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Advances in the Development of Molecularly Targeted Agents in Non-Small-Cell Lung Cancer

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Abstract

Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional ‘one-size-fits-all’ treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.

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References

  1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. Thomas A, Liu SV, Subramaniam DS, Giaccone G. Refining the treatment of NSCLC according to histological and molecular subtypes. Nat Rev Clin Oncol. 2015;12(9):511–26.

    Article  CAS  PubMed  Google Scholar 

  3. Hiley CT, Le Quesne J, Santis G, et al. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Lancet. 2016;388(10048):1002–11.

    Article  PubMed  Google Scholar 

  4. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543–51.

    Article  CAS  PubMed  Google Scholar 

  5. Russo A, Franchina T, Ricciardi GR, et al. A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): old successes and future perspectives. Oncotarget. 2015;6(29):26814–25.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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):4247–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol. 2009;22(4):508–15.

    Article  CAS  PubMed  Google Scholar 

  8. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81.

    Article  CAS  PubMed  Google Scholar 

  9. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013;13(11):772–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Castellanos EH, Horn L. Re-evaluating progression in an era of progress: a review of first- and second-line treatment options in anaplastic lymphoma kinase-positive non-small cell lung cancer. Oncologist. 2016;21(6):755–61.

    Article  CAS  PubMed  Google Scholar 

  11. Herzberg B, Campo MJ, Gainor JF. Immune checkpoint inhibitors in non-small cell lung cancer. Oncologist. 2017;22(1):81–8.

    Article  CAS  PubMed  Google Scholar 

  12. Hampton KK, Craven RJ. Pathways driving the endocytosis of mutant and wild-type EGFR in cancer. Oncoscience. 2014;1(8):504–12.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500.

    Article  CAS  PubMed  Google Scholar 

  14. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.

    Article  CAS  PubMed  Google Scholar 

  15. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50.

    Article  CAS  Google Scholar 

  16. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46.

    Article  CAS  PubMed  Google Scholar 

  17. 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(2):154–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol. 2004;22(6):1103–9.

    Article  CAS  PubMed  Google Scholar 

  19. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290(16):2149–58.

    Article  CAS  PubMed  Google Scholar 

  20. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.

    Article  CAS  PubMed  Google Scholar 

  21. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866–74.

    Article  CAS  PubMed  Google Scholar 

  22. 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):239–46.

    Article  CAS  PubMed  Google Scholar 

  23. 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):735–42.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou C, Wu YL, Chen G, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015;26(9):1877–83.

    Article  CAS  PubMed  Google Scholar 

  25. 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(25):2380–8.

    Article  CAS  PubMed  Google Scholar 

  26. Lovly CM, Shaw AT. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res. 2014;20(9):2249–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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):528–38.

    Article  CAS  PubMed  Google Scholar 

  29. 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):3076–83.

    Article  CAS  PubMed  Google Scholar 

  30. 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):1145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.

    Article  PubMed  Google Scholar 

  32. Park K, Han JY, Kim DW, et al. 190TiP: ELUXA 1: phase II study of BI 1482694 (HM61713) in patients (pts) with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). J Thorac Oncol. 2016;11(4 Suppl.):S139.

    Article  CAS  PubMed  Google Scholar 

  33. Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9:34.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Greig SL. Osimertinib: first global approval. Drugs. 2016;76(2):263–73.

    Article  CAS  PubMed  Google Scholar 

  35. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40.

    Article  PubMed  Google Scholar 

  36. 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):1036–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Niederst MJ, Hu H, Mulvey HE, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res. 2015;21(17):3924–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jia Y, Yun CH, Park E, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534(7605):129–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26.

    Article  CAS  PubMed  Google Scholar 

  42. 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):561–6.

    Article  CAS  PubMed  Google Scholar 

  43. 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):1734–9.

    Article  CAS  PubMed  Google Scholar 

  44. 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):3143–9.

    Article  CAS  PubMed  Google Scholar 

  45. 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):1450–4.

    Article  PubMed  Google Scholar 

  46. Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res. 2010;16(22):5581–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol. 2010;17(3):889–97.

    Article  PubMed  Google Scholar 

  48. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115(8):1723–33.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer. 2010;9:188.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 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):1011–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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(24):2866–73.

    Article  CAS  PubMed  Google Scholar 

  52. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.

    Article  CAS  PubMed  Google Scholar 

  53. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.

