Skip to main content
SpringerLink
Log in

Targeted Therapies in Non-small-Cell Lung Cancer

  • Chapter
  • First Online:
Precision Medicine in Cancer Therapy

Part of the book series: Cancer Treatment and Research ((CTAR,volume 178))

Abstract

The treatment landscape for non-small-cell lung cancer (NSCLC) has dramatically shifted over the past two decades. Targeted or precision medicine has primarily been responsible for this shift. Older paradigms of treating metastatic NSCLC with cytotoxic chemotherapy, while still important, have given way to evaluating tumor tissues for specific driver mutations that can be treated with targeted agents. Patients treated with targeted agents frequently have improved progression-free survival and overall survival compared to patients without a targetable driver mutation, highlighting the clinical benefit of precision medicine. In this chapter, we explore the historic landmark trials, the current state of the field, and potential future targets under investigation, in this exciting, rapidly evolving discipline of precision medicine in lung cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Wheeler DA, Wang L (2013) From human genome to cancer genome: the first decade. Genome Res 23(7):1054–1062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gong J et al (2018) Value-based genomics. Oncotarget 9(21):15792–15815

    Article  PubMed  PubMed Central  Google Scholar 

  3. National Human Genome Research Institute (NHGRI) (2003) Human genome project completion: frequently asked questions. In: National Human Genome Research Institute (ed) 2003 release: international consortium completes HGP

    Google Scholar 

  4. El-Metwally S, Ouda OM, Helmy M (2014) Next generation sequencing technologies and challenges in sequence assembly. SpringerBriefs in Systems Biology, vol 7. XII, 118 11 b/w illustrations, 1 illustrations in colour. Springer-Verlag, New York

    Chapter  Google Scholar 

  5. Mardis ER (2011) A decade’s perspective on DNA sequencing technology. Nature 470(7333):198–203

    Article  CAS  PubMed  Google Scholar 

  6. Wheeler DA et al (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452(7189):872–876

    Article  CAS  PubMed  Google Scholar 

  7. Goodwin S, McPherson JD, McCombie WR (2016) Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet 17(6):333–351

    Article  CAS  PubMed  Google Scholar 

  8. Heather JM, Chain B (2016) The sequence of sequencers: the history of sequencing DNA. Genomics 107(1):1–8

    Article  CAS  PubMed  Google Scholar 

  9. Quail MA et al (2012) A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers. BMC Genom 13:341

    Article  CAS  Google Scholar 

  10. Feliubadalo L et al (2017) Benchmarking of whole exome sequencing and ad hoc designed panels for genetic testing of hereditary cancer. Sci Rep 7:37984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Khotskaya YB, Mills GB, Mills Shaw KR (2017) Next-generation sequencing and result interpretation in clinical oncology: challenges of personalized cancer therapy. Annu Rev Med 68:113–125

    Article  CAS  PubMed  Google Scholar 

  12. Schram AM, Berger MF, Hyman DM (2017) Precision oncology: charting a path forward to broader deployment of genomic profiling. PLoS Med 14(2):e1002242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Cubiella J et al (1999) Prognostic factors in nonresectable pancreatic adenocarcinoma: a rationale to design therapeutic trials. Am J Gastroenterol 94(5):1271–1278

    Article  CAS  PubMed  Google Scholar 

  14. Frampton GM et al (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31(11):1023–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Herzog TJ et al (2016) Impact of molecular profiling on overall survival of patients with advanced ovarian cancer. Oncotarget 7(15):19840–19849

    Article  PubMed  PubMed Central  Google Scholar 

  16. Radovich M et al (2016) Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers. Oncotarget 7(35):56491–56500

    Article  PubMed  PubMed Central  Google Scholar 

  17. Weiss GJ et al (2015) Evaluation and comparison of two commercially available targeted next-generation sequencing platforms to assist oncology decision making. Onco Targets Ther 8:959–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sboner A et al (2011) The real cost of sequencing: higher than you think! Genome Biol 12(8):125

