Advertisement

ALK and Others: How Important Are ALK and Other Mutations in the Management of Lung Cancer?

  • Hisatsugu Goto
  • Yasuhiko Nishioka
Chapter
Part of the Respiratory Disease Series: Diagnostic Tools and Disease Managements book series (RDSDTDM)

Abstract

The discovery of gene aberrations that drive cancer progression has led to new ways in classifying lung cancer and to the development of various molecular-targeted agents. Over the last decade, treatment strategies for non-small cell lung cancer (NSCLC) patients have rapidly evolved beyond conventional chemotherapy with molecular-targeted agents. Gene aberration in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) has successfully being targeted, and the corresponding tyrosine kinase inhibitors revolutionarily improved the survival of a subset of NSCLC patients. In addition to EGFR and ALK, other oncogenic driver mutations such as ROS, RET, MET, and BRAF have also been identified as minor mutations, and some corresponding inhibitors are in development with success in clinical trials. In the near future, lung cancer is expected to be routinely fractionated into minor populations based on their gene aberration status. This chapter reviews oncogenic mechanisms of minor gene aberrations in NSCLC and discusses the corresponding treatment strategies, mechanism of resistance, and how they are important in the treatment of NSCLC, with particular emphasis on ALK rearrangement.

Keywords

Non-small cell lung cancer ALK Minor mutation 

Reference

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.  https://doi.org/10.3322/caac.21387.CrossRefPubMedGoogle Scholar
  2. 2.
    Passaro A, Lazzari C, Karachaliou N, Spitaleri G, Pochesci A, Catania C, et al. Personalized treatment in advanced ALK-positive non-small cell lung cancer: from bench to clinical practice. Onco Targets Ther. 2016;9:6361–76.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61:203–12.CrossRefPubMedGoogle Scholar
  4. 4.
    Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 1994;263:1281–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Lin JJ, Riely GJ, Shaw AT. Targeting ALK: precision medicine takes on drug resistance. Cancer Discov. 2017;7:137–55.  https://doi.org/10.1158/2159-8290.CD-16-1123.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Caccese M, Ferrara R, Pilotto S, Carbognin L, Grizzi G, Caliò A, et al. Current and developing therapies for the treatment of non-small cell lung cancer with ALK abnormalities: update and perspectives for clinical practice. Expert Opin Pharmacother. 2016;17:2253–66.CrossRefPubMedGoogle Scholar
  8. 8.
    Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.  https://doi.org/10.1200/JCO.2009.22.6993.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013;31:1105–11.  https://doi.org/10.1200/JCO.2012.44.5353.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, 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;13:1011–9.  https://doi.org/10.1016/S1470-2045(12)70344-3.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.  https://doi.org/10.1056/NEJMoa1408440.CrossRefPubMedGoogle Scholar
  12. 12.
    Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.  https://doi.org/10.1056/NEJMoa1214886.CrossRefPubMedGoogle Scholar
  13. 13.
    Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88:108–11.  https://doi.org/10.1016/j.lungcan.2015.01.020.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, 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.  https://doi.org/10.1200/JCO.2014.59.0539.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5.  https://doi.org/10.1200/JCO.2010.34.1313.CrossRefPubMedGoogle Scholar
  16. 16.
    Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013;56:5675–90.  https://doi.org/10.1021/jm400402q.CrossRefPubMedGoogle Scholar
  17. 17.
    Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, 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;17:452–63.  https://doi.org/10.1016/S1470-2045(15)00614-2.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Crinò L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, 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.  https://doi.org/10.1200/JCO.2015.65.5936.CrossRefPubMedGoogle Scholar
  19. 19.
    Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389:917–29.  https://doi.org/10.1016/S0140-6736(17)30123-X.CrossRefPubMedGoogle Scholar
  20. 20.
    Toyokawa G, Seto T, Takenoyama M, Ichinose Y. W'ALK' into the next stage. Clin Lung Cancer. 2017;18:122–6.  https://doi.org/10.1016/j.cllc.2016.10.005.CrossRefPubMedGoogle Scholar
  21. 21.
    Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, 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.  https://doi.org/10.1016/S1470-2045(13)70142-6.CrossRefPubMedGoogle Scholar
  22. 22.
    Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, 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.  https://doi.org/10.1016/S1470-2045(14)70362-6.CrossRefPubMedGoogle Scholar
  23. 23.
    Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, 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.  https://doi.org/10.1200/JCO.2015.63.9443.CrossRefPubMedGoogle Scholar
  24. 24.
    Gettinger SN, Bazhenova LA, Langer CJ, Salgia R, Gold KA, Rosell R, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:1683–96.  https://doi.org/10.1016/S1470-2045(16)30392-8.CrossRefPubMedGoogle Scholar
  25. 25.
    Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6(10):1118–33.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014;57:4720–44.  https://doi.org/10.1021/jm500261q.CrossRefPubMedGoogle Scholar
  27. 27.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.CrossRefPubMedGoogle Scholar
  28. 28.
    Bradshaw M, Mansfield A, Peikert T. The role of vascular endothelial growth factor in the pathogenesis, diagnosis and treatment of malignant pleural effusion. Curr Oncol Rep. 2013;15:207–16.  https://doi.org/10.1007/s11912-013-0315-7.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ilhan-Mutlu A, Osswald M, Liao Y, Gömmel M, Reck M, Miles D, et al. Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Mol Cancer Ther. 2016;15:702–10.  https://doi.org/10.1158/1535-7163.MCT-15-0582.CrossRefPubMedGoogle Scholar
  30. 30.
    Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15:1236–44.  https://doi.org/10.1016/S1470-2045(14)70381-X.CrossRefPubMedGoogle Scholar
  31. 31.
    Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.  https://doi.org/10.1056/NEJMoa1504627.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.  https://doi.org/10.1056/NEJMoa1501824.CrossRefGoogle Scholar
  33. 33.
    Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.  https://doi.org/10.1016/S0140-6736(15)01281-7.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22:4585–93.  https://doi.org/10.1158/1078-0432.CCR-15-3101.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res. 2015;21:4014–21.  https://doi.org/10.1158/1078-0432.CCR-15-0016.CrossRefPubMedGoogle Scholar
  36. 36.
    Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–71.  https://doi.org/10.1056/NEJMoa1406766.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med. 2017;5:42–50.  https://doi.org/10.1016/S2213-2600(16)30322-8.CrossRefPubMedGoogle Scholar
  38. 38.
    Zugazagoitia J, Molina-Pinelo S, Lopez-Rios F, Paz-Ares L. Biological therapies in nonsmall cell lung cancer. Eur Respir J. 2017;49. pii: 1601520.  https://doi.org/10.1183/13993003.01520-2016.CrossRefPubMedGoogle Scholar
  39. 39.
    Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5:842–9.  https://doi.org/10.1158/2159-8290.CD-14-1467.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, 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;17:642–50.  https://doi.org/10.1016/S1470-2045(16)00077-2.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, 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.  https://doi.org/10.1016/S1470-2045(16)30146-2.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mazières J, Barlesi F, Filleron T, Besse B, Monnet I, Beau-Faller M, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27:281–6.  https://doi.org/10.1093/annonc/mdv573.CrossRefPubMedGoogle Scholar
  43. 43.
    Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O'Connell J, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015;26(7):1421.  https://doi.org/10.1093/annonc/mdv186.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical SciencesTokushima UniversityTokushimaJapan

Personalised recommendations