Clinical Review

Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer

Hospital Physician: Hematology/Oncology. 2017 July;12(4):13-25

References

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7–30.
Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol 2016;893:1–19.
Alberg AJ, Brock MV, Ford JG, et al. Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e1S–29S.
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-3013, based on November 2015 SEER data submission, posted to the SEER website, April 2016. Bethesda (MD): National Cancer Institute; 2016.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer: 1–190.
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;350:2129–39.
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–6.
Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancer. J Clin Oncol 2012;30:863–70.
Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29:2046–51.
Kinno T, Tsuta K, Shiraishi K, et al. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol 2014;25:138–42.
Litvak AM, Paik PK, Woo KM, et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol 2014;9:1669–74.
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;121:448–56.
Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726–36.
Planchard D, Kim TM, Mazieres J, et al. DaBRAFenib in patients with BRAF V600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:642–50.
Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF cohort. J Thorac Oncol 2015;10:1451–7.
Planchard D, Besse B, Groen HJ, et al. DaBRAFenib plus trametinib in patients with previously treated BRAF V600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17:984–93.
Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology. J Thorac Oncol 2013;8:823–59.
Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology. Arch Pathol Lab Med 2013;137:828–60.
Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guideline. J Clin Oncol 2014;32:3673–9.
Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther 2012;11:2535–40.
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;5:842–9.
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;34:721–30.
Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J Thorac Oncol 2016;11:1493–502.
Reungwetwattana T, Liang Y, Zhu V, et al. The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The why, the how, the who, the unknown, and the inevitable. Lung Cancer 2017;103:27–37.
Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 2013;3:630–5.
Lin JJ, Kennedy E, Sequist LV, et al. Clinical activity of alectinib in advanced RET-rearranged non-small cell lung cancer. J Thorac Oncol 2016;11:2027–32.
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;17:1653–60.
Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 2006;354:2619–21.
Mazieres J. Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targted drugs: results from the European EUHER2 cohort. Annal Oncol 2016;27:281–6.
Ou SH, Schrock AB, Bocharov EV, et al. HER2 transmembrane (TMD) mutations (V659/G660) that stabilize homo- and heterodimerization are rare oncogenic drivers in lung adenocarcinoma that respond to afatinib. J Thorac Oncol 2017;12:446–57.
Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emergent therapies. Cancer Discov 2017;7:596–609.
Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998–2006.
Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016;387:1415–26.
Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–67.
Rosell R, Karachaliou N, et al. Large-scale screening for somatic mutations in lung cancer. Lancet 2016;387:1354–6.
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;97:339–46.
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;31:3327–34.
Wu YL, Chou 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;26:1883–9.
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Eng J Med 2010;362:2380–8.
Mitsudomi T, Morita S, Yatabe Y, et al. 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;11:121–8.
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;12:735–42.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46.
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;15:213–22.
Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol 2009;10:432–3.
Nelson V, Ziehr J, Aqulnik M, et al. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013;5:135–43.
Lee CK, Wu YL, Ding PN, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol 2015;33:1958–65.
Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54–9.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–57.