    Article  PubMed  CAS  Google Scholar 

  54. Gainor JF, Dardaei L, Yoda S, 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.

    Article  CAS  PubMed  Google Scholar 

  55. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):120ra17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 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):1472–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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):6051–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7(12):1807–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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):1881–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Friboulet L, Li N, Katayama R, Lee CC, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4(6):662–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lovly CM, McDonald NT, Chen H, et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med. 2014;20(9):1027–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Felip E, Orlov S, Park K, et al. ASCEND-3: a single-arm, open-label, 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:abstract 8060.

    Google Scholar 

  64. Scagliotti G, Kim TM, Crinò 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. Ann Oncol. 2016;27(6):1–36.

    Google Scholar 

  65. Kodama T, Tsukaguchi T, Yoshida M, et al. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett. 2014;351(2):215–21.

    Article  CAS  PubMed  Google Scholar 

  66. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19(5):679–90.

    Article  CAS  PubMed  Google Scholar 

  67. 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(2):234–42.

    Article  CAS  PubMed  Google Scholar 

  68. Soria JC, Tan DS, Chiari R, 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(10072):917–29.

    Article  CAS  PubMed  Google Scholar 

  69. 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:abstract 9008.

    Google Scholar 

  70. Gettinger SN, Bazhenova LA, Langer CJ, 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(12):1683–96.

    Article  CAS  PubMed  Google Scholar 

  71. 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:abstract 9009.

    Google Scholar 

  72. Lovly CM, Heuckmann JM, de Stanchina E, et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res. 2011;71(14):4920–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Iams WT, Lovly CM. Anaplastic lymphoma kinase as a therapeutic target in non-small cell lung cancer. Cancer J. 2015;21(5):378–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Isozaki H, Ichihara E, Takigawa N, et al. Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases. Cancer Res. 2016;76(6):1506–16.

    Article  CAS  PubMed  Google Scholar 

  75. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378–81.

    Article  CAS  PubMed  Google Scholar 

  76. Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res. 2012;18(17):4570–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131(6):1190–203.

    Article  CAS  PubMed  Google Scholar 

  79. Pan Y, Zhang Y, Li Y, et al. ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features. Lung Cancer. 2014;84(2):121–6.

    Article  PubMed  Google Scholar 

  80. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Kazandjian D, Blumenthal GM, Luo L, et al. Benefit-risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive, metastatic non-small cell lung cancer. Oncologist. 2016;21(8):974–80.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Mazieres J, Zalcman G, Crino L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol. 2015;33(9):992–9.

    Article  CAS  PubMed  Google Scholar 

  83. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016;8(1):32–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013;14(8):777–86.

    Article  CAS  PubMed  Google Scholar 

  85. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11(8):473–81.

    Article  CAS  PubMed  Google Scholar 

  86. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700–9.

    Article  PubMed  Google Scholar 

  87. Grommes C, Oxnard GR, Kris MG, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13(12):1364–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17(19):6298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Pop O, Pirvu A, Toffart AC, Moro-Sibilot D. Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol. 2012;7(8):e1–2.

    Article  PubMed  Google Scholar 

  90. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990–8.

    Article  CAS  PubMed  Google Scholar 

  91. Yap TA, Macklin-Doherty A, Popat S. Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer. Eur J Cancer. 2016;17(70):12–21.

    Google Scholar 

  92. Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501(7467):338–45.

    Article  CAS  PubMed  Google Scholar 

  93. Burrell RA, Swanton C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol Oncol. 2014;8(6):1095–111.

    Article  CAS  PubMed  Google Scholar 

  94. Frenel JS, Carreira S, Goodall J, et al. Serial next-generation sequencing of circulating cell-free DNA evaluating tumor clone response to molecularly targeted drug administration. Clin Cancer Res. 2015;21(20):4586–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ledford H. Cancer: the Ras renaissance. Nature. 2015;520(7547):278–80.

    Article  CAS  PubMed  Google Scholar 

  96. 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.

    Article  PubMed  CAS  Google Scholar 

  97. Jänne PA, van den Heuvel M, Barlesi F, et al. Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: results from the phase III SELECT-1 trial. Ann Oncol. 2016;27(6):894.

    Google Scholar 

  98. Carter CA, Rajan A, Keen C, et al. Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer. Ann Oncol. 2016;27(4):693–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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). Ann Oncol. 2015;26(5):894–901.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Harris SJ, Luken MJ, Perez DR, et al. Updated efficacy and safety results from the phase I study of intermittent dosing of the dual MEK/RAF inhibitor, RO5126766 in patients (pts) with RAS/RAF mutated advanced solid tumours. J Clin Oncol. 2016;34 Suppl:abstract 2582.

