Osimertinib for advanced non-small cell lung cancer harboring EGFR mutation exon 20 T790M, acquired resistant mutation for first- or second-generation EGFR-TKI

Abstract

Since the results of IDEAL-1 (1) and the approval of gefitinib, a first-class epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), 15 years have passed. The efficacy of first-line EGFR-TKI, gefitinib (2,3), erlotinib (4), icotinib (5), and second-line EGFR-TKI, afatinib (6), is 6.3-11.0 months for median progression-free survival (PFS), 19.4-28.2 months for median overall survival (OS), and 44.1-73.7% for the response rates, respectively.Osimertinib mesylate (AZD9291, Tagrisso TM ) is an oral mono-anilino-pyrimidine small molecule that is promising for the treatment of mutant-selective EGFR-TKI. In particular, osimertinib is anticipated to exhibit potent activity against advanced non-small cell lung cancer (NSCLC) harboring the EGFR mutation, T790M, indicating resistance to EGFR-TKI as the breakthrough therapy (7). Half of the resistance to EGFR-TKI occurs via acquired resistance associated with exon 20 T790M. In the standard of care, cytotoxic chemotherapy has been applied with a response rate of 30-40% and median PFS of four to seven months as a first-line cytotoxic chemotherapy or response rate of 10-20% and median PFS of two months as second-line (8) treatment until the advent of osimertinib. Medical oncologists have been anticipated to respond by following later lines of chemotherapy as a re-challenge of EGFR-TKI with response rates of 4.9-8.2% (9) or the second-generation EGFR-TKI, afatinib, following the failure of first-generation EGFR-TKIs (10). In a secondline setting after the failure of EGFR-TKI harboring exon 20 T790M, osimertinib was confirmatory improved PFS compared to the platinum-pemetrexed combination administered in the phase III trial (AURA3 trial) conducted by Mok et al. (11). In the AURA3, 419 patients with T790M-positive NSCLC were randomized to receive either 80 mg osimertinib once daily, or chemotherapy [pemetrexed 500 mg/m 2 every three weeks plus platinum (carboplatin targeting an area under the curve 5 or 75 mg/m 2 of cisplatin)]. The median PFS as the primary endpoint was successfully completed at 10.1 months for the osimertinib arm and over 4.4 months for the chemotherapy arm [hazard ratio (HR): 0.30; 95% confidence interval (CI): 0.23-0.41; P<0.001]. The objective response rate (ORR) was 71% vs. 31% for osimertinib and chemotherapy, respectively (odds ratio: 5.39; 95% CI: 3.47-8.4; P<0.001). In this trial, the patients exhibited CNS metastasis at 8.5 months for the PFS of osimertinib compared to 4.2 months for those receiving chemotherapy (HR: 0.32; 95% CI: 0.21-0.49). Among the patients without central nervous system (CNS) metastasis, the PFS was 10.8 months for osimertinib and 5.6 months for chemotherapy (HR: 0.40; 95% CI: 0.29-0.55). In addition, there is promising data indicating that osimertinib is preferable to the penetration of the CNS over other EGFR-TKIs using an animal J Thorac Dis 2017;9(3):470-473 jtd.amegroups.com model (12). In the BLOOM study (NCT02228369), 20 patients with leptomeningeal metastasis exhibiting an EGFR mutation were treated with 16...

March 2018 pulmonary case of the month

“…At that time osimertinib, an irreversible EGFR tyrosine kinase inhibitor that is selective for T790M mutations and has activity in the central nervous system, became available. Osimertinib has been shown to be superior to platinum doublet chemotherapy as a second-line therapy for advanced NSCLC harboring exon T790M following the failure of first or second-generation EGFR-TKI (4). She was begun on osimertinib and has had only mild fatigue as a side effect of the new therapy.…”