    Article  PubMed  PubMed Central  Google Scholar 

  19. Frank M et al (2013) Genome sequencing: a systematic review of health economic evidence. Health Econ Rev 3(1):29

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jardim DL et al (2015) Impact of a biomarker-based strategy on oncology drug development: a meta-analysis of clinical trials leading to FDA approval. J Natl Cancer Inst 107(11)

    Google Scholar 

  21. Schwaederle M et al (2015) Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. J Clin Oncol 33(32):3817–3825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schwaederle M et al (2016) Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis. JAMA Oncol 2(11):1452–1459

    Article  PubMed  Google Scholar 

  23. Ocana A et al (2015) Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses. Oncotarget 6(37):39538–39549

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511(7511):543–550

    Article  CAS  Google Scholar 

  25. Sholl LM et al (2015) Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the Lung Cancer Mutation Consortium experience. J Thorac Oncol 10(5):768–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sabari JK et al (2017) Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol 14(9):549–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. George J et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524(7563):47–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pesch B et al (2012) Cigarette smoking and lung cancer—relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer 131(5):1210–1219

    Article  CAS  PubMed  Google Scholar 

  29. Ellison G et al (2013) EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol 66(2):79–89

    Article  CAS  PubMed  Google Scholar 

  30. Mayo-de-Las-Casas C et al (2017) Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions. Ann Oncol 28(9):2248–2255

    Article  CAS  PubMed  Google Scholar 

  31. Toor OM et al (2018) Correlation of somatic genomic alterations between tissue genomics and ctDNA employing next-generation sequencing: analysis of lung and gastrointestinal cancers. Mol Cancer Ther 17(5):1123–1132

    Article  CAS  PubMed  Google Scholar 

  32. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137

    Article  CAS  PubMed  Google Scholar 

  33. Rosell R et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361(10):958–967

    Article  CAS  PubMed  Google Scholar 

  34. Midha A, Dearden S, McCormack R (2015) EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 5(9):2892–2911

    PubMed  PubMed Central  Google Scholar 

  35. Shi Y et al (2014) 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 9(2):154–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang S, Wang Z (2014) EGFR mutations in patients with non-small cell lung cancer from mainland China and their relationships with clinicopathological features: a meta-analysis. Int J Clin Exp Med 7(8):1967–1978

    PubMed  PubMed Central  Google Scholar 

  37. Information NCfB, NIH. PubChem. NIH

    Google Scholar 

  38. Soria JC et al (2018) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378(2):113–125

    Article  CAS  PubMed  Google Scholar 

  39. Xu J, Wang J, Zhang S (2017) Mechanisms of resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors and therapeutic strategies in non-small cell lung cancer. Oncotarget 8(52):90557–90578