Wu YL, Saijo N, Thongprasert S, et al. Efficacy according to blind independent central review: post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EFGR mutation-positive advanced NSCLC. Lung Cancer 2017;104:119–25.
Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR-mutation positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer 2014;110:55–62.
Hu JC, Sadeghi P, Pinter-Brown LC, et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol 2007;56:317–26.
Tarceva [package insert]. South San Francisco (CA): Genentech, Inc; 2010. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf. Accessed April 23, 2017.
Gilotrif [package insert.] Ridgefield (CT): Boehringer Ingelheim, Inc; 2013. www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf. Accessed April 23, 2017.
Iressa [package insert]. Wilmington (DE): AstraZeneca, Inc; 2015. Error! Hyperlink reference not valid. Accessed April 23, 2017.
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;17:1616–22.
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;19:2240–7.
Yun CH, Mengwasser KE, Tom AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008;105:2070–5.
Sos ML, Rode HB, Heynck S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010;70:868–74.
Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T190M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046–61.
Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629–40.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. N Engl J Med 2010;363:1693–703.
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;27:4247–53.
Kazandjian D, Blumenthal GM, Chen HY, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist 2014;19:e5–11.
Solomon BJ, Mok T, Kim DW, et al. First-ling crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167–77.
Xalkori [package insert]. New York: Pfizer, Inc; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s002lbl.pdf. Accessed April 23, 2017.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–94.
Marsilje TH, Pei W, Chen B, et al. Synthesis, structure-activity relationships and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem 2013;56:5675–90.
Khozin S, Blumenthal GM, Zhang L, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res 2015;21:2436–9.
Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389:917–29.
Zykadia [package insert]. East Hanover (NJ): Novartis Pharmaceuticals Corporation, Inc; 2016. www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zykadia.pdf. Accessed April 23, 2017.
Larkins E, Blumenthal GM, Chen H, et al. FDA approval: alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib. Clin Cancer Res 2016;22:5171–6.
Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. New Engl J Med 2017 June 6 [Epub ahead of print].
Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem 2012;20:1271–80.
Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011;19:679–90.
Kodama T, Tsukaguchi T, Yoshida M, et al. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett 2014;351:215–21.
Kodama T, Tsukaguchi T, Satoh T, et al. Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. Mol Cancer Ther 2014;13:2910–8.
Alecensa [package insert]. South San Francisco (CA): Genentech, Inc; 2015. www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf. Accessed April 23, 2017.
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 May 5 [Epub ahead of print].
Zhu V, Ou SH. Safety of alectinib for the treatment of metastatic ALK-rearranged non-small cell lung cancer. Expert Opin Drug Saf 2017;16:509–14.
Gadgeel SM, Shaw AT, Govindan R, et al. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non-small cell lung cancer. J Clin Oncol 2016;34:4079–85.
Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443–5.
Zhu Q, Zhan P, Zhang X, et al. Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res 2015;4:300–9.
Lin JJ, Ritterhouse LL, Ali SM, et al. ROS1 fusions rarely overlap with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol 2017;12:872–7.
Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 2009;1795:37–52.
Kazandjian D, Blumenthal G, Luo L, et al. Benefit-Risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive metastatic NSCLC. Oncologist 2016;21:974–80.
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963–71.
Zhu VW, Upadhyay D, Schrock AB, et al. TPD52L1-ROS1, a new ROS1 fusion variant in lung adenosquamous cell carcinoma identified by comprehensive genomic profiling. Lung Cancer 2016;97:48–50.

