In the last decade, the emergence of targeted therapies has changed the treatment paradigm for non-small cell lung cancer (NSCLC). The growing availability of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, have led to changes in the guidelines to reflect the need for molecular profiling. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC, and these may provide superior outcomes and have substantially better tolerability compared to chemotherapy. Immunotherapies currently available for NSCLC include the checkpoint inhibitors anti PD-1 antibodies nivolumab and pembrolizumab. Several other anti PD-L1 compounds such as atezolizumab, durvalumab and avelumab are also very advanced in clinical investigation, in monotherapy as well as in combination with immune priming phase activators anti-CTLA4 ipilimumab and tremelimumab, across all treatment lines. The challenge facing oncologists is identifying which therapy is best suited to the individual patient.
Non-small cell lung cancer, targeted therapy, checkpoint inhibitors, immunotherapy
Tu Nguyen-Ngoc is supported by the Leenaards Foundation. Martin Reck has received personal honoraria for lectures and consultancy from F. Hoffmann-La Roche, Lilly, BMS, MSD, AstraZeneca, Merck, Boehringer-Ingelheim, Pfizer, Novartis and Celgene. Daniel SW Tan has been an advisor and consultant to Novartis, Bayer, Boehringer-Ingelheim, Merrimack and Pfizer, received travel funding and honorarium from Merck, Pfizer, Novartis, AstraZeneca, Boehringer- Ingelheim and Ariad, and received research funding from Novartis, GSK, Bayer and AstraZeneca. Solange Peters has provided consultation, attended advisory boards and/or provided lectures for F. Hoffmann–La Roche, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo, Morphotek, Merrimack, Merck Serono, Amgen, Clovis and Tesaro, for which she received honoraria. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Medical writing assistance was provided by Kat Mountfort at Touch Medical Media, UK.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
September 05, 2016 Accepted:
November 19, 2016
Solange Peters, Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. E: email@example.com
The publication of this article was supported by Novartis. The views and opinions expressed are those of the authors and do not necessarily reflect those of Novartis. The authors provided Novartis with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.
Lung cancer is the leading cause of cancer mortality worldwide1 and remains one of the major therapeutic challenges in oncology. Traditionally, lung cancer is subdivided based on histology: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have completely different molecular and therapeutic profiles. The most common class is NSCLC, accounting for 85% of all cases.2 The prognosis of NSCLC dramatically changed following the discovery of genetic alterations affecting oncogenes, called drivers, including epidermal growth factor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangement, ROS1 or RET rearrangements, MET mutations or amplification, as well as BRAF or HER2 mutations (see Figure 1). The ability to target tumours at the molecular level has led to a paradigm shift in the management of patients with these mutations.
The availability of new therapies with differing modes of action is potentially confusing, not only for primary care physicians but also for medical oncologists. Furthermore, unmet needs remain in the treatment of NSCLC, including the development of resistance to targeted therapies and the fact that not all molecular subtypes are actionable to date. Furthermore, a large group of patients does not suffer from tumours characterised by oncogenic alterations, with the vast majority deprived of any actionable genetic change. These patients are currently treated by chemotherapy. There is a need for new treatments for these patients, and immunotherapy represents a promising approach, but also confers a challenge: identifying patients who will benefit optimally from these treatments. This article aims to discuss the use of targeted therapies and immunotherapy in the setting of NSCLC.
Targeted therapies for non-small cell lung cancer
Standard-of-care molecular characterisation of advanced NSCLC is performed by analysis of activating mutations of EGFR (in exons 19 and 21) and detection of an ALK rearrangement.3 Such screening of NSCLC patients for driver mutations have been standardised and validated.4 However, mutations on the EGFR gene are seen in fewer than 10% of NSCLC patients in Western populations,5,6 although this is higher (up to 50%) in Asian populations.5,7 The mutation has been reported with a higher frequency in non-smokers, women, and presence of adenocarcinoma.6 Clinical trials of approved targeted therapies for NSCLC are summarised in Table 1. The use of EGFR tyrosine kinase inhibitors (TKIs) is recommended as first-line therapy
for patients with an EGFR driver mutation, following an accumulation of evidence of superiority compared with chemotherapy. The first EGFR TKI was gefitinib8–11 followed by erlotinib12–14 and the second-generation TKI afatinib.15,16 In addition, dacomitinib is being evaluated as first-line therapy.17 However, despite high response rates, resistance to EGFR inhibitors invariably ensues in the majority of patients. One of the most common mechanisms of EGFR TKI resistance has been attributed to a single recurrent missense mutation: T790M within the EGFR kinase domain, which occurs in around half of resistant cases.18,19 Other mutations exist, including EGFR point mutations, EGFR amplification, bypass tracks and 15–20% unknown mechanisms.20 Several other agents are in clinical development.