    PubMed  PubMed Central  Google Scholar 

  40. Mok TS et al (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376(7):629–640

    Article  CAS  PubMed  Google Scholar 

  41. Lee CK et al (2013) Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 105(9):595–605

    Article  CAS  PubMed  Google Scholar 

  42. Zhou C et al (2011) 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 12(8):735–742

    Article  CAS  PubMed  Google Scholar 

  43. Zhou C et al (2015) 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 26(9):1877–1883

    Article  CAS  PubMed  Google Scholar 

  44. Rosell R et al (2012) 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 13(3):239–246

    Article  CAS  PubMed  Google Scholar 

  45. Wu YL et al (2015) First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 26(9):1883–1889

    Article  PubMed  Google Scholar 

  46. Fukuoka M et al (2011) 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 29(21):2866–2874

    Article  CAS  PubMed  Google Scholar 

  47. Mok TS et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957

    Article  CAS  PubMed  Google Scholar 

  48. Maemondo M et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388

    Article  CAS  PubMed  Google Scholar 

  49. Sequist LV et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3327–3334

    Article  CAS  PubMed  Google Scholar 

  50. Yang JC et al (2013) Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3342–3350

    Article  CAS  PubMed  Google Scholar 

  51. Wu YL et al (2014) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15(2):213–222

    Article  CAS  PubMed  Google Scholar 

  52. Yang JC et al (2015) Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 16(2):141–151

    Article  CAS  PubMed  Google Scholar 

  53. Yang JC et al (2015) Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16(7):830–838

    Article  CAS  PubMed  Google Scholar 

  54. Wu YL et al (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18(11):1454–1466

    Article  CAS  PubMed  Google Scholar 

  55. Yang JJ et al (2017) A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 116(5):568–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Paz-Ares L et al (2017) Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol 28(2):270–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chabon JJ et al (2016) Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 7:11815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Piotrowska Z et al (2017) MET amplification (amp) as a resistance mechanism to osimertinib. J Clin Oncol 35:6

    Article  Google Scholar 

  59. Sequist LV et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3(75):75ra26

    Google Scholar 

  60. Nishie K et al (2012) Epidermal growth factor receptor tyrosine kinase inhibitors beyond progressive disease: a retrospective analysis for Japanese patients with activating EGFR mutations. J Thorac Oncol 7(11):1722–1727

    Article  CAS  PubMed  Google Scholar 

  61. Seto T et al (2014) 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 15(11):1236–1244

    Article  CAS  PubMed  Google Scholar 

  62. Wu YL et al (2013) 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 14(8):777–786

    Article  CAS  PubMed  Google Scholar 

  63. Cheng Y et al (2016) Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol 34(27):3258–3266

    Article  CAS  PubMed  Google Scholar 

  64. Gatzemeier U et al (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25(12):1545–1552

    Article  CAS  PubMed  Google Scholar 

  65. Giaccone G et al (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 22(5):777–784

    Google Scholar 

  66. Herbst RS et al (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 22(5):785–794

    Google Scholar 

  67. Herbst RS et al (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23(25):5892–5899

    Article  CAS  PubMed  Google Scholar 

  68. Mok TSK et al (2017) Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses. J Clin Oncol 35(36):4027–4034

    Article  CAS  PubMed  Google Scholar 

  69. Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Crino L et al (2011) Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol 29(15):1

    Google Scholar 

  71. Solomon BJ et al (2014) First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371(23):2167–2177

    Article  CAS  PubMed  Google Scholar 

  72. Awad MM, Shaw AT (2014) ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol 12(7):429–439

    PubMed  PubMed Central  Google Scholar 

  73. Shaw AT et al (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371(21):1963–1971

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Shaw AT et al (2017) Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 18(7):874–886

    Article  CAS  PubMed  Google Scholar 

  75. Yang JC et al (2017) Pooled systemic efficacy and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small cell lung cancer. J Thorac Oncol 12(10):1552–1560

    Article  PubMed  PubMed Central  Google Scholar 

  76. Shaw AT et al (2016) Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17(2):234–242

    Article  CAS  PubMed  Google Scholar 

  77. Bendell JC et al (2016) Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 34(15):2

    Google Scholar 

  78. Peters S et al (2017) Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377(9):829–838

    Article  CAS  PubMed  Google Scholar 

  79. Kim DW et al (2017) Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 35(22):2490–2498

    Article  CAS  PubMed  Google Scholar 

  80. Shaw AT et al (2017) Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 18(12):1590–1599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Davies KD, Doebele RC (2013) Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res 19(15):4040–4045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rossi G et al (2017) Detection of ROS1 rearrangement in non-small cell lung cancer: current and future perspectives. Lung Cancer (Auckl) 8:45–55

    CAS  Google Scholar 

  83. Ogura H et al (2017) TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity. Sci Rep 7(1):5519

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Bergethon K et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30(8):863–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sporn JR (1999) Practical recommendations for the management of adenocarcinoma of the pancreas. Drugs 57(1):69–79

    Article  CAS  PubMed  Google Scholar 

  86. Davies H et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954

    Article  CAS  PubMed  Google Scholar 

  87. Ascierto PA et al (2012) The role of BRAF V600 mutation in melanoma. J Transl Med 10:85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kinno T et al (2014) Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol 25(1):138–142

