Haematology+Oncology_News

Vol. 9 • No. 1 • 2016 • H aematology & O ncology N ews 15 EXPERT COMMENTARY

2015 practice changers in oncology: FDA-approved EGFR TKIs for acquired resistance to targeted therapy in lung cancer BY DR JARUSHKA NAIDOO

Dr Jarushka Naidoo is an assistant professor of oncology at the Sidney Kimmel Cancer Center at Johns Hopkins, in Baltimore, Maryland. Her research interests include immunotherapy, novel immunotherapeutic combinations, toxicities of immunotherapy, lung cancer, and central nervous system metastatic disease.

L ung adenocarcinoma is the most common sub- type of non-small cell lung cancer (NSCLC), and it accounts for over one million new cases each year worldwide. 1 Oncogenic driver mutations can be found in up to 50% of advanced lung adeno- carcinomas, 2,3 15% of which will harbour mutations in the epidermal growth factor receptor (EGFR). Since EGFR-mutant NSCLCs were first identified in 2004, other driver oncogenic mutations have been discovered in lung adenocarcinomas, such as BRAF, KRAS, ERBB2, PTEN, AKT, and PIK3CA. Targeted agents directed against these alterations are currently under study in clinical trials. EGFR exon 19 deletions and exon 21 L858R point muta- tions are the main mutations that confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). 4–6 Phase III randomised studies have demonstrated that patients whose lung cancers harbour sensitising EGFR mutations benefit from first-line therapy with EGFR TKIs rather than standard chemo- therapy in terms of improved tolerability, quality of life, progression-free survival, and overall survival in selected studies. 7–10 Due to these impressive results, there are currently three Food and Drug Administration-approved EGFR TKIs licensed for the treatment of EGFR-mutant NSCLC: erlotinib, gefitinib, and afatinib. Favourable objective response rates of up to 80% have been described with some targeted therapies; however, cancer cells that harbour oncogenic drier mutations nearly universally “acquire resistance” under the selective pressure of these agents. This process is almost inevitable, and the emergence of acquired resistance to targeted therapy is seen after approximately 1 year of therapy on a targeted agent. 6 Re-biopsy of new or growing lesions at the time of acquired resistance has become a standard approach aimed at revealing the mechanisms of acquired resistance, which may in turn be thera- peutically targeted. In the case of EGFR-mutant NSCLC, mechanisms of acquired resistance to EGFR TKIs include: the development of a second gate-keeper mutation of the EGFR gene (T790M mutation), ERBB2 gene amplification, PIK3CA mutations, MET amplification, BRAFmuta- tions, AXL activation, MAPK gene amplification, and transformation to small-cell lung cancer histology. 11–13 From here, two third-generation EGFR TKIs mutant-specific for T790M were investigated in patients with EGFR-mutant NSCLC harbouring an EGFR T790M resistance mutation-rociletinib

(previously CO-1686) and osimertinib (previously AZD9291). These agents were both studied in clinical trials published in The New England Jour- nal of Medicine in early in 2015, and demonstrated promising overall response rates of up to 59% to 61% in patients with centrally confirmed T790M mutations. 14,15 Further, osimertinib was FDA-ap- proved for the treatment of patients with metastatic EGFR T790Mmutation-positive NSCLC who had progressed on prior systemic therapy including an EGFR TKI, based on the results of two clinical studies AURA andAURA2. 16,17 In the AURA study, 201 patients were treated with osimertinib and demonstrated an overall response rate of 61%.16 In AURA2, 210 patients treated with this agent demonstrated an overall response rate of 71%. 17 The duration of responses ranged from 1.1 to 5.6 months, with a median follow-up of 4.2 months and 4 months, respectively. Osimertinib is administered as a once-daily pill, at a dose of 80 mg. Most commonly reported adverse events (AEs) were mild in severity, and consisted of diarrhoea, rash, dry skin, nail toxicity, ocular toxicity, nausea, poor appetite, constipa- tion, prolonged QTc, and neutropenia. The lat- ter two AEs also led to dose interruptions. The most common serious AEs included pulmonary embolism and pneumonia, with treatment-related pneumonitis and cerebrovascular accident leading to treatment discontinuation. Osimertinib is currently being compared with standard platinum-doublet chemotherapy in a phase III clinical trial in patients with T790M- positive advanced NSCLC, in patients who have received prior EGFR TKI therapy and progressed (NCT02151981). Targeted therapy for acquired resistance in lung cancer is a truly practice-changing advancement in the treatment of NSCLC that came to fruition throughout 2015. The approval of osimertinib rein- forces the importance for oncologists to understand the concept of acquired resistance, need for re- biopsy at the time of suspected acquired resistance, and the potential choice of an appropriate further targeted agent in the setting of identifying a resist- ance mutation that is therapeutically targetable. This article was first published on PracticeUpdate. com, a site tailored to deliver the latest expert con- tent based on the clinician’s area of practice, and is optimised for viewing on any device. Access to Prac- ticeUpdate, an Elsevier website, is free.

References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. 2. Pao W, Girard N. New driver mutations in non-small cell lung cancer. Lancet Oncol 2011;12:175–180. 3. Clinical Lung Cancer Genome Project, Network Genomic Medicine. A genomics-based classification of human lung tumors. Sci Transl Med 2013;5:209ra153. 4. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500. 5. Lynch TJ, Bell DW, Sordella R, et al. Activating muta- tions in the epidermal growth factor receptor underly- ing responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139. 6. Naidoo J, Drilon AE. Molecular diagnostic testing in non-small cell lung cancer. Am J Hematol Oncol 2014;4:4–11. 7. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for Euro- pean patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial. Lancet Oncol 2012;13:239–246. 8. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carbo-platin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;36110):947–957. 9. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380–2388. 10. 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 muta- tions. J Clin Oncol 2013;31:3327–3334. 11. 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;3:75ra26. 12. 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;19:2240–2247. 13. Suda K, Mizuuchi H, Maehara Y, Mitsudomi T. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth fac- tor receptor mutation-diversity, ductility, and destiny. Cancer Metastasis Rev 2012;31:807–814. 14. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372:1700–1709. 15. Janne P, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689–1699. 16. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6–9, 2014; Denver, CO. Abstract 943. 17. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 phase II study. Presented at: 16th World Conference on Lung Cancer; September 6–9, 2014; Denver, CO. Abstract 1406.

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