Second-generation irreversible pan-HER EGFR TKIs, such as afatinib,21 dacomitinib22 and neratinib,23 do not seem to be highly effective after progression on first-generation TKI. As a result, third-generation EFGR inhibitors have been developed that selectively target EGFR-activating mutations (del19 and L858R), preserving their affinity in the presence of the T790M resistance mutation, but relatively sparing of EGFR wild type (WT) kinase. The most advanced of these are osimertinib (AZD9291)24 and rociletinib (CO-1686).25 In a phase I study, osimertinib showed a response rate of 61% and a progression-free survival (PFS) of 9.6 months among 127 T790M-positive patients previously treated with EGFR TKIs.26 The latest data from the two phase II studies (AURA extension and AURA2) showed a consistent efficacy and tolerability profile.27 Osimertinib received approval from the US Food and Drug Administration (FDA) in November 2015 and the European Medicines Agency (EMA) in December 2015 for EGFR T790M-positive NSCLC progressing after prior therapy with an EGFR TKI. Results of the confirmatory AURA3 phase III study are pending.
Rociletinib has also shown high efficacy (objective response rate [ORR] 59%, PFS 13.1 months) in T790M-mutated patients in a phase I/II study.28 However, due to a high proportion of unconfirmed responses, rociletinib has not received FDA approval yet and development has been halted. Interestingly, osimertinib and rociletinib also seem active in T790Mnegative NSCLC with lower response rates than in T790M-positive NSCLC. Unfortunately, resistance to third-generation EGFR TKIs occurs and new mechanisms of resistance have been found,29,30 which may differ for osimertinib, rociletinib and other agents in development. Of note, a few cases of NSCLC progressing after rociletinib have been shown to respond to osimertinib.31 Osimertinib and rociletinib are currently being tested in the first-line setting against first-generation TKIs. The results of these trials are eagerly awaited, as osimertinib have shown promising high efficacy (ORR 75%, 72% of PFS at 12 months) in preliminary data of first-line cohorts.32,33 The right sequence of EGFR TKIs is thus a big challenge. The choice may be guided by response to brain metastases: osimertinib and rociletinib appear to have almost as high efficacy in patients with brain metastases than without.34,35 Other agents in clinical development include HM6171336 and EGF816.37
1. Siegel RL, Miller KD, Jemal A, Cancer statistics, 2016, CA Cancer J Clin, 2016;66:7-30.
2. Navada S, Lai P, Schwartz AG, et al., Temporal trends in small cell lung cancer: analysis of the national Surveillance Epidemiology and End-Results (SEER) database [abstract 7082], J Clin Oncol, 2006;24(suppl):384S.
3. Lindeman NI, Cagle PT, Beasley MB, et al., Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology,J Mol Diagn, 2013;15:415–53.
4. Lindeman NI, Cagle PT, Beasley MB, et al., Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology, J Thorac Oncol, 2013;8:823–59.
5. Pao W, Miller VA, Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions, J Clin Oncol, 2005;23:2556–68.
6. Boch C, Kollmeier J, Roth A, et al., The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study, BMJ Open, 2013;3: pii: e002560.
7. Shi Y, Au JS, Thongprasert S, et al., A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER), J Thorac Oncol, 2014;9:154–62.
8. Mok TS, Wu YL, Thongprasert S, et al., Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma, N Engl J Med, 2009;361:947–57.
9. Inoue A, Kobayashi K, Maemondo M, et al., Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002), Ann Oncol, 2013;24:54–9.
10. Mitsudomi T, Morita S, Yatabe Y, et al., Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial, Lancet Oncol, 2010;11:121–8.
11. Maemondo M, Inoue A, Kobayashi K, et al., Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, N Engl J Med, 2010;362:2380–8. 12. Zhou C, Wu YL, Chen G, et al., Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study, Lancet Oncol, 2011;12:735–42.