    Article  CAS  PubMed  Google Scholar 

  89. Paik PK et al (2011) Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 29(15):2046–2051

    Article  PubMed  PubMed Central  Google Scholar 

  90. Sequist LV et al (2011) Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 22(12):2616–2624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Villaruz LC et al (2015) Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. Cancer 121(3):448–456

    Article  CAS  PubMed  Google Scholar 

  92. Litvak AM et al (2014) Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol 9(11):1669–1674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hyman DM et al (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 373(8):726–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Planchard D et al (2016) Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 17(5):642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Planchard D et al (2016) 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 17(7):984–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Planchard D et al (2017) Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 18(10):1307–1316

    Article  CAS  PubMed  Google Scholar 

  97. Giordano S et al (1989) Tyrosine kinase receptor indistinguishable from the c-met protein. Nature 339(6220):155–156

    Article  CAS  PubMed  Google Scholar 

  98. Bottaro DP et al (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251(4995):802–804

    Article  CAS  PubMed  Google Scholar 

  99. Naldini L et al (1991) Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J 10(10):2867–2878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ponzetto C et al (1994) A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77(2):261–271

    Article  CAS  PubMed  Google Scholar 

  101. Sadiq AA, Salgia R (2013) MET as a possible target for non-small-cell lung cancer. J Clin Oncol 31(8):1089–1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ma PC et al (2008) Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 47(12):1025–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sattler M, Salgia R (2016) MET in the driver’s seat: exon 14 skipping mutations as actionable targets in lung cancer. J Thorac Oncol 11(9):1381–1383

    Article  PubMed  Google Scholar 

  104. Maulik G et al (2002) Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 13(1):41–59

    Article  CAS  PubMed  Google Scholar 

  105. Krishnaswamy S et al (2009) Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res 15(18):5714–5723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stransky N et al (2014) The landscape of kinase fusions in cancer. Nat Commun 5:4846

    Article  CAS  PubMed  Google Scholar 

  107. Watermann I et al (2015) Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation? Diagn Pathol 10:130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Salgia R (2017) MET in lung cancer: biomarker selection based on scientific rationale. Mol Cancer Ther 16(4):555–565

    Article  CAS  PubMed  Google Scholar 

  109. Cappuzzo F et al (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27(10):1667–1674

    Article  PubMed  PubMed Central  Google Scholar 

  110. Raghav K et al (2018) Untying the gordion knot of targeting MET in cancer. Cancer Treat Rev 66:95–103

    Article  CAS  PubMed  Google Scholar 

  111. Waqar SN, Morgensztern D, Sehn J (2015) MET mutation associated with responsiveness to crizotinib. J Thorac Oncol 10(5):e29–e31

    Article  PubMed  PubMed Central  Google Scholar 

  112. Drilon A et al (2016) Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 17(12):1653–1660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Spigel DR et al (2017) Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol 35(4):412–420

    Article  CAS  PubMed  Google Scholar 

  114. Scagliotti G et al (2015) 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 33(24):2667–2674

    Article  CAS  PubMed  Google Scholar 

  115. Bean J et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104(52):20932–20937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Azuma K et al (2016) Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib. ESMO Open 1(4):e000063

    Article  PubMed  PubMed Central  Google Scholar 

  117. Yoshioka H et al (2015) A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann Oncol 26(10):2066–2072

    Article  CAS  PubMed  Google Scholar 

  118. Zenali M et al (2015) Retrospective review of MET gene mutations. Oncoscience 2(5):533–541

    Article  PubMed  PubMed Central  Google Scholar 

  119. McLornan DP, List A, Mufti GJ (2014) Applying synthetic lethality for the selective targeting of cancer. N Engl J Med 371(18):1725–1735

    Article  CAS  PubMed  Google Scholar 

  120. Kyriakopoulos CE et al (2017) A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors. Invest New Drugs 35(3):290–297

    Article  CAS  PubMed  Google Scholar 

  121. Preusser M et al (2014) Amplification and overexpression of CMET is a common event in brain metastases of non-small cell lung cancer. Histopathology 65(5):684–692