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵ BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

References

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7–30.
Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol 2016;893:1–19.
Alberg AJ, Brock MV, Ford JG, et al. Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e1S–29S.
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-3013, based on November 2015 SEER data submission, posted to the SEER website, April 2016. Bethesda (MD): National Cancer Institute; 2016.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer: 1–190.
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;350:2129–39.
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–6.
Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancer. J Clin Oncol 2012;30:863–70.
Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29:2046–51.
Kinno T, Tsuta K, Shiraishi K, et al. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol 2014;25:138–42.
Litvak AM, Paik PK, Woo KM, et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol 2014;9:1669–74.
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;121:448–56.
Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726–36.
Planchard D, Kim TM, Mazieres J, et al. DaBRAFenib in patients with BRAF V600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:642–50.
Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF cohort. J Thorac Oncol 2015;10:1451–7.
Planchard D, Besse B, Groen HJ, et al. DaBRAFenib plus trametinib in patients with previously treated BRAF V600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17:984–93.
Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology. J Thorac Oncol 2013;8:823–59.
Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology. Arch Pathol Lab Med 2013;137:828–60.
Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guideline. J Clin Oncol 2014;32:3673–9.
Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther 2012;11:2535–40.
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;5:842–9.
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;34:721–30.
Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J Thorac Oncol 2016;11:1493–502.
Reungwetwattana T, Liang Y, Zhu V, et al. The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The why, the how, the who, the unknown, and the inevitable. Lung Cancer 2017;103:27–37.
Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 2013;3:630–5.
Lin JJ, Kennedy E, Sequist LV, et al. Clinical activity of alectinib in advanced RET-rearranged non-small cell lung cancer. J Thorac Oncol 2016;11:2027–32.
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;17:1653–60.
Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 2006;354:2619–21.
Mazieres J. Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targted drugs: results from the European EUHER2 cohort. Annal Oncol 2016;27:281–6.
Ou SH, Schrock AB, Bocharov EV, et al. HER2 transmembrane (TMD) mutations (V659/G660) that stabilize homo- and heterodimerization are rare oncogenic drivers in lung adenocarcinoma that respond to afatinib. J Thorac Oncol 2017;12:446–57.
Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emergent therapies. Cancer Discov 2017;7:596–609.
Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998–2006.
Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016;387:1415–26.
Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–67.
Rosell R, Karachaliou N, et al. Large-scale screening for somatic mutations in lung cancer. Lancet 2016;387:1354–6.
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;97:339–46.
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;31:3327–34.
Wu YL, Chou 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;26:1883–9.
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Eng J Med 2010;362:2380–8.
Mitsudomi T, Morita S, Yatabe Y, et al. 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;11:121–8.
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;12:735–42.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46.
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;15:213–22.
Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol 2009;10:432–3.
Nelson V, Ziehr J, Aqulnik M, et al. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013;5:135–43.
Lee CK, Wu YL, Ding PN, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol 2015;33:1958–65.
Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54–9.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–57.
Wu YL, Saijo N, Thongprasert S, et al. Efficacy according to blind independent central review: post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EFGR mutation-positive advanced NSCLC. Lung Cancer 2017;104:119–25.
Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR-mutation positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer 2014;110:55–62.
Hu JC, Sadeghi P, Pinter-Brown LC, et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol 2007;56:317–26.
Tarceva [package insert]. South San Francisco (CA): Genentech, Inc; 2010. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf. Accessed April 23, 2017.
Gilotrif [package insert.] Ridgefield (CT): Boehringer Ingelheim, Inc; 2013. www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf. Accessed April 23, 2017.
Iressa [package insert]. Wilmington (DE): AstraZeneca, Inc; 2015. Error! Hyperlink reference not valid. Accessed April 23, 2017.
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;17:1616–22.
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;19:2240–7.
Yun CH, Mengwasser KE, Tom AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008;105:2070–5.
Sos ML, Rode HB, Heynck S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010;70:868–74.
Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T190M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046–61.
Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629–40.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. N Engl J Med 2010;363:1693–703.
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;27:4247–53.
Kazandjian D, Blumenthal GM, Chen HY, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist 2014;19:e5–11.
Solomon BJ, Mok T, Kim DW, et al. First-ling crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167–77.
Xalkori [package insert]. New York: Pfizer, Inc; 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s002lbl.pdf. Accessed April 23, 2017.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–94.
Marsilje TH, Pei W, Chen B, et al. Synthesis, structure-activity relationships and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem 2013;56:5675–90.
Khozin S, Blumenthal GM, Zhang L, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res 2015;21:2436–9.
Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389:917–29.
Zykadia [package insert]. East Hanover (NJ): Novartis Pharmaceuticals Corporation, Inc; 2016. www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zykadia.pdf. Accessed April 23, 2017.
Larkins E, Blumenthal GM, Chen H, et al. FDA approval: alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib. Clin Cancer Res 2016;22:5171–6.
Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. New Engl J Med 2017 June 6 [Epub ahead of print].
Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem 2012;20:1271–80.
Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011;19:679–90.
Kodama T, Tsukaguchi T, Yoshida M, et al. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett 2014;351:215–21.
Kodama T, Tsukaguchi T, Satoh T, et al. Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. Mol Cancer Ther 2014;13:2910–8.
Alecensa [package insert]. South San Francisco (CA): Genentech, Inc; 2015. www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf. Accessed April 23, 2017.
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 May 5 [Epub ahead of print].
Zhu V, Ou SH. Safety of alectinib for the treatment of metastatic ALK-rearranged non-small cell lung cancer. Expert Opin Drug Saf 2017;16:509–14.
Gadgeel SM, Shaw AT, Govindan R, et al. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non-small cell lung cancer. J Clin Oncol 2016;34:4079–85.
Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443–5.
Zhu Q, Zhan P, Zhang X, et al. Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res 2015;4:300–9.
Lin JJ, Ritterhouse LL, Ali SM, et al. ROS1 fusions rarely overlap with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol 2017;12:872–7.
Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 2009;1795:37–52.
Kazandjian D, Blumenthal G, Luo L, et al. Benefit-Risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive metastatic NSCLC. Oncologist 2016;21:974–80.
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963–71.
Zhu VW, Upadhyay D, Schrock AB, et al. TPD52L1-ROS1, a new ROS1 fusion variant in lung adenosquamous cell carcinoma identified by comprehensive genomic profiling. Lung Cancer 2016;97:48–50.

Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer

References

INTRODUCTION

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