Targeted Therapy for Non-Small Cell Lung Cancer

Abstract

Lung cancer is a heterogeneous disease, and the availability of comprehensive genomic profiling has allowed for the characterization of its molecular subtypes. This has increased the ability to deliver “personalized medicines” by tailoring therapies to target driver mutations in a patient's cancer. The development of targeted therapies for non-small cell lung cancer (NSCLC) has helped define the era of precision medicine throughout oncology. This article aims to contextualize recent research and provide an updated summary of targeted therapies available for patients with NSCLC. With practitioners and clinical researchers in mind, we note standard of care therapies, important approvals, practice guidelines, and treatments in development. The first section discusses mutations in the epidermal growth factor receptor (EGFR) gene, and the second section examines rearrangements in the anaplastic lymphoma kinase (ALK) and ROS1 fusions. Finally, we explore the rarer molecular alterations in BRAF, RET, MET, HER2, and KRAS. Given the many available therapies, it is important to understand the molecular alterations in NSCLC, and how to target them.

Keywords

targeted therapies - non-small cell lung cancer - EGFR - ALK - ROS1 - RET - HER2 - MET - KRAS

• References

• 1 Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411 (6835): 355-365
• 2 Kris MG, Johnson BE, Kwiatkowski DJ. , et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2011; 29 (18 suppl): CRA7506
• 3 AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov 2017; 7 (08) 818-831
• 4 Campbell JD, Alexandrov A, Kim J. , et al; Cancer Genome Atlas Research Network. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 2016; 48 (06) 607-616
• 5 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 (05) 339-346
• 6 Tsao AS, Tang XM, Sabloff B. , et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol 2006; 1 (03) 231-239
• 7 Rosell R, Moran T, Queralt C. , et al; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361 (10) 958-967
• 8 Zhang YL, Yuan JQ, Wang KF. , et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016; 7 (48) 78985-78993
• 9 Pao W, Miller V, Zakowski M. , et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004; 101 (36) 13306-13311
• 10 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) 2129-2139
• 11 Paez JG, Jänne PA, Lee JC. , et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304 (5676): 1497-1500
• 12 Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 1962; 237: 1555-1562
• 13 Burgess AW, Cho H-S, Eigenbrot C. , et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003; 12 (03) 541-552
• 14 Carpenter G, Lembach KJ, Morrison MM, Cohen S. Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts. J Biol Chem 1975; 250 (11) 4297-4304
• 15 de Larco JE, Todaro GJ. Epithelioid and fibroblastic rat kidney cell clones: epidermal growth factor (EGF) receptors and the effect of mouse sarcoma virus transformation. J Cell Physiol 1978; 94 (03) 335-342
• 16 Mendelsohn J, Masui H, Goldenberg A. Anti-epidermal growth factor receptor monoclonal antibodies may inhibit A431 tumor cell proliferation by blocking an autocrine pathway. Trans Assoc Am Physicians 1987; 100: 173-178
• 17 Dokala A, Thakur SS. Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery. Oncogene 2017; 36 (17) 2337-2344
• 18 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2 (02) 127-137
• 19 Ullrich A, Coussens L, Hayflick JS. , et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 1984; 309 (5967): 418-425
• 20 Garrett TPJ, McKern NM, Lou M. , et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 2002; 110 (06) 763-773
• 21 Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103 (02) 211-225
• 22 Lemmon MA, Schlessinger J, Ferguson KM. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb Perspect Biol 2014; 6 (04) a020768
• 23 Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7 (03) 169-181
• 24 Yasuda H, Park E, Yun CH. , et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013; 5 (216) 216ra177
• 25 Wang Y, Li RQ, Ai YQ. , et al. Exon 19 deletion was associated with better survival outcomes in advanced lung adenocarcinoma with mutant EGFR treated with EGFR-TKIs as second-line therapy after first-line chemotherapy: a retrospective analysis of 128 patients. Clin Transl Oncol 2015; 17 (09) 727-736
• 26 Zhang Y, Sheng J, Kang S. , et al. Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis. PLoS One 2014; 9 (09) e107161
• 27 Ichihara E, Hotta K, Nogami N. , et al. Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol 2015; 10 (03) 486-491
• 28 Seto T, Kato T, Nishio M. , 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 (11) 1236-1244
• 29 Yang JC-H, Wu Y-L, Schuler M. , et al. 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 2015; 16 (02) 141-151
• 30 Qu J, Wang YN, Xu P. , et al. Clinical efficacy of icotinib in lung cancer patients with different EGFR mutation status: a meta-analysis. Oncotarget 2017; 8 (20) 33961-33971
• 31 Moyer JD, Barbacci EG, Iwata KK. , et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 1997; 57 (21) 4838-4848
• 32 Barker AJ, Gibson KH, Grundy W. , et al. Studies leading to the identification of ZD1839 (IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001; 11 (14) 1911-1914
• 33 Ward WH, Cook PN, Slater AM, Davies DH, Holdgate GA, Green LR. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol 1994; 48 (04) 659-666
• 34 Thatcher N, Chang A, Parikh P. , et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366 (9496): 1527-1537
• 35 Herbst RS, Giaccone G, Schiller JH. , et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 2004; 22 (05) 785-794
• 36 Giaccone G, Herbst RS, Manegold C. , et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 2004; 22 (05) 777-784
• 37 Gatzemeier U, Pluzanska A, Szczesna A. , et al. 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 2007; 25 (12) 1545-1552
• 38 Herbst RS, Prager D, Hermann R. , et al; TRIBUTE Investigator Group. 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 2005; 23 (25) 5892-5899
• 39 Mok TS, Wu Y-L, Thongprasert S. , et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361 (10) 947-957
• 40 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) 2866-2874
• 41 Mitsudomi T, Morita S, Yatabe Y. , et al; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11 (02) 121-128
• 42 Maemondo M, Inoue A, Kobayashi K. , et al; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362 (25) 2380-2388
• 43 Wu YL, Zhou C, Liam CK. , et al. 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 2015; 26 (09) 1883-1889
• 44 Rosell R, Carcereny E, Gervais R. , et al; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. 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 (03) 239-246
• 45 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 (08) 735-742
• 46 Shen YW, Zhang XM, Li ST. , et al. Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer. OncoTargets Ther 2016; 9: 929-935
• 47 Lee CK, Davies L, Wu YL. , et al. Gefitinib or erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival. J Natl Cancer Inst 2017; 109 (06) 109
• 48 Yang JJ, Zhou Q, Yan HH. , et al. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 2017; 116 (05) 568-574
• 49 Urata Y, Katakami N, Morita S. , et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol 2016; 34 (27) 3248-3257
• 50 Bria E, Milella M, Cuppone F. , et al. Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis. Ann Oncol 2011; 22 (10) 2277-2285
• 51 Petrelli F, Borgonovo K, Cabiddu M, Barni S. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer 2012; 13 (02) 107-114
• 52 Gao G, Ren S, Li A. , et al. Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials. Int J Cancer 2012; 131 (05) E822-E829
• 53 Lee CK, Brown C, Gralla RJ. , et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 2013; 105 (09) 595-605
• 54 Paz-Ares L, Soulières D, Moecks J, Bara I, Mok T, Klughammer B. Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC. J Cell Mol Med 2014; 18 (08) 1519-1539
• 55 Thongprasert S, Duffield E, Saijo N. , et al. Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J Thorac Oncol 2011; 6 (11) 1872-1880
• 56 Chen G, Feng J, Zhou C. , et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann Oncol 2013; 24 (06) 1615-1622
• 57 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 (08) 990-998
• 58 Mok TSK, Kim SW, Wu YL. , et al. 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 2017; 35 (36) 4027-4034
• 59 Li D, Ambrogio L, Shimamura T. , et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27 (34) 4702-4711
• 60 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 (05) 528-538
• 61 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 (08) 1145-1154
• 62 Sequist LV, Yang JC, Yamamoto N. , et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31 (27) 3327-3334
• 63 Wu YL, Zhou C, Hu CP. , et al. 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 2014; 15 (02) 213-222
• 64 Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer 2015; 88 (01) 74-79
• 65 Wu YL, Cheng Y, Zhou X. , et al. 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 2017; 18 (11) 1454-1466
• 66 Park K, Tan E-H, O'Byrne K. , et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016; 17 (05) 577-589
• 67 Wang LY, Cui JJ, Guo AX, Yin JY. Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients. OncoTargets Ther 2018; 11: 529-538
• 68 Yang CJ, Tsai MJ, Hung JY. , et al. The clinical efficacy of afatinib 30 mg daily as starting dose may not be inferior to afatinib 40 mg daily in patients with stage IV lung adenocarcinoma harboring exon 19 or exon 21 mutations. BMC Pharmacol Toxicol 2017; 18 (01) 82
• 69 Califano R, Tariq N, Compton S. , et al. Expert consensus on the management of adverse events from EGFR tyrosine kinase inhibitors in the UK. Drugs 2015; 75 (12) 1335-1348
• 70 Paz-Ares L, Tan EH, O'Byrne K. , et al. 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 2017; 28 (02) 270-277
• 71 VIZIMPRO (dacomitinib) tablets, for oral use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf . Accessed October 10, 2019
• 72 Oxnard GR, Arcila ME, Sima CS. , et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011; 17 (06) 1616-1622
• 73 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 (08) 2240-2247
• 74 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
• 75 Gaut D, Sim MS, Yue Y. , et al. Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Clin Lung Cancer 2018; 19 (01) e19-e28
• 76 Sequist LV, Soria JC, Goldman JW. , et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015; 372 (18) 1700-1709
• 77 Sequist LV, Soria J-C, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med 2016; 374 (23) 2296-2297
• 78 Park K, Jänne PA, Yu CJ. , et al. 412OA global phase II study of olmutinib (HM61713) in patients with T790M-positive NSCLC after failure of first-line EGFR-TKI. Ann Oncol 2017; 28: mdx671
• 79 Kim D-W, Tan DS-W, Ponce Aix S. , et al. Preliminary Phase II results of a multicenter, open-label study of nazartinib (EGF816) in adult patients with treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC). J Clin Oncol 2018; 36: 9094
• 80 Wang H, Zhang L, Hu P, et al. Penetration of the blood-brain barrier by avitinib and its control of intra/extra-cranial disease in non-small cell lung cancer harboring the T790M mutation. Lung Cancer 2018;122:1–6
• 81 Murakami H, Nokihara H, Hayashi H. , et al. Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations. Cancer Sci 2018; 109 (09) 2852-2862
• 82 Husain H, Martins RG, Goldberg SB. , et al. 1358PFirst-in-human phase I study of PF-06747775, a third-generation mutant selective EGFR tyrosine kinase inhibitor (TKI) in metastatic EGFR mutant NSCLC after progression on a first-line EGFR TKI. Ann Oncol 2017; 28: mdx380
• 83 Gao X, Le X, Costa DB. The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer. Expert Rev Anticancer Ther 2016; 16 (04) 383-390
• 84 Mok TS, Wu YL, Ahn MJ. , et al; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017; 376 (07) 629-640
• 85 Soria JC, Ohe Y, Vansteenkiste J. , et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378 (02) 113-125
• 86 Wu YL, Ahn MJ, Garassino MC. , et al. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized Phase III trial (AURA3). J Clin Oncol 2018; 36 (26) 2702-2709
• 87 Osimertinib (TAGRISSO). U.S. Food and Drug Administration (FDA). Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm549683.htm . Accessed October 12, 2018
• 88 FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. U.S. Food and Drug Administration (FDA). Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm605113.htm . Accessed October 13, 2018
• 89 Kim ES, Hirsh V, Mok T. , et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372 (9652): 1809-1818
