Non-Small Cell Lung Cancer – from Immunobiology to Immunotherapy

Česká verzia

Authors: O. Bílek ^1,2; L. Bohovicová ¹; R. Demlová ^2,3; A. Poprach ¹; R. Lakomý ¹; L. Zdražilová-Dubská ^2,4
Authors place of work: Klinika komplexní onkologické péče, Masarykův onkologický ústav, Brno ¹; Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno ²; Oddělení klinických hodnocení, Masarykův onkologický ústav, Brno ³; Oddělení laboratorní medicíny, Masarykův onkologický ústav, Brno ⁴
Published in the journal: Klin Onkol 2016; 29(Supplementum 4): 78-87
Category: Review
doi: https://doi.org/10.14735/amko20164S78

Summary

Background:
The treatment of early or locally advanced stages of non-small cell lung cancer (NSCLC) is based on surgical resection or radiotherapy. Metastatic disease is always incurable, treatment is palliative, systemic based on chemotherapy or target therapy. NSCLC is the most common cause of cancer-related death worldwide, and new therapeutic approaches are needed. Based on the emerging data on the role of immune system in shaping of tumor outbreak and outcome, immunotherapy is currently in the center of interest of cancer research and therapy of solid cancers including NSCLC. Various anti-cancer vaccination approaches and antigen-independent immunomodulatory drugs are being developed and trialed. The most advanced in terms of approaching clinical practice are the so-called checkpoint inhibitors blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death of the protein and its ligand (PD-1, PD-L1). Beside innovative drug development, the field of cancer immunotherapy focuses on the identification and clinical application of effective biomarkers of clinical efficacy and on the evaluation of combinations of immunotherapeutic drugs or with classical anti-cancer approaches, such as chemotherapy, radiotherapy or with targeted therapy.

Aim:
In this review, we summarize basic principles of immnobiology of NSCLC in the context of innovative immunotherapeutics, strategy and phase III results of anti-cancer vaccines in NSCLC, results of NSCLC treatment with checkpoint inhibitors, and current challenges in immunotherapy of lung cancers.

Key words:
non-small cell lung cancer – immunotherapy – cancer vaccines – drug response biomarkers

This work was supported by MEYS – NPS I – LO1413.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
10. 6. 2016

Accepted:
16. 6. 2016

Zdroje

1. Chen Z, Fillmore CM, Hammerman PS et al. Non-small- -cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 2014; 14 (8): 535–546. doi: 10.1038/nrc3775.

2. Lee DH, Park K, Kim JH et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res 2010; 16 (4): 1307–1314. doi: 10.1158/1078-0432.CCR-09-1903.

3. Han JY, Park K, Kim SW et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012; 30 (10): 1122–1128. doi: 10.1200/JCO.2011.36.8456.

4. 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 (2): 121–128. doi: 10.1016/S1470-2045 (09) 70364-X.

5. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361 (10): 947–957. doi: 10.1056/NEJMoa0810699.

6. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12 (8): 735–742. doi: 10.1016/S1470-2045 (11) 70184-X.

7. 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 (3): 239–246. doi: 10.1016/S1470-2045 (11) 70393-X.

8. Katakami N, Atagi S, Goto K et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013; 31 (27): 3335–3341. doi: 10.1200/JCO.2012.45.0981.

9. Janjigian YY, Smit EF, Groen HJ et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov 2014; 4 (9): 1036–1045. doi: 10.1158/2159-8290.CD-14-0326.

10. 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 (18): 3076–3083. doi: 10.1200/JCO.2009.27.9414.

11. Oxnard GR, Arcila ME, Sima CS et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011; 17 (6): 1616–1622. doi: 10.1158/1078-0432.CCR-10-2692.

12. 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 (8): 1145–1154. doi: 10.1002/cncr.28561.

13. Lee JS, Hirsh V, Park K et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 2012; 30 (10): 1114–1121. doi: 10.1200/JCO.2011.36.1709.

14. Sequist LV, Soria JC, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Eng J Med 2016; 374 (23): 2296–2297. doi: 10.1056/NEJMc1602688.

15. Sequist LV, Soria JC, Goldman JW et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Eng J Med 2015; 372 (18): 1700–1709. doi: 10.1056/NEJMoa1413654.

16. 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 (9): 1046–1061. doi: 10.1158/2159-8290.CD-14-0337.

17. Yver A. Osimertinib (AZD9291) -a science-driven, collaborative approach to rapid drug design and development. Ann Oncol 2016; 27 (6): 1165–1170. doi: 10.1093/annonc/mdw129.

18. Janne PA, Yang JC, Kim DW et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Eng J Med 2015; 372 (18): 1689–1699. doi: 10.1056/NEJMoa1411817.

19. 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 (17): 1881–1888. doi: 10.1200/JCO.2014.59.0539.