    Google Scholar 

  101. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Villaruz LC, Socinski MA, Abberbock S, et al. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. Cancer. 2015;121(3):448–56.

    Article  CAS  PubMed  Google Scholar 

  103. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18(10):2095–103.

    Article  CAS  PubMed  Google Scholar 

  105. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: the TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18(12):2354–62.

    Article  CAS  PubMed  Google Scholar 

  106. 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):642–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Planchard D, Groen HJM, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 Suppl:abstract 8006.

    Google Scholar 

  108. Guo B, Cen H, Tan X, et al. Prognostic value of MET gene copy number and protein expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of published literatures. PLoS One. 2014;9(6):e99399.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Kubo T, Yamamoto H, Lockwood WW, et al. MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. Int J Cancer. 2009;124(8):1778–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Spigel DR, Edelman MJ, O’Byrne K, et al. Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. J Clin Oncol. 2014;32(5 Suppl):abstract 8000.

    Google Scholar 

  111. Munshi N, Jeay S, Li Y, et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010;9(6):1544–53.

    Article  CAS  PubMed  Google Scholar 

  112. Katayama R, Aoyama A, Yamori T, et al. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res. 2013;73(10):3087–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Basilico C, Pennacchietti S, Vigna E, et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin Cancer Res. 2013;19(9):2381–92.

    Article  CAS  PubMed  Google Scholar 

  114. Scagliotti G, von Pawel J, Novello S, et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015;33(24):2667–74.

    Article  CAS  PubMed  Google Scholar 

  115. Koeppen H, Yu W, Zha J, et al. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib ± onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014;20(17):4488–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850–9.

    Article  CAS  PubMed  Google Scholar 

  117. Spoerke JM, O’Brien C, Huw L, et al. Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res. 2012;18(24):6771–83.

    Article  CAS  PubMed  Google Scholar 

  118. Malanga D, Scrima M, De Marco C, et al. Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle. 2008;7(5):665–9.

    Article  CAS  PubMed  Google Scholar 

  119. Soria JC, Shepherd FA, Douillard JY, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol. 2009;20(10):1674–81.

    Article  PubMed  Google Scholar 

  120. Ramalingam SS, Owonikoko TK, Behera M, et al. Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer. J Thorac Oncol. 2013;8(3):369–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Vansteenkiste JF, Canon JL, Braud FD, et al. Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the phase II BASALT-1 study. J Thorac Oncol. 2015;10(9):1319–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Basu B, Roda-Perez D, Wong HH, et al. Phase I multicentre TAX-TORC trial of the dual MTORC1/2 inhibitor AZD2014 (A) plus weekly paclitaxel (P) in patients (pts) with solid tumours. Ann Oncol 2014;25(Suppl 4):iv156.

  123. Krebs M, Spicer J, Steele N, et al. TAX-TORC: the novel combination of weekly paclitaxel and the dual mTORC1/2 inhibitor AZD2014 for the treatment of squamous NSCLC. In: Presented at WCLC; 2016.

  124. Janne PA, Cohen RB, Laird AD, et al. Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J Thorac Oncol. 2014;9(3):316–23.

    Article  PubMed  CAS  Google Scholar 

  125. Mukherjee B, Tomimatsu N, Amancherla K, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia. 2012;14(1):34–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–25.

    Article  CAS  Google Scholar 

  127. Nogova L, Sequist LV, Cassier PA, et al. Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398. J Clin Oncol. 2014;32(5 Suppl):abstract 8034.

    Google Scholar 

  128. Paik PK, Shen R, Ferry D, et al. A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: preliminary antitumor activity and pharmacodynamic data. J Clin Oncol. 2014;32(5 Suppl):abstract 8035.

    Google Scholar 

  129. Weeden CE, Solomon B, Asselin-Labat ML. FGFR1 inhibition in lung squamous cell carcinoma: questions and controversies. Cell Death Discov. 2015;1:15049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Michels S, Scheel AH, Scheffler M, et al. Clinicopathological characteristics of RET rearranged lung cancer in European patients. J Thorac Oncol. 2016;11(1):122–7.

    Article  PubMed  Google Scholar 

  131. Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30(35):4352–9.

    Article  CAS  PubMed  Google Scholar 

  132. Lin C, Wang S, Xie W, et al. Apatinib inhibits cellular invasion and migration by fusion kinase KIF5B-RET via suppressing RET/Src signaling pathway. Oncotarget. 2016;7(37):59236–44.

    PubMed  PubMed Central  Google Scholar 

  133. Kohno T, Tsuta K, Tsuchihara K, et al. RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci. 2013;104(11):1396–400.