• 90 Sundaresan TK, Sequist LV, Heymach JV. , et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res 2016; 22 (05) 1103-1110
• 91 Vanderlaan PA, Yamaguchi N, Folch E. , et al. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer. Lung Cancer 2014; 84 (01) 39-44
• 92 Folch E, Yamaguchi N, VanderLaan PA. , et al. Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer. J Thorac Oncol 2013; 8 (11) 1438-1444
• 93 Overman MJ, Modak J, Kopetz S. , et al. Use of research biopsies in clinical trials: are risks and benefits adequately discussed?. J Clin Oncol 2013; 31 (01) 17-22
• 94 Sacher AG, Paweletz C, Dahlberg SE. , et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol 2016; 2 (08) 1014-1022
• 95 Lokhandwala T, Bittoni MA, Dann RA. , et al. Costs of diagnostic assessment for lung cancer: a Medicare claims analysis. Clin Lung Cancer 2017; 18 (01) e27-e34
• 96 Piotrowska Z, Niederst MJ, Mino-Kenudson M. , et al. Variation in mechanisms of acquired resistance among EGFR-mutant NSCLC patients with more than 1 postresistant biopsy. Int J Rad Oncol 2014; 90 (05) S6-S7
• 97 Goldman JW, Noor ZS, Remon J, Besse B, Rosenfeld N. Are liquid biopsies a surrogate for tissue EGFR testing?. Ann Oncol 2018; 29 (Suppl. 01) i38-i46
• 98 Zhang J, Fujimoto J, Zhang J. , et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 2014; 346 (6206): 256-259
• 99 de Bruin EC, McGranahan N, Mitter R. , et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 2014; 346 (6206): 251-256
• 100 Lawrence MS, Stojanov P, Polak P. , et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499 (7457): 214-218
• 101 Jamal-Hanjani M, Wilson GA, McGranahan N. , et al; TRACERx Consortium. Tracking the evolution of non-small-cell lung cancer. N Engl J Med 2017; 376 (22) 2109-2121
• 102 Remon J, Caramella C, Jovelet C. , et al. Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol 2017; 28 (04) 784-790
• 103 Oxnard GR, Thress KS, Alden RS. , et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016; 34 (28) 3375-3382
• 104 Goldman JW, Karlovich C, Sequist LV. , et al. EGFR genotyping of matched urine, plasma, and tumor tissue in patients with non–small-cell lung cancer treated with rociletinib, an EGFR tyrosine kinase inhibitor. JCO Precision Oncol 2018; 2: 1-13
• 105 Ortiz-Cuaran S, Scheffler M, Plenker D. , et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res 2016; 22 (19) 4837-4847
• 106 Yang Z, Yang N, Ou Q. , et al. Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients. Clin Cancer Res 2018; 24 (13) 3097-3107
• 107 Yu HA, Tian SK, Drilon AE. , et al. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol 2015; 1 (07) 982-984
• 108 Kim TM, Song A, Kim D-W. , et al. Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol 2015; 10 (12) 1736-1744
• 109 Tang Z-H, Lu J-J. Osimertinib resistance in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Lett 2018; 420: 242-246
• 110 Liu Y, Hao X, Hu X. , et al. Heterogeneity-based, multiple mechanisms in the resistance to osimertinib (AZD9291): a case report. Thorac Cancer 2018; 9 (04) 498-501
• 111 Iams W, Chae Y. P3.02–034 acquired resistance to osimertinib by CCDC6-RET fusion in a patient with EGFR T790M mutant metastatic lung adenocarcinoma. J Thorac Oncol 2017; 12: S2249-S50
• 112 Yu HA, Suzawa K, Jordan E. , et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin Cancer Res 2018; 24 (13) 3108-3118
• 113 Ho C-C, Liao W-Y, Lin C-A, Shih J-Y, Yu C-J, Chih-Hsin Yang J. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol 2017; 12 (03) 567-572
• 114 Oxnard GR, Hu Y, Mileham KF. , et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR t790m–positive lung cancer and acquired resistance to osimertinib. JAMA Oncol 2018; 4 (11) 1527-1534
• 115 Piotrowska Z, Isozaki H, Lennerz JK. , et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov 2018; 8 (12) 1529-1539
• 116 Ou SI, Cui J, Schrock AB. , et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer 2017; 108: 228-231
• 117 Hidaka N, Iwama E, Kubo N. , et al. Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer. Lung Cancer 2017; 108: 75-82
• 118 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) 3924-3933
• 119 Wang Z, Yang JJ, Huang J. , et al. Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance. J Thorac Oncol 2017; 12 (11) 1723-1727
• 120 Arulananda S, Do H, Musafer A, Mitchell P, Dobrovic A, John T. Combination osimertinib and gefitinib in C797S and T790M EGFR-mutated non-small cell lung cancer. J Thorac Oncol 2017; 12 (11) 1728-1732
• 121 Jia Y, Yun C-H, Park E. , et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016; 534 (7605): 129-132
• 122 Huang W-S, Liu S, Zou D. , et al. Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of anaplastic lymphoma kinase. J Med Chem 2016; 59 (10) 4948-4964
• 123 Uchibori K, Inase N, Araki M. , et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun 2017; 8: 14768
• 124 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) 1683-1696
• 125 Ou SI, Agarwal N, Ali SM. High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer 2016; 98: 59-61
• 126 York ER, Varella-Garcia M, Bang TJ, Aisner DL, Camidge DR. Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplification sequentially emerging after T790M positivity in EGFR-mutant non-small cell lung cancer. J Thorac Oncol 2017; 12 (07) e85-e88
• 127 Ahn M, Han J, Sequist L. , et al. OA 09.03 TATTON Ph Ib expansion cohort: osimertinib plus savolitinib for pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. J Thorac Oncol 2017; 12: S1768
• 128 Patnaik A, Gordon M, Tsai F. , et al. A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer. Cancer Chemother Pharmacol 2018; 82 (03) 407-418
• 129 Haura EB, Cho BC, Lee JS. , et al. JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2019; 37: 9009
• 130 Romaniello D, Mazzeo L, Mancini M. , et al. A combination of approved antibodies overcomes resistance of lung cancer to osimertinib by blocking bypass pathways. Clin Cancer Res 2018; 24 (22) 5610-5621
• 131 Janne PA, Yu HA, Johnson ML. , et al. Phase 1 study of the anti-HER3 antibody drug conjugate U3–1402 in metastatic or unresectable EGFR-mutant NSCLC. J Clin Oncol 2018; 36: TPS9110
• 132 Ge M, Zhuang Y, Zhou X, Huang R, Liang X, Zhan Q. High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases. J Neurooncol 2017; 135 (02) 413-418
• 133 Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 2014; 9 (02) 195-199