13. Rosell R, Carcereny E, Gervais R, et al., Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial, Lancet Oncol, 2012;13:239–46.
14. Wu YL, Zhou C, Liam CK, et al., First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study, Ann Oncol, 2015;26:1883–9.
15. Sequist LV, Yang JC, Yamamoto N, et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, J Clin Oncol, 2013;31:3327–34.
16. Wu YL, Zhou C, Hu CP, et al., Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial, Lancet Oncol, 2014;15:213–22.
17. NCT01774721, ARCHER-1050: A Study of Dacomitinib vs. Gefitinib in 1st-Line Treatment Of Advanced NSCLC. (ARCHER 1050). Available at: https://clinicaltrials.gov/show/NCT01774721 (accessed 17 April 2016).
18. Kobayashi S, Boggon TJ, Dayaram T, et al., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, N Engl J Med, 2005;352:786–92.
19. Pao W, Miller VA, Politi KA, et al., Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain, PLoS Med, 2005;2:e73.
20. Camidge DR, Pao W, Sequist LV, Acquired resistance to TKIs in solid tumours: learning from lung cancer, Nat Rev Clin Oncol, 2014;11:473–81.
21. Miller VA, Hirsh V, Cadranel J, et al., Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial, Lancet Oncol, 2012;13:528–38.
22. Reckamp KL, Giaccone G, Camidge DR, et al., A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib, Cancer, 2014;120:1145–54.
23. Sequist LV, Besse B, Lynch TJ, et al., Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer, J Clin Oncol, 2010;28:3076–83.
24. Cross DA, Ashton SE, Ghiorghiu S, et al., AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov, 2014;4:1046–61.
25. Walter AO, Sjin RT, Haringsma HJ, et al., Discovery of a mutantselective covalent inhibitor of EGFR that overcomes T790Mmediated resistance in NSCLC, Cancer Discov, 2013;3:1404–15.
26. Janne PA, Yang JC, Kim DW, et al., AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med, 2015;372:1689–99.
27. Yang JC, Ramalingam, S.S., Janne, P.A. et al, Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase I and pooled Phase II results, Presented at: European Lung Cancer Conference; 13–16 April 2016, Geneva. Switzerland, LBA2.
28. Sequist LV, Soria JC, Goldman JW, et al., Rociletinib in EGFR-mutated non-small-cell lung cancer, N Engl J Med, 2015;372:1700–9.
29. Ayeni D, Politi K, Goldberg SB, Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer, Clin Cancer Res, 2015;21:3818–20.
30. Tan CS, Cho BC, Soo RA, Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer, Lung Cancer, 2016;93:59–68.
31. Sequist LV, Piotrowska Z, Niederst MJ, et al., Osimertinib Responses After Disease Progression in Patients Who Had Been Receiving Rociletinib, JAMA Oncol, 2016;2:541–3.
32. Ramalingam SS, Yang, JC, Lee CK, Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expasnsion cohorts, Presented at the European Lung Cancer Conference (ELCC), 2016 in Geneva, Switzerland. Abstract LBA1_PR, 2016.
33. Yang J, Ramalingam SS, Janne PA, et al., Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results, J Thorac Oncol, 2016;11:(4 Suppl):S152-3. 34.
34. Camidge DR, Activity of rociletinib in EGFR mutant NSCLC patients with a history of CNS involvement, Presented at the 16th World Conference on Lung Cancer, September 6–9 1015, Denver, USA. Abstract 965.
35. Ahn JS, Tsai, CM, Yang JCH, et al., AZD9291 activity in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) and brain metastases: data from Phase II studies, European J Cancer, 2015;51:(Suppl 3); S625–S6.
36. Kim DW, Lee DH, Kang JH, et al., Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs), J Clin Oncol, 2014;32:Abstract 8011.
37. Tan DS, Yang JC, Leighl NB, et al., Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M, J Clin Oncol, 2016;34(Suppl): abstr 9044.
38. Shaw AT, Kim DW, Nakagawa K, et al., Crizotinib versus chemotherapy in advanced ALK-positive lung cancer, N Engl J Med, 2013;368:2385–94.
39. Solomon BJ, Mok T, Kim DW, et al., First-line crizotinib versus chemotherapy in ALK-positive lung cancer, N Engl J Med, 2014;371:2167–77.
40. Kim DW, Mehra R, Tan DS, et al., Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial, Lancet Oncol, 2016;.
41. Shaw AT, Kim DW, Mehra R, et al., Ceritinib in ALK-rearranged non-small-cell lung cancer, N Engl J Med, 2014;370:1189–97.
42. Mok T, Spigel D, Felip E, et al., ASCEND-2: A single-arm, openlabel, multicenter phase II study of ceritinib in adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ). J Clin Oncol, 2015;33(Suppl): abstr 8059).
43. Crino L, Ahn MJ, De Marinis F, et al., Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2, J Clin Oncol, 2016;34:2866–73.
44. Ou SH, Ahn JS, De Petris L, et al., Alectinib in Crizotinib- Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study, J Clin Oncol, 2016;34:661–8.
45. Barlesi F, Dingemans AC, Ou I, et al., 3101 Updated efficacy and safety results from a global phase 2, open-label, single-arm study (NP28673) of alectinib in crizotinib-refractory ALK+ nonsmall- cell lung cancer (NSCLC), Eur J Cancer, 2015;51:P S635.
46. Shaw AT, Gandhi L, Gadgeel S, et al., Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial, Lancet Oncol, 2016;17:234–42.
47. Seto T, Kiura K, Nishio M, et al., CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study, Lancet Oncol, 2013;14:590–8.
48. Felip E, Orlov S, Park K, et al., ASCEND-3: A single-arm, openlabel, multicenter phase II study of ceritinib in ALKi-naïve adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), J Clin Oncol, 2015;33(suppl): abstr 8060.
49. Gadgeel SM, Gandhi L, Riely GJ, et al., Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study, Lancet Oncol, 2014;15:1119–28.
50. Ou SH, Sommers KR, Azada MC, et al., Alectinib induces a durable (>15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis, Oncologist, 2015;20:224–6.
51. Gainor JF, Sherman CA, Willoughby K, et al., Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib, J Thorac Oncol, 2015;10:232–6.
52. Gandhi L, Shaw A, Gadgeel SM, et al., A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761), J Clin Oncol, 2015;33(Suppl):abstr 8019.
53. Tan CS, Araujo A, Signorovitch JE, et al., Comparative efficacy of ceritinib and crizotinib in previously treated crizotinib-naïve anaplastic lymphoma kinase-positive (ALK+) advanced or metastatic non-small cell lung cancer (NSCLC): An adjusted indirect comparison, J Clin Oncol, 2015;33:(Suppl): abstr 8058.
54. Felip E, Orlov K, Park K, et al., Phase 2 study of ceritinib in previously treated ALKi-naïve patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC): whole body efficacy in all pts and in pts with baseline brain metastases (BM), Ann Oncol, 2016;27(Suppl 6): 1208O.
55. Scagliotti G, Kim TM, Crino L, et al., Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study, Presented at the 2016 European Society for Medical Oncology (ESMO) Congress, 7-11 October 2016, Copenhagen; Abstract LBA42_PR.
56. Costa DB, Shaw AT, Ou SH, et al., Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non- Small-Cell Lung Cancer and Brain Metastases, J Clin Oncol, 2015;33:1881–8.
57. Kerstein D, Gettinger S, Gold K, et al., LBA4 - Evaluation of anaplastic lymphoma kinase (ALK) inhibitor brigatinib [AP26113] in patients (Pts) with ALK+ non–small cell lung cancer (NSCLC) and brain metastases, Presented at ESMO 2015, Abstr LBA4, 2015.
58. Kim D-W, Tiseo, M, Ahn, M-J, et al., Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): First report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA), J Clin Oncol, 2016;34(Suppl): abstr 9007.
59. Camidge DR, Bazenhova L, Salgia R, et al., Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non–small cell lung cancer (NSCLC), J Clin Oncol, 2015;33(Suppl): abstr 8062.
60. Solomon BJ, Bauer TM, Felip E, et al., Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC), J Clin Oncol, 2016;34(Suppl): abstr 9009.
61. Horn L, Infante JR, Blumenschein GR, et al., A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors, J Clin Oncol, 2014;33:5s.