    Article  CAS  PubMed  Google Scholar 

  134. Borrello MG, Ardini E, Locati LD, et al. RET inhibition: implications in cancer therapy. Expert Opin Ther Targets. 2013;17(4):403–19.

    Article  CAS  PubMed  Google Scholar 

  135. Lin JJ, Kennedy E, Sequist LV, et al. Clinical activity of alectinib in advanced RET-rearranged non-small cell lung cancer. J Thorac Oncol. 2016;11(11):2027–32.

    Article  PubMed  Google Scholar 

  136. Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3(6):630–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mologni L, Gambacorti-Passerini C, Goekjian P, Scapozza L. RET kinase inhibitors: a review of recent patents (2012–2015). Expert Opin Ther Patents. 2017;27(1):91–9.

    Article  CAS  Google Scholar 

  138. Gautschi O, Zander T, Keller FA, et al. A patient with lung adenocarcinoma and RET fusion treated with vandetanib. J Thorac Oncol. 2013;8(5):e43–4.

    Article  PubMed  Google Scholar 

  139. Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17(12):1653–60.

    Article  CAS  PubMed  Google Scholar 

  140. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Scarborough HA, Helfrich BA, Casas-Selves M, et al. AZ1366: an inhibitor of tankyrase and the canonical Wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition. Clin Cancer Res. 2017;23(6):1531–41.

    Article  CAS  PubMed  Google Scholar 

  142. Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18(18):4910–8.

    Article  CAS  PubMed  Google Scholar 

  143. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004;15(1):19–27.

    Article  CAS  PubMed  Google Scholar 

  144. De Greve J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012;76(1):123–7.

    Article  PubMed  Google Scholar 

  145. Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol. 2014;32(2):68–75.

    Article  CAS  PubMed  Google Scholar 

  146. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rolfo C, Ruiz R, Giovannetti E, et al. Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493–500.

    Article  CAS  PubMed  Google Scholar 

  148. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1(1):78–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Johnson FM, Bekele BN, Feng L, et al. Phase II study of dasatinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(30):4609–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ramalingam S, Goss G, Rosell R, et al. A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ann Oncol. 2015;26(8):1741–8.

    Article  CAS  PubMed  Google Scholar 

  151. 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):4953–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ramalingam SS, Maitland ML, Frankel P, et al. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(1):56–62.

    Article  CAS  PubMed  Google Scholar 

  153. Kroesen M, Gielen P, Brok IC, et al. HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget. 2014;5(16):6558–72.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011;104(3):392–8.

    Article  CAS  PubMed  Google Scholar 

  155. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  157. Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31(8):1039–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Tsao AS, Scagliotti GV, Bunn PA Jr, et al. Scientific advances in lung cancer 2015. J Thorac Oncol. 2016;11(5):613–38.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Royal Marsden NHS Foundation Trust, London, UK

    Saoirse O. Dolly, Dearbhaile C. Collins, Raghav Sundar, Sanjay Popat & Timothy A. Yap

  2. Drug Development Unit and Lung Cancer Unit, The Institute of Cancer Research and Royal Marsden Hospital, Downs Road, London, SM2 5PT, UK

    Timothy A. Yap

  3. National University Health System, Singapore, Singapore

    Raghav Sundar

  4. National Heart and Lung Institute, Imperial College London, London, UK

    Sanjay Popat

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  1. Saoirse O. Dolly
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  2. Dearbhaile C. Collins
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Correspondence to Timothy A. Yap.

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Funding

No direct funding was received for the preparation of this manuscript. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research UK. Support is also provided by the Experimental Cancer Medicine Centre (to the Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research). TAY acknowledges funding from the Academy of Medical Sciences and the British Lung Foundation.

Conflict of interest

TAY is a consultant to Pfizer, Bristol-Myers Squibb, Clovis Oncology, and Ignyta Inc., has received research funding from AstraZeneca, Vertex, and Clearbridge Biomedics, and has received travel support from MSD Oncology, Janssen-Cilag, Vertex, and Bristol-Myers Squibb. SP is a consultant to Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer, and Eli Lilly, has received honoraria from Boehringer Ingelheim, Pfizer, and Eli Lilly, has received travel expenses from Boehringer Ingelheim, Bristol-Myers Squibb, MSD, and Pfizer, and has received research funding from Boehringer Ingelheim and Pierre Fabre.

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Dolly, S.O., Collins, D.C., Sundar, R. et al. Advances in the Development of Molecularly Targeted Agents in Non-Small-Cell Lung Cancer. Drugs 77, 813–827 (2017). https://doi.org/10.1007/s40265-017-0732-2

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