• 134 Hsiao SH, Chou YT, Lin SE. , et al. Brain metastases in patients with non-small cell lung cancer: the role of mutated-EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination. Oncotarget 2017; 8 (32) 53405-53418
• 135 Mak KS, Gainor JF, Niemierko A. , et al. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases. Neuro-oncol 2015; 17 (02) 296-302
• 136 Yang JC, Cho BC, Kim CH. , et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study. J Clin Oncol 2017; 35: 2020
• 137 Ahn MJ, Kim DW, Cho BC. , et al. Phase I study (BLOOM) of AXD3759, a BBB penetrable EGFR inhibitor, in TKI naïve EGFRm NSCLC patients in CNS metastases. J Clin Oncol 2017; 35: abst 2006
• 138 Cross DAE, Ashton SE, Ghiorghiu S. , et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4 (09) 1046-1061
• 139 Xie L, Nagpal S, Wakelee HA, Li G, Soltys SG, Neal JW. Osimertinib for EGFR-mutant lung cancer with brain metastases: results from a single-center retrospective study. Oncologist 2019; 24 (06) 836-843
• 140 Corre R, Gervais R, Guisier F. , et al. Octogenarians with EGFR-mutated non-small cell lung cancer treated by tyrosine-kinase inhibitor: a multicentric real-world study assessing tolerance and efficacy (OCTOMUT study). Oncotarget 2018; 9 (09) 8253-8262
• 141 Morikawa N, Minegishi Y, Inoue A. , et al; North-East Japan Study Group. First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies. Expert Opin Pharmacother 2015; 16 (04) 465-472
• 142 Yoshioka H, Komuta K, Imamura F, Kudoh S, Seki A, Fukuoka M. Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. Lung Cancer 2014; 86 (02) 201-206
• 143 Roviello G, Zanotti L, Cappelletti MR. , et al. Are EGFR tyrosine kinase inhibitors effective in elderly patients with EGFR-mutated non-small cell lung cancer?. Clin Exp Med 2018; 18 (01) 15-20
• 144 Spigel DR, Hainsworth JD, Burkett ER. , et al. Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status: a Minnie Pearl Cancer Research Network Phase II Trial. Clin Lung Cancer 2005; 7 (02) 127-132
• 145 Lee SM, Khan I, Upadhyay S. , et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2012; 13 (11) 1161-1170
• 146 Oxnard GR, Lo PC, Nishino M. , et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 2013; 8 (02) 179-184
• 147 Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012; 13 (01) e23-e31
• 148 Arcila ME, Nafa K, Chaft JE. , et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013; 12 (02) 220-229
• 149 Yang M, Xu X, Cai J, Ning J, Wery JP, Li QX. NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J Cancer 2016; 139 (01) 171-176
• 150 Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci 2016; 107 (09) 1179-1186
• 151 Robichaux JP, Elamin YY, Tan Z. , et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med 2018; 24 (05) 638-646
• 152 Heymach JNM, MV Negrao JP, Robichaux J. , et al. OA02.06 A Phase II trial of poziotinib in EGFR and HER2 Exon 20 mutant non-small cell lung cancer (NSCLC). J Thorac Oncol 2018; 13: S323-S4
• 153 Janne PA, Neal JW, Camidge DR, et al. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. Clin Oncol 2019;37(15 suppl):9007–9007
• 154 GILOTRIF (afatinib). FDA 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf . Accessed November 1, 2018
• 155 Yang JC, Sequist LV, Geater SL. , et al. 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 2015; 16 (07) 830-838
• 156 Ahn M-J, Cho JH, Sun J-M. , et al. An open-label, multicenter, phase II single arm trial of osimertinib in non-small cell lung cancer patients with uncommon EGFR mutation (KCSG-LU15–09). J Clin Oncol 2018; 36: 9050
• 157 Cheng Y, Murakami H, Yang PC. , et al. 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 2016; 34 (27) 3258-3266
• 158 Noronha V, Joshi A, Patil VM. , et al. Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C). J Clin Oncol 2019; 37: 9001
• 159 NCCN Clinical Practice Guidelines in Oncology - Non-Small Cell Lung Cancer. 2018 . Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf . Accessed October 30, 2018
• 160 Furuya N, Fukuhara T, Saito H. , et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. J Clin Oncol 2018; 36: 9006
• 161 Saito H, Fukuhara T, Furuya N. , et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019; 20 (05) 625-635
• 162 Nakagawa K, Garon EB, Seto T. , et al. RELAY: a multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2019; 37: 9000
• 163 Garassino MC, Gelibter AJ, Grossi F. , et al. Italian nivolumab expanded access program in nonsquamous non-small cell lung cancer patients: results in never-smokers and EGFR-mutant patients. J Thorac Oncol 2018; 13 (08) 1146-1155
• 164 Lee CK, Man J, Lord S. , et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis. J Thorac Oncol 2017; 12 (02) 403-407
• 165 Ahn MJ, Yang J, Yu H. , et al. 136O: osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial. J Thorac Oncol 2016; 11: S115
• 166 Mezquita L, Planchard D. Durvalumab for the treatment of non-small cell lung cancer. Expert Rev Respir Med 2018; 12 (08) 627-639
• 167 Socinski MA, Jotte RM, Cappuzzo F. , et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018; 378 (24) 2288-2301
• 168 Reck M, Mok TSK, Nishio M. , et al; IMpower150 Study Group. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 2019; 7 (05) 387-401
• 169 Rikova K, Guo A, Zeng Q. , et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131 (06) 1190-1203
• 170 Lee JJ, Park S, Park H. , et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 2019; 177 (07) 1842-1857.e21
• 171 Morris SW, Kirstein MN, Valentine MB. , et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994; 263 (5151): 1281-1284
• 172 Soda M, Choi YL, Enomoto M. , et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448 (7153): 561-566
• 173 Murray PB, Lax I, Reshetnyak A. , et al. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Sci Signal 2015; 8 (360) ra6
• 174 Pulford K, Lamant L, Espinos E. , et al. The emerging normal and disease-related roles of anaplastic lymphoma kinase. Cell Mol Life Sci 2004; 61 (23) 2939-2953
• 175 Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci 2008; 99 (12) 2349-2355
• 176 Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009; 27 (26) 4232-4235
• 177 Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46 (10) 1773-1780
• 178 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 (09) 3143-3149