62. Maitland ML, Ou S-H, Tolcher AW, et al., Safety, activity, and pharmacokinetics of an oral anaplastic lymphoma kinase (ALK) inhibitor, ASP3026, observed in a “fast follower” phase 1 trial design, J Clin Oncol, 2014;32:5s.
63. Weiss GJ, Sachdev JC, Infante JR, et al., Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinibresistant ALK mutations, J Clin Oncol, 2014;32(suppl): abstr e19005.
64. Nokihara H, Hida T, Kondo M, et al., Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study, J Clin Oncol, 2016;34(Suppl): abstr 9008.
65. Shaw A, Tan DSW, Crino L, et al., Two Phase III studies evaluating ceritinib in patients with anaplastic lymphoma kinase-rearraged non-small cell lung cancer: ASCEND 4 and ASCEND 5, Ann Oncol, 2014;25(Suppl 4): iv469.
66. NCT02737501, ALTA-1L Study: A Phase 3 Study of Brigatinib Versus Crizotinib in ALK-positive Advanced Non-Small Cell Lung Cancer Patients (ALTA-1L). Available at: https://clinicaltrials.gov/ ct2/show/NCT02737501 (accessed 23 November 2016).
67. Rothenstein JM, Letarte N, Managing treatment-related adverse events associated with Alk inhibitors, Curr Oncol, 2014;21:19–26.
68. Katayama R, Friboulet L, Koike S, et al., Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib, Clin Cancer Res, 2014;20:5686–96.
69. Ou SH, Milliken JC, Azada MC, et al., ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression, Lung Cancer, 2016;91:70–2.
70. Shaw AT, Ou SH, Bang YJ, et al., Crizotinib in ROS1-rearranged non-small-cell lung cancer, N Engl J Med, 2014;371:1963–71.
71. Chen D, Zhang LQ, Huang JF, et al., BRAF mutations in patients with non-small cell lung cancer: a systematic review and metaanalysis, PLoS One, 2014;9:e101354.
72. Planchard D, Min Kim T B, Mazieres J, et al., Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial, Lancet Oncol, 2016;17:642–50.
73. Planchard D, Besse B, Groen HJ, et al.,Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)- mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial, Lancet Oncol, 2016,17:984-93.
74. Hyman DM, Puzanov I, Subbiah V, et al., Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations, N Engl J Med, 2015;373:726–36.
75. McCoach CE, Doebele RC, The minority report: targeting the rare oncogenes in NSCLC, Curr Treat Options Oncol, 2014;15:644–57.
76. Rekhtman N, Paik PK, Arcila ME, et al., Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/ AKT1 mutations, Clin Cancer Res, 2012;18:1167–76.
77. Giaccone G, Bazhenova LA, Nemunaitis J, et al., A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer, Eur J Cancer, 2015;51:2321–9.
78. Butts C, Socinski MA, Mitchell PL, et al., Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-smallcell lung cancer (START): a randomised, double-blind, phase 3 trial, Lancet Oncol, 2014;15:59–68.
79. Vansteenkiste J, Zielinski M, Linder A, et al., Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results, J Clin Oncol, 2013;31:2396–403.
80. 79. DuPage M, Cheung AF, Mazumdar C, et al., Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression, Cancer Cell, 2011;19:72–85.
81. 80. Rizvi NA, Hellmann MD, Snyder A, et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science, 2015;348:124–8.
82. Pardoll DM, The blockade of immune checkpoints in cancer immunotherapy, Nat Rev Cancer, 2012;12:252–64.
83. Hodi FS, O’Day SJ, McDermott DF, et al., Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 2010;363:711–23.
84. Lynch TJ, Bondarenko I, Luft A, et al., Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study, J Clin Oncol, 2012;30:2046–54.
85. Zatloukal P, Heo DS, Park K, et al., Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care following first-line platinum-based therapy in patients with advanced non-small cell lung cancer, J Clin Oncol, 2009;27:15s (suppl; abtr 8071).
86. Tumeh PC, Harview CL, Yearley JH, et al., PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature, 2014;515:568–71.
87. Chen DS, Irving BA, Hodi FS, Molecular pathways: nextgeneration immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1, Clin Cancer Res, 2012;18:6580–7.
88. Brahmer J, Reckamp KL, Baas P, et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer, N Engl J Med, 2015;373:123–35.
89. Borghaei H, Brahmer JR, Horn L, et al., Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses, J Clin Oncol, 2016;34(Suppl): abstr 9025.
90. Borghaei H, Paz-Ares L, Horn L, et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer, N Engl J Med, 2015;373:1627–39.
91. Rizvi NA, Mazieres J, Planchard D, et al., Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial, Lancet Oncol, 2015;16:257–65.
92. Gangadhar TC, Vonderheide RH, Mitigating the toxic effects of anticancer immunotherapy, Nat Rev Clin Oncol, 2014;11:91–9.
93. Garon EB, Rizvi NA, Hui R, et al., Pembrolizumab for the treatment of non-small-cell lung cancer, N Engl J Med, 2015;372:2018–28.
94. Hui R, Gandhi L, Costa EC, et al., Long-term OS for patients with advanced NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab (pembro), J Clin Oncol, 2016;34(Suppl): abstr 9026.
95. Herbst RS, Baas P, Kim DW, et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced nonsmall- cell lung cancer (KEYNOTE-010): a randomised controlled trial, Lancet, 2016;387:1540–50.
96. Soria JC, Flatten O, Felip E, et al., LBA 33: Efficacy and Safety of Pembrolizumab (Pembro; MK-3475) for Patients (Pts) With Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Enrolled in KEYNOTE-001, European J Cancer, 2015; 51:Suppl 3: S1–S810.
97. Hellmann M D, Efficacy of pembrolizumab in key subgroups of patients with advanced NSCLC, J Thorac Oncol, 2015;10(Suppl 2): MINI03.5.
98. Horn L, Spigel D, Gettinger SN et al., Clinical activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study, J Clin Oncol, 2015;33(Suppl): abstr 8029.
99. Rivzi NA, Brahmer JR, Ou S-H I, et al., Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC), J Clin Oncol, 2015;33(Suppl): abstr 8032.
100. Gulley JL, Spigel D, Kelly K, et al., Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy, J Clin Oncol, 2015;33(Suppl): abstr 8034.
101. Verschraegen CF, Chen F, Spigel DR, et al., Avelumab (MSB0010718C; anti-PD-L1) as a first-line treatment for patients with advanced NSCLC from the JAVELIN Solid Tumor phase 1b trial: Safety, clinical activity, and PD-L1 expression, J Clin Oncol, 2016;34(Suppl): abstr 9036.
102. Spigel DR, Chaft JE, Gettinger SN, et al., Clinical activity and safety from a phase II study (FIR) of MPDL3280A (anti-PDL1) in PD-L1–selected patients with non-small cell lung cancer (NSCLC), J Clin Oncol, 2015;33(Suppl): abstr 8028.
103. Fehrenbacher L, Spira A, Ballinger M, et al., Atezolizumab versus docetaxel for patients with previously treated nonsmall- cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial, Lancet, 2016;387:1837–46.
104. Smith DA, Vansteenkiste JF, Fehrenbacher L, et al., Updated survival and biomarker analyses of a randomized phase II study of atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR), J Clin Oncol, 2016;34(Suppl): abstr 9028.
105. Besse B, Johnson M, Janne PA, et al., 16LBA Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC), Eur J Cancer, 2015;51:(Suppl 3): S717–8.
106. Barlesi F, Park K, Ciadiello F, Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC, Presented at the 2016 European Society for Medical Oncology (ESMO) Congress, 7-11 October 2016, Copenhagen; Abstract LBA44_PR, 2016.
107. Socinski MA, Creelan B, Horn L, et al., CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator’s Choice (IC) of Platinum- Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1) − Positive NSCLC, Ann Oncol, 2016;27.
108. Reck M, Rodriguez-Abreu D, Robinson AG, et al., Pembrolizumab or Chemotherapy in PD-L1–Positive Non– Small-Cell Lung Cancer, N Engl J Med, 2016;epub DOI: 10.1056/ NEJMoa1606774.
109. NCT02220894, Study of MK-3475 (Pembrolizumab) Versus Platinum-based Chemotherapy for Participants With PD-L1- positive Advanced or Metastatic Non-small Cell Lung Cancer (MK-3475-042/KEYNOTE-042). Available at: https://clinicaltrials. gov/ct2/show/NCT02220894 (accessed 26 Fenruary 2016).
110. NCT01285609, Trial in Squamous Non Small Cell Lung Cancer Subjects Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin. Available at: https://clinicaltrials.gov/ct2/show/NCT01285609 (accessed 11 December 2015).
111. Mok T, Cappuzzo F, Jotte RM, et al., 356TiP - Phase III clinical trials of atezolizumab in combination with chemotherapy in chemotherapy-naive patients with advanced NSCLC, Ann Oncol, 2015;26(Suppl 9):103–6.
112. Langer CJ, Gadgeel SM, Borghaei H, 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.
113. NCT02578680, Study of Platinum+Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Non-squamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189). Available at: https://clinicaltrials. gov/ct2/show/NCT02578680 (accessed 26 May 2016).
114. NCT02775435, A Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With First Line Metastatic Squamous Non-small Cell Lung Cancer (MK-3475-407/KEYNOTE-407). Available at: https://clinicaltrials.gov/ct2/show/NCT02775435 (accessed 23 November 2016).
115. Sharon E, Polley MY, Bernstein MB, et al., Immunotherapy and radiation therapy: considerations for successfully combining radiation into the paradigm of immuno-oncology drug development, Radiat Res, 2014;182:252–7.
116. Golden EB, Demaria S, Schiff PB, et al., An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer, Cancer Immunol Res, 2013;1:365–72.
117. Stewart R, Mullins S, Watkins A, et al., Preclinical modelling of immune checkpoint blockade (P2012), J Immunol, 2013;190 (1 Meeting Abstracts): Abstract 214.7.
118. Patnaik A, Socinski MA, Gubens MA, et al., Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D, J Clin Oncol, 2015;33:suppl; abstr 8011.
119. 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:supple; abstr 9027.
120. Hellmann MD, Gettinger S, Goldman JW, et al., CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC, J Clin Oncol, 2016;34(Suppl): abstr 3001.
121. NCT02477826, An Open-Label, Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Subjects With Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227). Available at: https://clinicaltrials.gov/ct2/ show/NCT02477826 (accessed 26 February 2016).
122. Antonia S, Goldberg SB, Balmanoukian A, et al., Safety and antitumour activity of durvalumab plus tremelimumab in nonsmall cell lung cancer: a multicentre, phase 1b study, Lancet Oncol, 2016;17(3):299–308.
123. NCT02453282, Phase III Open Label First Line Therapy Study of MEDI 4736 With or Without Tremelimumab Versus SOC in Non Small-Cell Lung Cancer (NSCLC). (MYSTIC). Available at: https://clinicaltrials.gov/ct2/show/NCT02453282 (accessed 26 May 2016).
124. NCT01968109, Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors. Available at: www.clinicaltrials.gov/ct2/show/NCT01968109 (accessed 26 May 2016).
125. Infante JR, Hansen AR, Pishvaian MJ et al., A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors, J Clin Oncol, 2016;34(Suppl): abstr 101.
126. Merck, Keytruda® (pembrolizumab) for injection, for intravenous use. Available at: www.merck.com/product/usa/pi_ circulars/k/keytruda/keytruda_pi.pdf (accessed 11 July 2016).
127. BMS, Opdivo (nivolumab) for intarvenous use. Available at: http://packageinserts.bms.com/pi/pi_opdivo.pdf (accessed 11 July 2016).
128. Chan BA, Hughes BG, Targeted therapy for non-small cell lung cancer: current standards and the promise of the future, Transl Lung Cancer Res, 2015;4:36–54.
129. Soria JC, Cruz C, Bahleda R, et al., Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1), Eur J Cancer, 2013;49(Suppl):abstract 3408.
130. Paz-Ares L, Horn L, Borghaei H, et al., Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC), J Clin Oncol, 2015;33(Suppl): Abstr LBA109.
131. Lawrence MS, Stojanov P, Polak P, et al., Mutational heterogeneity in cancer and the search for new cancerassociated genes, Nature, 2013;499:214–8.
132. Alexandrov LB, Nik-Zainal S, Wedge DC, et al., Signatures of mutational processes in human cancer, Nature, 2013;500:415–21.
133. Vogelstein B, Papadopoulos N, Velculescu VE, et al., Cancer genome landscapes, Science, 2013;339:1546–58.
134. Govindan R, Ding L, Griffith M, et al., Genomic landscape of non-small cell lung cancer in smokers and never-smokers, Cell, 2012;150:1121–34.
135. Lee W, Jiang Z, Liu J, et al., The mutation spectrum revealed by paired genome sequences from a lung cancer patient, Nature, 2010;465:473–7.
136. Rooney MS, Shukla SA, Wu CJ, et al., Molecular and genetic properties of tumors associated with local immune cytolytic activity, Cell, 2015;160:48–61.
137. Carbognin L, Pilotto S, Milella M, et al., Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers, PLoS One, 2015;10:e0130142.
138. Rizvi NA, Garon EB, Leighl N, et al., Optimizing PD-L1 as a biomarker of response with pembrolizumab (pembro; MK-3475) as first-line therapy for PD-L1-positive metastatic non-small cell lung cancer (NSCLC): updated data from KEYNOTE-001, J Clin Oncol, 2015;33:suppl; abstr8026.
139. Gandini S, Massi D, Mandala M, PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis, Crit Rev Oncol Hematol, 2016;100:88–98.
140. Teixido C, Karachaliou N, Gonzalez-Cao M, et al., Assays for predicting and monitoring responses to lung cancer immunotherapy, Cancer Biol Med, 2015;12:87–95.
141. Hussein M, McCleod J, Chandler G, et al., ORAL02.02 Safety and Efficacy on nivolimumab in an ongoing trail of a PD-L1 +/- patient population with metastatic no small cell lung cancer, Presented at the 16th World Conference on Lung Cancer; September 6-9, 2015; Denver, CO, US, 2015.
142. Schalper KA, Brown J, Carvajal-Hausdorf D, et al., Objective measurement and clinical significance of TILs in non-small cell lung cancer, J Natl Cancer Inst, 2015;107.
143. D’Incecco A, Andreozzi M, Ludovini V, et al., PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients, Br J Cancer, 2015;112:95–102.
144. Sharma P, Allison JP, Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential, Cell, 2015;161:205–14.
145. Akbay EA, Koyama S, Carretero J, et al., Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors, Cancer Discov, 2013;3:1355–63.
146. Ribas A, Hodi FS, Callahan M, et al., Hepatotoxicity with combination of vemurafenib and ipilimumab, N Engl J Med, 2013;368:1365–6.
147. 146. Puzanov I, Callahan MK, Linette GP, et al., Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM), J Clin Oncol, 2014;32:5s (suppl; abstr 2511).
148. AstraZeneca pauses two lung cancer drug combination trials, October 9 2015. Available at: www.reuters.com/article/usastrazeneca- cancer-idUSKCN0S31AW20151009 (accessed 1 March 2016).
149. Ahn M, Yang J, Yu H, et al., Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial, Presented at ELCC 2016, Abstr 136O, 2016.
150. NCT02439450, Study of Combination Therapies With Viagenpumatucel-L (HS-110) in Patients With Non-Small Cell Lung Cancer. Available at: https://clinicaltrials.gov/ct2/show/ NCT02439450 (accessed 1 March 2016).
151. Wu X, Chen H, Wang X, Can lung cancer stem cells be targeted for therapies?, Cancer Treat Rev, 2012;38:580–8.
152. Guo Y, Wang Y, Han W, Chimeric Antigen Receptor-Modified T Cells for Solid Tumors: Challenges and Prospects, J Immunol Res, 2016;2016:3850839.
153. Rosenberg SA, Restifo NP, Adoptive cell transfer as personalized immunotherapy for human cancer, Science, 2015;348:62–8.
154. Thunnissen E, van der Oord K, den Bakker M, Prognostic and predictive biomarkers in lung cancer. A review, Virchows Arch, 2014;464:347–58.
155. Kim DW, Ahn MJ, Shi Y, et al., Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC), J Clin Oncol, 2012;30(Suppl): abstr 7533.
156. NCT02041533, An Open-Label, Randomized, Phase 3 Trial of Nivolumab Versus Investigator’s Choice Chemotherapy as First- Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer (CheckMate 026). Available at: https://clinicaltrials. gov/ct2/show/NCT02041533 (accessed 26 February 2016).
157. Reck M, Rodriguez-Abreu D, Robinson AG, et al., Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer, N Engl J Med, 2016: [epub ahead of print].
158. Patnaik A, Socinski M, Gubens MA, et al., Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D, J Clin Oncol, 2015;33:(Suppl; abstr 8011).