Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors

Clinical Epidemiology

Volumn 6, Issue , 2014, Pages 423-432

  Chia, Puey Ling ^a   Dobrovic, Alexander ^a,b,c   John, Thomas ^a,c  

^a AUSTIN HEALTH   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c LA TROBE UNIVERSITY   (Australia)

Author keywords

Anaplastic lymphoma kinase (ALK); Gene rearrangements; Kinase inhibitors; Lung adenocarcinoma; Lung cancer

Indexed keywords

2 [[2 (ISOPROPYLSULFONYL)PHENYL]AMINO] 4 [[2 METHOXY 4 [4 (4 METHYL 1 PIPERAZINYL) 1 PIPERIDINYL]PHENYL]AMINO] 1,3,5 TRIAZINE; 5 CHLORO 4 [[2 (ISOPROPYLSULFONYL)PHENYL]AMINO] 2 [[2 METHOXY 4 [4 (4 METHYL 1 PIPERAZINYL) 1 PIPERIDINYL]PHENYL]AMINO]PYRIMIDINE; 6 AMINO 5 [1 (2,6 DICHLORO 3 FLUOROPHENYL)ETHOXY] N [4 (4 METHYL 1 PIPERAZINYLCARBONYL)PHENYL] 3 PYRIDAZINECARBOXAMIDE; ALECTINIB; ANAPLASTIC LYMPHOMA KINASE; ANTINEOPLASTIC AGENT; CARBOPLATIN; CEP 14083; CEP 14513; CEP 28122; CERITINIB; CISPLATIN; CRIZOTINIB; DEBIO 0932; ENZYME INHIBITOR; ERLOTINIB; GANETESPIB; GSK 1838705 A; LUMINESPIB; NMS E 628; ONALESPIB; PEMETREXED; PLATINUM DERIVATIVE; PLATINUM DOUBLET; RETASPIMYCIN; UNCLASSIFIED DRUG; X 276;

ALK GENE; CANCER PROGNOSIS; DIARRHEA; DRUG APPROVAL; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; GENE IDENTIFICATION; GENE MUTATION; GENE REARRANGEMENT; GENE TARGETING; HUMAN; HYPOGONADISM; IMMUNOTHERAPY; LIVER DYSFUNCTION; LUNG ADENOCARCINOMA; NAUSEA; NON SMALL CELL LUNG CANCER; ONCOGENE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PREVALENCE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIDE EFFECT; TESTOSTERONE BLOOD LEVEL; VISUAL DISORDER; VOMITING;

EID: 84923611342     PISSN: None     EISSN: 11791349     Source Type: Journal    
DOI: 10.2147/CLEP.S69718     Document Type: Review

References (102)

1. Ferlay J, Soerjomataram I, Ervik M, et al. Cancer Incidence and Mortality Worldwide. GLOBOCAN 2012 v1.0. 20Available from: http://www.iarc.fr/en/media-centre/pr/2013/pdfs/pr223_E.pdf.
2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
3. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol. 2007;25(5):561–570.
4. Infante M, Lutman FR, Cavuto S, et al. Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. Lung Cancer. 2008;59(3):355–363.
5. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395–409.
6. Soda M, Choi YL, Enomoto M, et al. Identification of the transform­ing EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–566.
7. Arteaga CL. The epidermal growth factor receptor: from mutant onco­gene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol. 2001;19(Suppl 18):32S–40S.
8. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954.
9. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26):3574–3579.
10. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006.
11. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247–4253.
12. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14(13):4275–4283.
13. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplas­tic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8(1):11–23.
14. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013;31(8):1105–1111.
15. Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer. 2004;101(1):3–27.
16. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263(5151):1281–1284.
17. Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci. 2008;99(12):2349–2355.
18. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14(20):6618–6624.
19. Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA. 2008;105(50):19893–19897.
20. Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773–1780.
21. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15(9):3143–3149.
22. Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S. Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene. 1994;9(6):1567–1574.
23. Lamant L, Dastugue N, Pulford K, Delsol G, Mariame B. A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Blood. 1999;93(9):3088–3095.
24. Meech SJ, McGavran L, Odom LF, et al. Unusual childhood extramed­ullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4 – anaplastic lymphoma kinase gene fusion. Blood. 2001;98(4):1209–1216.
25. Colleoni GW, Bridge JA, Garicochea B, Liu J, Filippa DA, Ladanyi M. ATIC-ALK: a novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35). Am J Pathol. 2000;156(3):781–789.
26. Hernández L, Pinyol M, Hernández S, et al. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma produc­ing two structurally different TFG-ALK translocations. Blood. 1999;94(9):3265–3268.
27. Touriol C, Greenland C, Lamant L, et al. Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Blood. 2000;95(10):3204–3207.
28. Tort F, Pinyol M, Pulford K, et al. Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest. 2001;81(3):419–426.
29. Lamant L, Gascoyne RD, Duplantier MM, et al. Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. Genes Chromosomes Cancer. 2003;37(4):427–432.
30. Cools J, Wlodarska I, Somers R, et al. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer. 2002;34(4):354–362.
31. Lawrence B, Perez-Atayde A, Hibbard MK, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol. 2000;157(2):377–384.
32. Bridge JA, Kanamori M, Ma Z, et al. Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. Am J Pathol. 2001;159(2):411–415.
33. Takeuchi K, Soda M, Togashi Y, et al. Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma. Haematologica. 2011;96(3):464–467.
34. Van Roosbroeck K, Cools J, Dierickx D, et al. ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica. 2010;95(3):509–513.
35. Li T, Maus MK, Desai SJ, et al. Large-scale screening and molecular characterization of EML4-ALK fusion variants in archival non-small-cell lung cancer tumor specimens using quantitative reverse transcription polymerase chain reaction assays. J Thorac Oncol. 2014;9(1):18–25.
36. Tsao M-S, Hirsch FR, Yatabe Y. IASLC Atlas of ALK Testing in Lung Cancer. Aurora, CO, USA: IASLC; 2013.
37. Karachaliou N, Rosell R. Optimal detection of ALK rearranged lung adenocarcinomas. J Thorac Oncol. 2013;8(3):255–256.
38. Hofman P, Ilie M, Hofman V, et al. Immunohistochemistry to iden­tify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma. Ann Oncol. 2012;23(7):1738–1743.
39. Wynes MW, Sholl LM, Dietel M, et al. An International Interpretation Study using the ALK IHC antibody D5F3 and a sensitive detec­tion kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators. J Thorac Oncol. 2014;9(5):631–638.
40. Cabillic F, Gros A, Dugay F, et al. Parallel FISH and immunohistochemi­cal studies of ALK status in 3244 non-small-cell lung cancers reveal major discordances. J Thorac Oncol. 2014;9(3):295–306.
41. Conklin CM, Craddock KJ, Have C, Laskin J, Couture C, Ionescu DN. Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-small-cell lung carcinoma and is antibody dependent. J Thorac Oncol. 2013;8(1):45–51.
42. Wallander ML, Geiersbach KB, Tripp SR, Layfield LJ. Comparison of reverse transcription-polymerase chain reaction, immunohis­tochemistry, and fluorescence in situ hybridization methodologies for detection of echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase fusion-positive non-small cell lung carcinoma: implications for optimal clinical testing. Arch Pathol Lab Med. 2012;136(7):796–803.
43. Just PA, Cazes A, Audebourg A, et al. Histologic subtypes, immuno­histochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: a comprehensive study of Caucasian non-smokers. Lung Cancer. 2012;76(3):309–315.
44. Sanders HR, Li HR, Bruey JM, et al. Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer Genet. 2011;204(1):45–52.
45. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011;17(8):2081–2086.
46. Doebele RC, Lu X, Sumey C, et al. Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer. 2012;118(18):4502–4511.
47. Kang HJ, Lim HJ, Park JS, et al. Comparison of clinical character­istics between patients with ALK-positive and EGFR-positive lung adenocarcinoma. Respir Med. 2014;108(2):388–394.
48. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008;3(1):13–17.
49. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15(16):5216–5223.
50. Yoshida A, Tsuta K, Watanabe S, et al. Frequent ALK rearrangement and TTF-1/p63 co-expression in lung adenocarcinoma with signet-ring cell component. Lung Cancer. 2011;72(3):309–315.
51. Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19(15):4273–4281.
52. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4(12):1450–1454.
53. Wang J, Dong Y, Cai Y, et al. Clinicopathologic characteristics of ALK rearrangements in primary lung adenocarcinoma with identi­fied EGFR and KRAS status. J Cancer Res Clin Oncol. 2014;140(3):453–460.
54. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbour­ing ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011;12(11):1004–1012.
55. Yang P, Kulig K, Boland JM, et al. Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol. 2012;7(1):90–97.
56. Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer. 2012;118(3):729–739.
57. Lee JK, Park HS, Kim DW, et al. Comparative analyses of overall survival in patients with anaplastic lymphoma kinase-positive and matched wild-type advanced nonsmall cell lung cancer. Cancer. 2012;118(14):3579–3586.
58. Koh Y, Kim DW, Kim TM, et al. Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strat­egy for these tumors. J Thorac Oncol. 2011;6(5):905–912.
59. Fallet V, Cadranel J, Doubre H, et al. Prospective screening for ALK: clinical features and outcome according to ALK status. Eur J Cancer. 2014;50(7):1239–1246.
60. Kulig K, Wang Y, Iyer S, Yang P. Predictive and prognostic value of ALK gene rearrangement in non- small cell lung cancer. Epidemiology. 2014;4:146.
61. Zhang XC, Blanckmeister CA, Yang J, et al. Retrospective study of clinicopathologic factors associated with ALK rearrangement and survival outcome in Chinese patients with NSCLC. Cancer Res. 2012;72(8 Suppl 1):4504.
62. Wu SG, Kuo YW, Chang YL, et al. EML4-ALK translocation predicts better outcome in lung adenocarcinoma patients with wild-type EGFR. J Thorac Oncol. 2012;7(1):98–104.
63. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378–381.
64. Altavilla G, Santarpia M, Arrigo C, et al. EML4-ALK fusion gene in lung adenocarcinoma: a retrospective analysis of the outcome of cisplatin plus pemetrexed treated patients. ASCO Proc. 2010;28:565S. (abstract 7610).
65. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6(4):774–780.
66. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus che­motherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–2394.
67. Sun JM, Han J, Ahn JS, Park K, Ahn MJ. Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol. 2011;6(8):1392–1399.
68. Gandara DR, Huang E, Desai S, et al. Thymidylate synthase (TS) gene expression in patients with ALK positive (+) non-small cell lung cancer (NSCLC): implications for therapy. J Clin Oncol. 2012;30:(abstr 7582).
69. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693–1703.
70. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10): 1011–1019.
71. Weickhardt AJ, Rothman MS, Salian-Mehta S, et al. Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer. 2012;118(21):5302–5309.
72. Crinò L, Kim D, Riely GJ, et al. Initial phase 2 results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol. 2011;29(Suppl):7514.
73. Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol. 2014;32:5s(Suppl; abstr 8002).
74. 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.
75. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res. 2006;12(19):5764–5769.
76. 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(3):e73.
77. Suda K, Onozato R, Yatabe Y, Mitsudomi T. EGFR T790M mutation: a double role in lung cancer cell survival? J Thorac Oncol. 2009;4(1):1–4.
78. Bardelli A, Corso S, Bertotti A, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658–673.
79. 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(5):528–538.
80. Ohashi K, Sequist LV, Arcila ME, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene muta­tions but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci USA. 2012;109(31):E2127–E2133.
81. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31(31):3987–3996.
82. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472–1482.
83. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired cri­zotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4(120):120ra117.
84. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363(18):1734–1739.
85. Lovly CM, Pao W. Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci Transl Med. 2012;4(120):120s122.
86. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011;71(18):6051–6060.
87. 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(7):590–598.
88. Kaneda H, Yoshida T, Okamoto I. Molecularly targeted approaches herald a new era of non-small-cell lung cancer treatment. Cancer Manag Res. 2013;5:91–101.
89. Ou SH, Gadgeel S, Chiappori AA, et al. Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Paper presented at: 15th World Conference on Lung Cancer 2013; October 29, 2013; Sydney, Australia.
90. Chen J, Jiang C, Wang S. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem. 2013;56(14):5673–5674.
91. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rear­ranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–1197.
92. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C. Crizotinib-resistant NPM-ALK mutants confer dif­ferential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013;11(2):122–132.
93. Sessa C, Shapiro GI, Bhalla KN, et al. First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res. 2013;19(13):3671–3680.
94. Chen Z, Sasaki T, Tan X, et al. Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res. 2010;70(23):9827–9836.
95. Normant E, Paez G, West KA, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30(22):2581–2586.
96. Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 2010;28(33):4953–4960.
97. Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem. 2002;277(42):39858–39866.
98. Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. Curr Treat Options Oncol. August 6, 2014.
99. Rizvi NA, Chow LQM, Dirix LY, et al. Clinical trials of MPDL3280A (anti-PDL1) in patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32:5s[Suppl; Abstract TPS8123].
100. Gettinger SN, Shepherd FA, Antonia SJ, et al. First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and correlation of outcomes with PD-L1 status. J Clin Oncol. 2014;32:5s[Suppl; Abstract 8024].
101. D’Incecco A, Andreozzi M, Ludovini V, et al. PD-L1 and PD-1 expres­sion in molecularly selected non-small-cell lung cancer. J Thorac Oncol. 2014;9(Suppl 9):S7–S52.
102. Gridelli C, Peters S, Sgambato A, Casaluce F, Adjei AA, Ciardiello F, ALK inhibitors in the treatment of advanced NSCLC, 300–306.