    Article  PubMed  Google Scholar 

  122. Chi AS et al (2012) Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J Clin Oncol 30(3):e30–e33

    Article  PubMed  Google Scholar 

  123. Klempner SJ et al (2017) Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases. J Thorac Oncol 12(1):152–156

    Article  PubMed  Google Scholar 

  124. Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1(2):e000023

    Article  PubMed  PubMed Central  Google Scholar 

  125. Broderick JM (2017) Entrectinib granted breakthrough designation by FDA for NTRK + solid tumors. Targeted Oncology News article

    Google Scholar 

  126. Hyman DM et al (2017) The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol 35(18_suppl):LBA2501

    Article  Google Scholar 

  127. Bagheri-Yarmand R et al (2015) A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis. J Biol Chem 290(18):11749–11761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Cascone T, Subbiah V, Heymach JV (2017) Targeting RET rearrangements in non-small cell lung cancer

    Google Scholar 

  129. Amarnath S et al (2011) The PDL1-PD1 axis converts human T H1 cells into regulatory T cells. Sci Transl Med 3(111)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Francisco LM et al (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Shin DS, Ribas A (2015) The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr Opin Immunol 33:23–35

    Article  CAS  PubMed  Google Scholar 

  132. Kusnierczyk P (2013) Killer cell immunoglobulin-like receptor gene associations with autoimmune and allergic diseases, recurrent spontaneous abortion, and neoplasms. Front Immunol 4:8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Brahmer JR et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19):3167–3175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Borghaei H et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Vokes EE et al (2018) Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 29(4):959–965

    Article  CAS  PubMed  Google Scholar 

  136. Brahmer J et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Horn L et al (2017) Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol 35(35):3924–3933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Carbone DP et al (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376(25):2415–2426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hellmann MD et al (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378(22):2093–2104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Forde PM et al (2018) Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 378(21):1976–1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Reck M et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833

    Article  CAS  PubMed  Google Scholar 

  142. Langer CJ et al (2016) Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17(11):1497–1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Gandhi L et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092

    Article  CAS  PubMed  Google Scholar 

  144. Herbst RS et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550

    Article  CAS  PubMed  Google Scholar 

  145. Rittmeyer A et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265

    Article  PubMed  Google Scholar 

  146. Jotte RM et al (2018) IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol 36(18_suppl):LBA9000

    Article  Google Scholar 

  147. Socinski MA et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301

    Article  CAS  PubMed  Google Scholar 

  148. Antonia SJ et al (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377(20):1919–1929

    Article  CAS  PubMed  Google Scholar 

  149. Lynch TJ et al (2012) 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 30(17):2046–2054

    Article  CAS  PubMed  Google Scholar 

  150. Weber JS et al (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35(7):785–792

    Article  CAS  PubMed  Google Scholar 

  151. Brahmer JR, Lacchetti C, Thompson JA (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline summary. J Oncol Pract 14(4):247–249

    Article  PubMed  Google Scholar 

  152. The Lancet Respiratory Medicine (2018) Lung cancer immunotherapy biomarkers: refine not reject. Lancet Respir Med 6(6):403

    Google Scholar 

  153. Liu D, Wang S, Bindeman W (2017) Clinical applications of PD-L1 bioassays for cancer immunotherapy. J Hematol Oncol 10(1):110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Stephens P et al (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431(7008):525

    Article  CAS  PubMed  Google Scholar 

  155. Shigematsu H et al (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Can Res 65(5):1642–1646

    Article  CAS  Google Scholar 

  156. Kris M et al (2015) 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 26(7):1421–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gandhi L et al (2017) MA04. 02 neratinib ± temsirolimus in HER2-mutant lung cancers: an international, randomized phase II study. J Thorac Oncol 12(1): S358–S359

    Article  Google Scholar 

  158. Lai WCV et al (2017) Afatinib in patients with metastatic HER2-mutant lung cancers: an international multicenter study. Am Soc Clin Oncol

    Google Scholar 

  159. Li BT et al (2018) Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol. https://doi.org/10.1200/JCO.2018.77.9777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Blumenschein G Jr et al (2015) 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 26(5):894–901