20. Ou SH, Janne PA, Bartlett CH et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol 2014; 25 (2): 415–422. doi: 10.1093/annonc/mdt572.

21. 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 (10): 1119–1128. doi: 10.1016/S1470-2045 (14) 70362-6.

22. Li S, Qi X, Huang Y et al. Ceritinib (LDK378): a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer. Clin Lung Cancer 2015; 16 (2): 86–91. doi: 10.1016/j.cllc.2014.09.011.

23. Gainor JF, Tan DS, De Pas T et al. Progression-free and overall survival in ALK-positive NSCLC patients treated with sequential crizotinib and ceritinib. Clinical Cancer Res 2015; 21 (12): 2745–2752. doi: 10.1158/1078-0432.CCR-14-3009.

24. Bergethon K, Shaw AT, Ou SH et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012; 30 (8): 863–870. doi: 10.1200/JCO.2011.35.6345.

25. Rosell R, Gettinger SN, Bazhenova LA et al. 1330: Brigatinib efficacy and safety in patients (Pts) with anaplastic lymphoma kinase (ALK) -positive (ALK+) non-small cell lung cancer (NSCLC) in a phase 1/2 trial. J Thorac Oncol 2016; 11 (4 Suppl): S114. doi: 10.1016/S1556-0864 (16) 30245-3.

26. Chin LP, Soo RA, Soong R et al. Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol 2012; 7 (11): 1625–1630. doi: 10.1097/JTO.0b013e31826baf83.

27. Zou HY, Li Q, Lee JH et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 2007; 67 (9): 4408–4417.

28. Drilon A, Wang L, Hasanovic A et al. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 2013; 3 (6): 630–635.

29. Padda S, Neal JW, Wakelee HA. MET inhibitors in combination with other therapies in non-small cell lung cancer. Transl Lung Cancer Res 2012; 1 (4): 238–253. doi: 10.3978/j.issn.2218-6751.2012.10.08.

30. Dabrafenib active in rare NSCLC subtype. Cancer Discov 2016; 6 (7). OF4. doi: 10.1158/2159-8290.CD-NB2016-062.

31. Blumenschein GR Jr, Smit EF, Planchard D et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC) dagger. Ann Oncol 2015; 26 (5): 894–901. doi: 10.1093/annonc/mdv072.

32. Planchard D, Kim TM, Mazieres J et al. Dabrafenib in patients with BRAF (V600E) -positive advanced non-small- -cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 17 (5): 642–650. doi: 10.1016/S1470-2045 (16) 00077-2.

33. Janne PA, Shaw AT, Pereira JR et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013; 14 (1): 38–47. doi: 10.1016/S1470-2045 (12) 70489-8.

34. Heymach JV, Lockwood SJ, Herbst RS et al. EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer. Ann Oncol 2014; 25 (10): 1941–1948. doi: 10.1093/annonc/mdu269.

35. Coley WB. II. Contribution to the Knowledge of Sarcoma. Ann Surg 1891; 14 (3): 199–220.

36. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. Clin Orthop Relat Res 1893; 1991 (262): 3–11.

37. Ehrlich P. The partial function of cells. (Nobel Prize address given on 11 December 1908 at Stockholm). Int Arch Allergy Appl Immunol 1954; 5 (2): 67–86.

38. Ehrlich P. Address in pathology, on chemiotherapy: delivered before the Seventeenth International Congress of Medicine. Br Med J 1913; 2 (2746): 353–359.

39. Alexandrov LB, Nik-Zainal S, Wedge DC et al. Signatures of mutational processes in human cancer. Nature 2013; 500 (7463): 415–421. doi: 10.1038/nature12477.

40. McGranahan N, Furness AJ, Rosenthal R et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016; 351 (6280): 1463–1469. doi: 10.1126/science.aaf1490.

41. Gettinger SN, Horn L, Gandhi L 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 (18): 2004–2012. doi: 10.1200/JCO.2014.58.3708.

42. Jansen RL, Slingerland R, Goey SH et al. Interleukin-2 and interferon-alpha in the treatment of patients with advanced non-small-cell lung cancer. J Immunother 1992; 12 (1): 70–73.

43. Agrawal B, Gendler SJ, Longenecker BM. The biological role of mucins in cellular interactions and immune regulation: prospects for cancer immunotherapy. Mol Med Today 1998; 4 (9): 397–403.

44. DeGregorio M, Soe L, Wolf M. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small cell lung cancer (START): a randomized, double-blind, phase III trial. J Thorac Dis 2014; 6 (6): 571–573. doi: 10.3978/j.issn.2072-1439.2014.05.15.

45. Rochlitz C, Figlin R, Squiban P et al. Phase I immunotherapy with a modified vaccinia virus (MVA) ex- pressing human MUC1 as antigen-specific immunother-apy in patients with MUC1-positive advanced cancer. J Gene Med 2003; 5 (8): 690–699.

46. Quoix E, Lena H, Losonczy G et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controll- ed, phase 2b/3 trial. Lancet Oncol 2016; 17 (2): 212–223. doi: 10.1016/S1470-2045 (15) 00483-0.

47. Jang SJ, Soria JC, Wang L et al. Activation of melanoma antigen tumor antigens occurs early in lung carcinogenesis. Cancer Res 2001; 61 (21): 7959–7963.

48. Vansteenkiste JF, Cho BC, Vanakesa T et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small- -cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17 (6): 822–835. doi: 10.1016/S1470-2045 (16) 00099-1.

49. Rodriguez PC, Popa X, Martinez O et al. A Phase III clinical trial of the epidermal growth factor vaccine CIMAvax-EGF as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res 2016; 22 (15): 3782–3790. doi: 10.1158/1078-0432.CCR-15-0855.

50. 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 (16): 2321–2329. doi: 10.1016/j.ejca.2015.07.035.

51. Alfonso S, Valdes-Zayas A, Santiesteban ER et al. A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res 2014; 20 (14): 3660–3671. doi: 10.1158/1078-0432.CCR-13-1674.

52. Keir ME, Butte MJ, Freeman GJ et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677–704. doi: 10.1146/annurev.immunol.26.021607.090331.

53. 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 (17): 2046–2054. doi: 10.1200/JCO.2011.38.4032.

54. Lakomy R, Poprach A. Side effects of modern immunotherapy and how to solve them in the clinics. Klin Onkol 2015; 28 (Suppl 4): 4S103–4S114. doi: 10.14735/amko20154S103.

55. Zatloukal P, Heo DS, Park K et al. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2009; 27 (Suppl 15): abstr. 8071.

56. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Eng J Med 2015; 372 (4): 320–330. doi: 10.1056/NEJMoa1412082.

57. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Eng J Med 2012; 366 (26): 2443–2454. doi: 10.1056/NEJMoa1200690.

58. Herbst RS, Baas P, Kim DW 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 (10027): 1540–1550. doi: 10.1016/S0140-6736 (15) 01281-7.

59. Fehrenbacher L, Spira A, Ballinger M et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016; 387 (10030): 1837–1846. doi: 10.1016/S0140-6736 (16) 00587-0.

60. Besse B, Johnson M, Janne PA. 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). Ann Oncol 2015; 26 (Suppl 6): 16LBA.

61. Galon J, Mlecnik B, Bindea G et al. Towards the introduction of the ‚Immunoscore‘ in the classification of malignant tumours. J Pathol 2014; 232 (2): 199–209. doi: 10.1002/path.4287.

62. Donnem T, Kilvaer TK, Andersen S et al. Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol 2016; 27 (2): 225–232. doi: 10.1093/annonc/mdv560.

63. Antonia SJ, Larkin J, Ascierto PA. Immuno-oncology combinations: a review of clinical experience and future prospects. Clin Cancer Res 2014; 20 (24): 6258–6268. doi: 10.1158/1078-0432.CCR-14-1457.

64. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Eng J Med 2011; 364 (26): 2517–2526. doi: 10.1056/NEJMoa1104621.

65. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 2013; 105 (4): 256–265. doi: 10.1093/jnci/djs629.

66. Schilling B, Sucker A, Griewank K et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer 2013; 133 (7): 1653–1663. doi: 10.1002/ijc.28168.

67. Wolchok JD, Neyns B, Linette G et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11 (2): 155–164. doi: 10.1016/S1470-2045 (09) 70334-1.

68. Gowrishankar K, Gunatilake D, Gallagher SJ et al. Inducible but not constitutive expression of PD-L1 in human melanoma cells is dependent on activation of NF-κB. PloS One 2015; 10 (4): e0123410. doi: 10.1371/journal.pone.0123410.

69. Weide B, Martens A, Hassel JC et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res. In press 2016.

70. Martens A, Wistuba-Hamprecht K, Geukes Foppen M et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 2016; 22 (12): 2908–2918. doi: 10.1158/1078-0432.CCR-15-2412.

71. Hinman LM, Huang SM, Hackett J et al. The drug diag- nostic co-development concept paper: commentary from the 3rd FDA-DIA-PWG-PhRMA-BIO pharmacogenomics workshop. Pharmacogenomics J 2006; 6 (6): 375–380.

72. Fda.gov [homepage on the Internet]. Drug-diagnostic co-development concept paper. U.S. Food and Drug Administration, MD; [updated 2016 June 22; cited 2016 June 23]. Available from: www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm116689.pdf.

73. Fda.gov [homepage on the Internet]. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). U.S. Food and Drug Administration, MD; [updated 2016 June 22; cited 2016 June 23]. Available from: www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.