• 179 Togashi Y, Soda M, Sakata S. , et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7 (02) e31323
• 180 Fang DD, Zhang B, Gu Q. , et al. HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. J Thorac Oncol 2014; 9 (03) 285-294
• 181 Choi YL, Lira ME, Hong M. , et al. A novel fusion of TPR and ALK in lung adenocarcinoma. J Thorac Oncol 2014; 9 (04) 563-566
• 182 Ou SH, Klempner SJ, Greenbowe JR. , et al. Identification of a novel HIP1-ALK fusion variant in non-small-cell lung cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib. J Thorac Oncol 2014; 9 (12) 1821-1825
• 183 Hong M, Kim RN, Song JY. , et al. HIP1-ALK, a novel fusion protein identified in lung adenocarcinoma. J Thorac Oncol 2014; 9 (03) 419-422
• 184 Iyevleva AG, Raskin GA, Tiurin VI. , et al. Novel ALK fusion partners in lung cancer. Cancer Lett 2015; 362 (01) 116-121
• 185 Nakanishi Y, Masuda S, Iida Y, Takahashi N, Hashimoto S. Case report of non-small cell lung cancer with STRN-ALK translocation: a nonresponder to alectinib. J Thorac Oncol 2017; 12 (12) e202-e204
• 186 Tian Q, Deng WJ, Li ZW. Identification of a novel crizotinib-sensitive BCL11A-ALK gene fusion in a nonsmall cell lung cancer patient. Eur Respir J 2017; 49 (04) 49
• 187 Evangelista AF, Zanon MF, Carloni AC. , et al. Detection of ALK fusion transcripts in FFPE lung cancer samples by NanoString technology. BMC Pulm Med 2017; 17 (01) 86
• 188 Tsou TC, Gowen K, Ali SM. , et al. Variable response to ALK inhibitors in NSCLC with a novel MYT1L-ALK fusion. J Thorac Oncol 2019; 14 (02) e29-e30
• 189 Zhao R, Zhang J, Han Y. , et al. Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: a Chinese retrospective analysis. Mol Diagn Ther 2019; 23 (03) 395-405
• 190 Pagan C, Barua S, Hsiao SJ. , et al. Targeting SLMAP-ALK-a novel gene fusion in lung adenocarcinoma. Cold Spring Harb Mol Case Stud 2019; 5 (03) 5
• 191 George RE, Sanda T, Hanna M. , et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 2008; 455 (7215): 975-978
• 192 Wiesner T, Lee W, Obenauf AC. , et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature 2015; 526 (7573): 453-457
• 193 Perner S, Wagner PL, Demichelis F. , et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia 2008; 10 (03) 298-302
• 194 Shaw AT, Yeap BY, Mino-Kenudson M. , et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009; 27 (26) 4247-4253
• 195 Ali SM, Hensing T, Schrock AB. , et al. Comprehensive genomic profiling identifies a subset of crizotinib-responsive ALK-rearranged non-small cell lung cancer not detected by fluorescence in situ hybridization. Oncologist 2016; 21 (06) 762-770
• 196 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 (04) 508-515
• 197 Rodig SJ, Mino-Kenudson M, Dacic S. , et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009; 15 (16) 5216-5223
• 198 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 (02) 121-126
• 199 Gainor JF, Varghese AM, Ou SH. , et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19 (15) 4273-4281
• 200 Martelli MP, Sozzi G, Hernandez L. , et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol 2009; 174 (02) 661-670
• 201 Boland JM, Erdogan S, Vasmatzis G. , et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol 2009; 40 (08) 1152-1158
• 202 Conklin CM, Craddock KJ, Have C, Laskin J, Couture C, Ionescu DN. Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-small-cell lung carcinoma and is antibody dependent. J Thorac Oncol 2013; 8 (01) 45-51
• 203 Lin C, Shi X, Yang S. , et al. Comparison of ALK detection by FISH, IHC and NGS to predict benefit from crizotinib in advanced non-small-cell lung cancer. Lung Cancer 2019; 131: 62-68
• 204 Shaw AT, Solomon BJ, Besse B. , et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol 2019; 37 (16) 1370-1379
• 205 Paweletz CP, Sacher AG, Raymond CK. , et al. Bias-corrected targeted next-generation sequencing for rapid, multiplexed detection of actionable alterations in cell-free DNA from advanced lung cancer patients. Clin Cancer Res 2016; 22 (04) 915-922
• 206 Christopoulos P, Kirchner M, Bozorgmehr F. , et al. Identification of a highly lethal V3⁺ TP53⁺ subset in ALK⁺ lung adenocarcinoma. Int J Cancer 2019; 144 (01) 190-199
• 207 Shaw AT, Varghese AM, Solomon BJ. , et al. Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer. Ann Oncol 2013; 24 (01) 59-66
• 208 Gandhi L, Rodríguez-Abreu D, Gadgeel S. , et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378 (22) 2078-2092
• 209 Lisberg A, Cummings A, Goldman JW. , et al. A Phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol 2018; 13 (08) 1138-1145
• 210 Solomon BJ, Mok T, Kim DW. , et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371 (23) 2167-2177
• 211 Cui JJ, Tran-Dubé M, Shen H. , et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011; 54 (18) 6342-6363
• 212 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
• 213 Gainor JF, Tseng D, Yoda S. , et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol 2017; 2017 DOI: 10.1200/PO.17.00063. . [Epub August 16, 2017]
• 214 Li J, Sun R, Wu Y. , et al. L1198F mutation resensitizes crizotinib to ALK by altering the conformation of inhibitor and ATP binding sites. Int J Mol Sci 2017; 18 (03) 18
• 215 Couts KL, Bemis J, Turner JA. , et al. ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms. Mol Cancer Ther 2018; 17 (01) 222-231
• 216 Soria JC, Tan DSW, 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): 917-929
• 217 Gainor JF, Ou SH, Logan J, Borges LF, Shaw AT. The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer. J Thorac Oncol 2013; 8 (12) 1570-1573
• 218 Shaw AT, Kim TM, Crinò L. , et al. 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 2017; 18 (07) 874-886
• 219 Friboulet L, Li N, Katayama R. , et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 2014; 4 (06) 662-673
• 220 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) 1118-1133
• 221 Hida T, Nokihara H, Kondo M. , et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017; 390 (10089): 29-39
• 222 Novello S, Mazières J, Oh IJ. , et al. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol 2018; 29 (06) 1409-1416
• 223 Zhou C, Kim SW, Reungwetwattana T. , et al. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med 2019; 7 (05) 437-446
• 224 Peters S, Camidge DR, Shaw AT. , et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017; 377 (09) 829-838
• 225 Gadgeel S, Peters S, Mok T. , et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018; 29 (11) 2214-2222
• 226 Gainor JF. Alectinib-a new chapter in the management of ALK-positive lung cancer. Transl Lung Cancer Res 2016; 5 (03) 343-346
• 227 Kim DW, Tiseo M, Ahn MJ. , et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 2017; 35 (22) 2490-2498
• 228 Camidge DR, Kim HR, Ahn MJ. , et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018; 379 (21) 2027-2039
• 229 Lin JJ, Zhu VW, Schoenfeld AJ. , et al. Brigatinib in patients with alectinib-refractory ALK-positive NSCLC. J Thorac Oncol 2018; 13 (10) 1530-1538
• 230 Johnson TW, Richardson PF, Bailey S. , 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 (11) 4720-4744
• 231 Baglivo S, Ricciuti B, Ludovini V. , et al. Dramatic response to lorlatinib in a heavily pretreated lung adenocarcinoma patient harboring G1202R mutation and a synchronous novel R1192P ALK point mutation. J Thorac Oncol 2018; 13 (08) e145-e147
• 232 Shaw AT, Felip E, Bauer TM. , et al. 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 2017; 18 (12) 1590-1599
• 233 Solomon BJ, Besse B, Bauer TM. , et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018; 19 (12) 1654-1667
• 234 Yoda S, Lin JJ, Lawrence MS. , et al. Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer. Cancer Discov 2018; 8 (06) 714-729
• 235 Gainor JF, Shaw AT, Sequist LV. , 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 (18) 4585-4593
• 236 Spigel DR, Reynolds C, Waterhouse D. , et al. Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (CheckMate 370). J Thorac Oncol 2018; 13 (05) 682-688
• 237 Matsushime H, Wang LH, Shibuya M. Human c-ros-1 gene homologous to the v-ros sequence of UR2 sarcoma virus encodes for a transmembrane receptorlike molecule. Mol Cell Biol 1986; 6 (08) 3000-3004
• 238 Bergethon K, Shaw AT, Ou SH. , et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012; 30 (08) 863-870
• 239 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) 4570-4579
• 240 Takeuchi K, Soda M, Togashi Y. , et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18 (03) 378-381
• 241 Liu Y, Liu T, Li N, Wang T, Pu Y, Lin R. Identification of a novel WNK1-ROS1 fusion in a lung adenocarcinoma sensitive to crizotinib. Lung Cancer 2019; 129: 92-94
• 242 Hicks JK, Boyle T, Albacker LA, Madison R, Frampton G, Creelan BC. Clinical activity of crizotinib in lung adenocarcinoma harboring a rare ZCCHC8-ROS1 fusion. J Thorac Oncol 2018; 13 (08) e148-e150
• 243 Birchmeier C, Sharma S, Wigler M. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A 1987; 84 (24) 9270-9274
• 244 Marks EI, Pamarthy S, Dizon D. , et al. ROS1-GOPC/FIG: a novel gene fusion in hepatic angiosarcoma. Oncotarget 2019; 10 (02) 245-251
• 245 Lee J, Lee SE, Kang SY. , et al. Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer 2013; 119 (09) 1627-1635
• 246 Davare MA, Henderson JJ, Agarwal A. , et al. Rare but recurrent ROS1 fusions resulting from chromosome 6q22 microdeletions are targetable oncogenes in glioma. Clin Cancer Res 2018; 24 (24) 6471-6482
• 247 Pietrantonio F, Di Nicolantonio F, Schrock AB. , et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst 2017; 109 (12) 109
• 248 Aydin HA, Pestereli E, Ozcan M, Bayramoglu Z, Erdogan G, Simsek T. A study detection of the ROS1 gene fusion by FISH and ROS1 protein expression by IHC methods in patients with ovarian malignant or borderline serous tumors. Pathol Res Pract 2018; 214 (11) 1868-1872
• 249 Park S, Ahn BC, Lim SW. , et al. Characteristics and outcome of ROS1-positive non-small cell lung cancer patients in routine clinical practice. J Thorac Oncol 2018; 13 (09) 1373-1382
• 250 Zhao J, Zheng J, Kong M, Zhou J, Ding W, Zhou J. Advanced lung adenocarcinomas with ROS1-rearrangement frequently show hepatoid cell. Oncotarget 2016; 7 (45) 74162-74170
• 251 Mezquita L, Benito A, Ruano-Raviña A. , et al. Indoor radon in EGFR- and BRAF-mutated and ALK-rearranged non-small-cell lung cancer patients. Clin Lung Cancer 2019; 20 (04) 305-312.e3
• 252 Mazières J, Zalcman G, Crinò L. , et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 2015; 33 (09) 992-999
• 253 Selinger CI, Li BT, Pavlakis N. , et al. Screening for ROS1 gene rearrangements in non-small-cell lung cancers using immunohistochemistry with FISH confirmation is an effective method to identify this rare target. Histopathology 2017; 70 (03) 402-411
• 254 Hofman V, Rouquette I, Long-Mira E. , et al. Multicenter evaluation of a novel ROS1 immunohistochemistry assay (SP384) for detection of ROS1 rearrangements in a large cohort of lung adenocarcinoma patients. J Thorac Oncol 2019; 14 (07) 1204-1212
• 255 Clavé S, Rodon N, Pijuan L. , et al. Next-generation sequencing for ALK and ROS1 rearrangement detection in patients with non-small-cell lung cancer: implications of FISH-positive patterns. Clin Lung Cancer 2019; 20 (04) e421-e429
• 256 Davies KD, Le AT, Sheren J. , et al. Comparison of molecular testing modalities for detection of ROS1 rearrangements in a cohort of positive patient samples. J Thorac Oncol 2018; 13 (10) 1474-1482
• 257 Suh JH, Schrock AB, Johnson A. , et al. Hybrid capture-based comprehensive genomic profiling identifies lung cancer patients with well-characterized sensitizing epidermal growth factor receptor point mutations that were not detected by standard of care testing. Oncologist 2018; 23 (07) 776-781
• 258 Lin JJ, Shaw AT. Recent advances in targeting ROS1 in lung cancer. J Thorac Oncol 2017; 12 (11) 1611-1625
• 259 Shaw AT, Riely GJ, Bang YJ. , et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol 2019; mdz131
• 260 Patil T, Smith DE, Bunn PA. , et al. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib. J Thorac Oncol 2018; 13 (11) 1717-1726
• 261 Gou W, Zhou X, Liu Z. , et al. CD74-ROS1 G2032R mutation transcriptionally up-regulates Twist1 in non-small cell lung cancer cells leading to increased migration, invasion, and resistance to crizotinib. Cancer Lett 2018; 422: 19-28
• 262 McCoach CE, Le AT, Gowan K. , et al. Resistance mechanisms to targeted therapies in ROS1 ⁺ and ALK ⁺ non-small cell lung cancer. Clin Cancer Res 2018; 24 (14) 3334-3347
• 263 Watanabe J, Furuya N, Fujiwara Y. Appearance of a BRAF mutation conferring resistance to crizotinib in non-small cell lung cancer harboring oncogenic ROS1 fusion. J Thorac Oncol 2018; 13 (04) e66-e69
• 264 Dagogo-Jack I, Rooney M, Nagy RJ. , et al. Molecular analysis of plasma from patients with ROS1-positive NSCLC. J Thorac Oncol 2019; 14 (05) 816-824
• 265 Liu D, Offin M, Harnicar S, Li BT, Drilon A. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag 2018; 14: 1247-1252
• 266 Drilon A, Ou SI, Cho BC. , et al. Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent- front mutations. Cancer Discov 2018; 8 (10) 1227-1236
• 267 Lim SM, Kim HR, Lee JS. , et al. Open-label, multicenter, phase ii study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 2017; 35 (23) 2613-2618
• 268 Ou SI, Zhu VW. CNS metastasis in ROS1+ NSCLC: an urgent call to action, to understand, and to overcome. Lung Cancer 2019; 130: 201-207
• 269 Sun TY, Niu X, Chakraborty A, Neal JW, Wakelee HA. Lengthy progression-free survival and intracranial activity of cabozantinib in patients with crizotinib and ceritinib-resistant ROS1-positive non-small cell lung cancer. J Thorac Oncol 2019; 14 (02) e21-e24
• 270 Lee J, Sun JM, Lee SH. , et al. Efficacy and safety of lorlatinib in Korean non-small-cell lung cancer patients with ALK or ROS1 rearrangement whose disease failed to respond to a previous tyrosine kinase inhibitor. Clin Lung Cancer 2019; 20 (03) 215-221
• 271 Chen H, Zhang Q, Zhang Y, Jia B, Zhang B, Wang C. Afatinib reverses ceritinib resistance (CR) in ALK/ROS1-positive non-small-cell lung cancer cell (NSCLC) via suppression of NRG1 pathway. OncoTargets Ther 2018; 11: 8201-8209
• 272 Kato Y, Ninomiya K, Ohashi K. , et al. Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. Cancer Sci 2018; 109 (10) 3149-3158
• 273 Drilon A, Somwar R, Wagner JP. , et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res 2016; 22 (10) 2351-2358
• 274 Katayama R, Kobayashi Y, Friboulet L. , et al. Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer. Clin Cancer Res 2015; 21 (01) 166-174
• 275 Chong CR, Bahcall M, Capelletti M. , et al. Identification of existing drugs that effectively target NTRK1 and ROS1 rearrangements in lung cancer. Clin Cancer Res 2017; 23 (01) 204-213
• 276 Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev 2007; 17 (01) 31-39
• 277 Davies H, Bignell GR, Cox C. , et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892): 949-954
• 278 Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511 (7511): 543-550
• 279 Lin L, Asthana S, Chan E. , et al. Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci U S A 2014; 111 (07) E748-E757
• 280 Litvak AM, Paik PK, Woo KM. , et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol 2014; 9 (11) 1669-1674
• 281 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 (03) 448-456
• 282 Cui G, Liu D, Li W. , et al. A meta-analysis of the association between BRAF mutation and nonsmall cell lung cancer. Medicine (Baltimore) 2017; 96: e6552
• 283 Marchetti A, Felicioni L, Malatesta S. , et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011; 29 (26) 3574-3579
• 284 Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene 2018; 37 (24) 3183-3199
• 285 Dagogo-Jack I, Martinez P, Yeap BY. , et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin Cancer Res 2019; 25 (01) 158-165
• 286 Baik CS, Myall NJ, Wakelee HA. Targeting BRAF-mutant non-small cell lung cancer: from molecular profiling to rationally designed therapy. Oncologist 2017; 22 (07) 786-796
• 287 Long GV, Stroyakovskiy D, Gogas H. , et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371 (20) 1877-1888
• 288 Chan XY, Singh A, Osman N, Piva TJ. Role played by signalling pathways in overcoming BRAF inhibitor resistance in melanoma. Int J Mol Sci 2017; 18 (07) 18
• 289 Planchard D, Besse B, Groen HJM. , 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 (07) 984-993
• 290 Planchard D, Smit EF, Groen HJM. , et al. 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 2017; 18 (10) 1307-1316
• 291 Ascierto PA, McArthur GA, Dréno B. , et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016; 17 (09) 1248-1260
• 292 Dummer R, Ascierto PA, Gogas HJ. , et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2018; 19 (05) 603-615
• 293 Dummer R, Ascierto PA, Gogas HJ. , et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018; 19 (10) 1315-1327
• 294 Nakamura T, Ishizaka Y, Nagao M, Hara M, Ishikawa T. Expression of the ret proto-oncogene product in human normal and neoplastic tissues of neural crest origin. J Pathol 1994; 172 (03) 255-260
• 295 Wang Y, Xu Y, Wang X. , et al. RET fusion in advanced non-small-cell lung cancer and response to cabozantinib: a case report. Medicine (Baltimore) 2019; 98 (03) e14120
• 296 Fusco A, Grieco M, Santoro M. , et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987; 328 (6126): 170-172
• 297 Mulligan LM, Kwok JB, Healey CS. , et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993; 363 (6428): 458-460
• 298 Donis-Keller H, Dou S, Chi D. , et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993; 2 (07) 851-856
• 299 Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2018; 13 (01) 27-45
• 300 Kohno T, Ichikawa H, Totoki Y. , et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 2012; 18 (03) 375-377
• 301 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) 4352-4359
• 302 Gautschi O, Milia J, Filleron T. , et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol 2017; 35 (13) 1403-1410
• 303 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) 1653-1660
• 304 Yoh K, Seto T, Satouchi M. , 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 (01) 42-50
• 305 Drilon AE, Subbiah V, Oxnard GR. , et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol 2018; 36: 102
• 306 Oxnard G, Subbiah V, Park K. , et al. OA12.07 clinical activity of LOXO-292, a highly selective RET inhibitor, in patients with RET fusion+ non-small cell lung cancer. J Thorac Oncol 2018; 13: S349-S50
• 307 Subbiah V, Taylor M, Lin J. , et al. Abstract CT043: Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors. Cancer Res 2018; 78: CT043
• 308 Kong-Beltran M, Seshagiri S, Zha J. , et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res 2006; 66 (01) 283-289
• 309 Okuda K, Sasaki H, Yukiue H, Yano M, Fujii Y. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci 2008; 99 (11) 2280-2285
• 310 Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009; 4 (01) 5-11
• 311 Seo JS, Ju YS, Lee WC. , et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012; 22 (11) 2109-2119
• 312 Awad MM, Oxnard GR, Jackman DM. , et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol 2016; 34 (07) 721-730
• 313 Sterlacci W, Fiegl M, Gugger M, Bubendorf L, Savic S, Tzankov A. MET overexpression and gene amplification: prevalence, clinico-pathological characteristics and prognostic significance in a large cohort of patients with surgically resected NSCLC. Virchows Arch 2017; 471 (01) 49-55
• 314 Cappuzzo F, Marchetti A, Skokan M. , et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009; 27 (10) 1667-1674
• 315 Camidge DR, Ou S-HI, Shapiro G. , et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014; 32: 8001
• 316 Noonan SA, Berry L, Lu X. , et al. Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis. J Thorac Oncol 2016; 11 (08) 1293-1304
• 317 Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res 2015; 4 (01) 67-81
• 318 Nakade J, Takeuchi S, Nakagawa T. , et al. Triple inhibition of EGFR, Met, and VEGF suppresses regrowth of HGF-triggered, erlotinib-resistant lung cancer harboring an EGFR mutation. J Thorac Oncol 2014; 9 (06) 775-783
• 319 Xu L, Kikuchi E, Xu C. , et al. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res 2012; 72 (13) 3302-3311
• 320 Nakagawa T, Takeuchi S, Yamada T. , et al. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther 2012; 11 (10) 2149-2157
• 321 Wu DW, Chen TC, Huang HS, Lee H. TC-N19, a novel dual inhibitor of EGFR and cMET, efficiently overcomes EGFR-TKI resistance in non-small-cell lung cancer cells. Cell Death Dis 2016; 7 (06) e2290
• 322 Mendenhall MA, Goldman JW. MET-mutated NSCLC with major response to crizotinib. J Thorac Oncol 2015; 10 (05) e33-e34
• 323 Drilon AE, Camidge DR, Ou S-HI. , et al. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol 2016; 34: 108
• 324 Ou SH, Kwak EL, Siwak-Tapp C. , et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011; 6 (05) 942-946
• 325 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 (08) 850-859
• 326 Paik PK, Drilon A, Fan PD. , et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015; 5 (08) 842-849
• 327 Felip E, Horn L, Patel JD. , et al. Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14-skipping mutations: Phase II trial. J Clin Oncol 2018; 36: 9016
• 328 Wolf J, Hochmair M, Kattan JG. , et al. 478TiP: A phase II, multicenter, four-cohort study of oral cMET inhibitor capmatinib (INC280) in patients with EGFR wild-type, advanced NSCLC who have received one or two prior lines of systemic therapy for advanced/metastatic disease. Ann Oncol 2015; 26: ix146
• 329 Pinkas-Kramarski R, Soussan L, Waterman H. , et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 1996; 15 (10) 2452-2467
• 330 Wang L-M, Kuo A, Alimandi M. , et al. ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4. Proc Natl Acad Sci U S A 1998; 95 (12) 6809-6814
• 331 Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem 1999; 274 (13) 8865-8874
• 332 Roy V, Perez EA. Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer. Oncologist 2009; 14 (11) 1061-1069
• 333 Wang SE, Narasanna A, Perez-Torres M. , et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 2006; 10 (01) 25-38
• 334 Pillai RN, Behera M, Berry LD. , et al. HER2 mutations in lung adenocarcinomas: a report from the Lung Cancer Mutation Consortium. Cancer 2017; 123 (21) 4099-4105
• 335 Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008; 359 (13) 1367-1380
• 336 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 (01) 19-27
• 337 Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH. ; Eastern Cooperative Oncology Group Study 2598. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol 2004; 22 (07) 1180-1187
• 338 Lara Jr PN, Laptalo L, Longmate J. , et al; California Cancer Consortium. Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. Clin Lung Cancer 2004; 5 (04) 231-236
• 339 Krug LM, Miller VA, Patel J. , et al. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma. Cancer 2005; 104 (10) 2149-2155
• 340 Zinner RG, Glisson BS, Fossella FV. , et al. Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease. Lung Cancer 2004; 44 (01) 99-110
• 341 Herbst RS, Davies AM, Natale RB. , et al. Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin Cancer Res 2007; 13 (20) 6175-6181
• 342 Shigematsu H, Takahashi T, Nomura M. , et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005; 65 (05) 1642-1646
• 343 Buttitta F, Barassi F, Fresu G. , et al. Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int J Cancer 2006; 119 (11) 2586-2591
• 344 Mazières J, Barlesi F, Filleron T. , 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 (02) 281-286
• 345 Li BT, Shen R, Buonocore D. , et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol 2018; 36 (24) 2532-2537
• 346 Tetlow AL, Tamanoi F. The Ras superfamily G-proteins. The Enzymes 2013; 33 (Pt A): 1-14
• 347 Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science 2001; 294 (5545): 1299-1304
• 348 Takashima A, Faller DV. Targeting the RAS oncogene. Expert Opin Ther Targets 2013; 17 (05) 507-531
• 349 Román M, Baraibar I, López I. , et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer 2018; 17 (01) 33
• 350 Janes MR, Zhang J, Li LS. , et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 2018; 172 (03) 578-589.e17
• 351 Renaud S, Seitlinger J, Falcoz PE. , et al. Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery. Br J Cancer 2016; 115 (03) 346-353
• 352 O'Byrne KJ, Gatzemeier U, Bondarenko I. , et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011; 12 (08) 795-805
• 353 Lohinai Z, Klikovits T, Moldvay J. , et al. KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep 2017; 7: 39721
• 354 Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013; 24 (09) 2371-2376
• 355 Kaufman J, Stinchcombe TE. Treatment of KRAS-mutant non-small cell lung cancer: the end of the beginning for targeted therapies. JAMA 2017; 317 (18) 1835-1837
• 356 Gysin S, Salt M, Young A, McCormick F. Therapeutic strategies for targeting ras proteins. Genes Cancer 2011; 2 (03) 359-372
• 357 Jänne 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 (01) 38-47
• 358 Jänne PA, van den Heuvel MM, Barlesi F. , et al. 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 2017; 317 (18) 1844-1853
• 359 Papadopoulos KP, Ou S-HI, Johnson ML. , et al. A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation. J Clin Oncol 2019; 37: TPS3161
• 360 Fakih M, O'Neil B, Price TJ. , et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J Clin Oncol 2019; 37: 3003