    Article  PubMed  PubMed Central  Google Scholar 

  161. Gandara DR et al (2013) Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial. Am Soc Clin Oncol

    Google Scholar 

  162. Kelly K et al (2013) Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial. Am Soc Clin Oncol

    Google Scholar 

  163. Jänne PA et al (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14(1):38–47

    Article  PubMed  CAS  Google Scholar 

  164. Jänne PA et al (2017) Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with kras-mutant advanced non-small cell lung cancer: the select-1 randomized clinical trial. JAMA 317(18):1844–1853

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Aviel-Ronen S et al (2006) K-ras mutations in non-small-cell lung carcinoma: a review. Clin Lung Cancer 8(1):30–38

    Article  CAS  PubMed  Google Scholar 

  166. Reuter CW, Morgan MA, Bergmann L (2000) Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood 96(5):1655–1669

    CAS  PubMed  Google Scholar 

  167. Chenard-Poirier M et al (2017) Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma. Am Soc Clin Oncol

    Google Scholar 

  168. Vansteenkiste JF et al (2015) 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 10(9):1319–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Soria J-C et al (2015) Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors. Oncologist 20(3):245–246

    Article  PubMed  PubMed Central  Google Scholar 

  170. Levy B et al (2014) A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer. J Thorac Oncol 9(7):1031–1035

    Article  CAS  PubMed  Google Scholar 

  171. Wade JL et al (2017) A phase II study of GDC-0032 (taselisib) for previously treated PI3K positive patients with stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400B. Am Soc Clin Oncol

    Google Scholar 

  172. Soria J-C et al (2017) A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-small cell lung cancer. Eur J Cancer 86:186–196

    Article  CAS  PubMed  Google Scholar 

  173. Besse B et al (2015) A phase II trial of pictilisib with chemotherapy in first-line non-squamous NSCLC. J Thorac Oncol. Elsevier

    Google Scholar 

  174. Thomas JS et al (2018) A first-in-human phase I study of sEphB4-HSA (sEphB4) with expansion in hepatocellular (HCC) and cholangiocarcinoma (CCA). Am Soc Clin Oncol

    Google Scholar 

  175. Nogova L et al (2017) Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol 35(2):157–165

    Article  CAS  PubMed  Google Scholar 

  176. Tabernero J et al (2015) Phase I dose-escalation study of JNJ-42756493, an oral pan–fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol 33(30):3401–3408

    Article  CAS  PubMed  Google Scholar 

  177. Paik PK et al (2014) A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: preliminary antitumor activity and pharmacodynamic data. Am Soc Clin Oncol

    Google Scholar 

  178. Smyth EC et al (2015) Phase II multicenter proof of concept study of AZD4547 in FGFR amplified tumours. Am Soc Clin Oncol

    Google Scholar 

Download references

Acknowledgements

Special thanks to Sam Garcia, Library Assistant, and Andrea Lynch, Scholarly Communications Librarian at the City of Hope Graff Library in Duarte, California.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Addie Hill, Rohan Gupta, Dan Zhao, Idoroenyi Amanam & Ravi Salgia

  2. Department of Hematology-Oncology, Harbor-UCLA Medical Center, Torrance, CA, USA

    Ritika Vankina

Authors
  1. Addie Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rohan Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ritika Vankina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Idoroenyi Amanam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ravi Salgia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ravi Salgia .

Editor information

Editors and Affiliations

  1. Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, USA

    Daniel D. Von Hoff

  2. Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, USA

    Haiyong Han

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hill, A., Gupta, R., Zhao, D., Vankina, R., Amanam, I., Salgia, R. (2019). Targeted Therapies in Non-small-Cell Lung Cancer. In: Von Hoff, D., Han, H. (eds) Precision Medicine in Cancer Therapy . Cancer Treatment and Research, vol 178. Springer, Cham. https://doi.org/10.1007/978-3-030-16391-4_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-16391-4_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-16390-7

  • Online ISBN: 978-3-030-16391-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation