.org/10.1111/j.1365-2567.2011.03415.x] [PMID: 21342183]
[36]
Benson DM Jr, Caligiuri MA. Killer immunoglobulin-like receptors and tumor immunity. Cancer Immunol Res 2014; 2(2): 99-104.
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0219] [PMID: 24592397]
[37]
He Y, Liu S, Mattei J, Bunn PA Jr, Zhou C, Chan D. The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC. Drug Des Devel Ther 2018; 12: 981-6.
[http://dx.doi.org/10.2147/DDDT.S163304] [PMID: 29731605]
[38]
Vinay DS, Kwon BS. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Rep 2014; 47(3): 122-9.
[http://dx.doi.org/10.5483/BMBRep.2014.47.3.283] [PMID: 24499671]
[39]
Wang C, Lin GH, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 2009; 229(1): 192-215.
[http://dx.doi.org/10.1111/j.1600-065X.2009.00765.x] [PMID: 19426223]
[40]
Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018; 131(1): 49-57.
[http://dx.doi.org/10.1182/blood-2017-06-741041] [PMID: 29118009]
[41]
Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 2016; 65(10): 1243-8.
[http://dx.doi.org/10.1007/s00262-016-1829-2] [PMID: 27034234]
[42]
Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 2009; 229(1): 173-91.
[http://dx.doi.org/10.1111/j.1600-065X.2009.00766.x] [PMID: 19426222]
[43]
Jensen SM, Maston LD, Gough MJ, et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol 2010; 37(5): 524-32.
[http://dx.doi.org/10.1053/j.seminoncol.2010.09.013] [PMID: 21074068]
[44]
Carrizosa DR, Gold KA. New strategies in immunotherapy for non-small cell lung cancer. Transl Lung Cancer Res 2015; 4(5): 553-9.
[PMID: 26629424]
[45]
Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C. GITR/GITRL: more than an effector T cell co-stimulatory system. Eur J Immunol 2007; 37(5): 1165-9.
[http://dx.doi.org/10.1002/eji.200636933] [PMID: 17407102]
[46]
Riether C, Schürch C, Ochsenbein AF. Modulating CD27 signaling to treat cancer. OncoImmunology 2012; 1(9): 1604-6.
[http://dx.doi.org/10.4161/onci.21425] [PMID: 23264908]
[47]
Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR cancer immunotherapy. Eur J Cancer 2016; 67: 1-10.
[http://dx.doi.org/10.1016/j.ejca.2016.06.028] [PMID: 27591414]
[48]
van de Ven K, Borst J. Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential. Immunotherapy 2015; 7(6): 655-67.
[http://dx.doi.org/10.2217/imt.15.32] [PMID: 26098609]
[49]
Hornyák L, Dobos N, Koncz G, et al. The Role of indoleamine-2, 3-dioxygenase in cancer development, diagnostics, and therapy. Front Immunol 2018; 9: 151.
[http://dx.doi.org/10.3389/fimmu.2018.00151] [PMID: 29445380]
[50]
Zhai L, Ladomersky E, Lenzen A, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol 2018; 15(5): 447-57.
[http://dx.doi.org/10.1038/cmi.2017.143] [PMID: 29375124]
[51]
Volaric A, Gentzler R, Hall R, et al. Indoleamine-2,3-dioxygenase in non-small cell lung cancer: A targetable mechanism of immune resistance frequently coexpressed with PD-L1. Am J Surg Pathol 2018; 42(9): 1216-23.
[http://dx.doi.org/10.1097/PAS.0000000000001099] [PMID: 29901571]
[52]
Schalper KA, Carvajal-Hausdorf D, McLaughlin J, et al. Differential expression and significance of PD-L1, IDO-1, and B7-H4 in human lung cancer. Clin Cancer Res 2017; 23(2): 370-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0150] [PMID: 27440266]
[53]
Li F, Zhang R, Li S, Liu J. IDO1: An important immunotherapy target in cancer treatment. Int Immunopharmacol 2017; 47: 70-7.
[http://dx.doi.org/10.1016/j.intimp.2017.03.024] [PMID: 28365507]
[54]
Liu M, Wang X, Wang L, et al. Targeting the IDO1 pathway in cancer: from bench to bedside. J Hematol Oncol 2018; 11(1): 100.
[http://dx.doi.org/10.1186/s13045-018-0644-y] [PMID: 30068361]
[55]
Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer 2017; 76: 167-82.
[http://dx.doi.org/10.1016/j.ejca.2017.01.011] [PMID: 28324751]
[56]
Fishman P, Bar-Yehuda S, Synowitz M, et al. Adenosine receptors and cancer. Handb Exp Pharmacol 2009; (193): 399-441.
[http://dx.doi.org/10.1007/978-3-540-89615-9_14] [PMID: 19639290]
[57]
Leone RD, Lo YC, Powell JD. 2015.
[58]
Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Cancer 2018; 6(1): 57.
[http://dx.doi.org/10.1186/s40425-018-0360-8] [PMID: 29914571]
[59]
Massagué J. TGFbeta in Cancer. Cell 2008; 134(2): 215-30.
[http://dx.doi.org/10.1016/j.cell.2008.07.001] [PMID: 18662538]
[60]
Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev 2006; 25(3): 435-57.
[http://dx.doi.org/10.1007/s10555-006-9006-2] [PMID: 16951986]
[61]
Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer 2017; 3(1): 56-71.
[http://dx.doi.org/10.1016/j.trecan.2016.11.008] [PMID: 28718426]
[62]
de Gramont A, Faivre S, Raymond E. Novel TGF-β inhibitors ready for prime time in onco-immunology. OncoImmunology 2016; 6(1)e1257453
[http://dx.doi.org/10.1080/2162402X.2016.1257453] [PMID: 28197376]
[63]
Katz LH, Li Y, Chen JS, et al. Targeting TGF-β signaling in cancer. Expert Opin Ther Targets 2013; 17(7): 743-60.
[http://dx.doi.org/10.1517/14728222.2013.782287] [PMID: 23651053]
[64]
Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017; 168(4): 707-23.
[http://dx.doi.org/10.1016/j.cell.2017.01.017] [PMID: 28187290]
[65]
Rieth J, Subramanian S. Mechanisms of intrinsic tumor resistance to immunotherapy. Int J Mol Sci 2018; 19(5): 1340.
[http://dx.doi.org/10.3390/ijms19051340] [PMID: 29724044]
[66]
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab vs. docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2015.
[PMID: 26712084]
[67]
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab vs. docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627-39.
[http://dx.doi.org/10.1056/NEJMoa1507643] [PMID: 26412456]
[68]
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab vs. docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2): 123-35.
[http://dx.doi.org/10.1056/NEJMoa1504627] [PMID: 26028407]
[69]
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab vs. docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2016.
[PMID: 27979383]
[70]
Schmidt C. The benefits of immunotherapy combinations. Nature 2017; 552(7685): S67-9.
[http://dx.doi.org/10.1038/d41586-017-08702-7] [PMID: 29293245]
[71]
Harris SJ, Brown J, Lopez J, Yap TA. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol Med 2016; 13(2): 171-93.
[http://dx.doi.org/10.20892/j.issn.2095-3941.2016.0015] [PMID: 27458526]
[72]
Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD. Combination immunotherapy: a road map. J Immunother Cancer 2017; 5: 16.
[http://dx.doi.org/10.1186/s40425-017-0218-5] [PMID: 28239469]
[73]
Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 2016; 17(3): 299-308.
[http://dx.doi.org/10.1016/S1470-2045(15)00544-6] [PMID: 26858122]
[74]
Mok T, Schmid P, Arén O, et al. 192TiP: NEPTUNE: A global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy vs. Standard of Care (SoC) platinum-based chemotherapy in the first-line treatment of patients (pts) with advanced or metastatic NSCLC. J Thorac Oncol 2016; 11(4): 140-1.
[http://dx.doi.org/10.1016/S1556-0864(16)30301-X]
[75]
Rizvi N, Barlesi F, Brahmer J, et al. Phase III, randomized, open-label study of durvalumab (MEDI4736) in combination with tremelimumab or durvalumab alone vs. platinum-based chemotherapy in first-line treatment of patients with advanced/metastatic NSCLC: MYSTIC. J Immunother Cancer 2015; 3(Suppl. 2). P171
[http://dx.doi.org/10.1186/2051-1426-3-S2-P171]
[76]
Planchard D, Yokoi T, McCleod MJ, et al. A Phase III study of durvalumab (MEDI4736) with or without tremelimumab for previously treated patients with advanced NSCLC: rationale and protocol design of the ARCTIC study. Clin Lung Cancer 2016; 17(3): 232-236.e1.
[http://dx.doi.org/10.1016/j.cllc.2016.03.003] [PMID: 27265743]
[77]
Muñoz-Unceta N, Burgueño I, Jiménez E, Paz-Ares L. Durvalumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol 2018; 101758835918804151
[http://dx.doi.org/10.1177/1758835918804151] [PMID: 30344651]
[78]
Gubens MA, Sequist LV, Stevenson J, et al. Phase I/II study of pembrolizumab (pembro) plus ipilimumab (ipi) as second-line therapy for NSCLC: KEYNOTE-021 cohorts D and H. J Clin Oncol 2016; 34
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.9027]
[79]
ClinicalTrials.gov [Internet]. Bethesda (MD): National Li-brary of Medicine (US) Study of pembrolizumab given with ipilimumab or placebo in participants with untreated meta-static non-small cell lung cancer (MK-3475-598/KEYNOTE-598); identifier: NCT03302234; available at:. https://clinicaltrials.gov/ct2/show/NCT03302234 [Accessed December 2018]
[80]
Hellmann MD, Rizvi NA, Goldman JW, 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(1): 31-41.
[http://dx.doi.org/10.1016/S1470-2045(16)30624-6] [PMID: 27932067]
[81]
Ramalingam SS, Hellmann MD, Awad MM, et al. Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) Non-Small Cell Lung Cancer (NSCLC): Identification of TMB cutoff from Check Mate 568. Cancer Res 2018; 78: CT078.
[http://dx.doi.org/10.1158/1538-7445.AM2018-CT078]
[82]
Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378(22): 2093-104.
[83]
BMS Press Release [internet] Bristol-Myers Squibb Provides Update on the Ongoing Regulatory Review of Opdivo Plus Low-Dose Yervoy in First-Line Lung Cancer Patients with Tumor Mutational Burden ≥10 mut/Mb. Available at:. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-provides-update-ongoing-regulatory-review [Accessed December 2018]

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