Abstract CT034: Osimertinib plus selumetinib for patients (pts) withEGFR-mutant (EGFRm) NSCLC following disease progression on an EGFR-TKI: Results from the Phase Ib TATTON study

The EGFR T790M mutation is the most common cause of resistance in pts receiving a first or second-generation EGFR-TKI for EGFRm NSCLC. Other resistance mechanisms include upregulation of the RAS/RAF/MEK/ERK signaling pathway. The Phase Ib TATTON study (NCT02143466) assessed osimertinib in combination with novel therapeutics including the oral, potent and selective MEK1/2 inhibitor, selumetinib (AZD6244, ARRY-142886). Here we present data from the dose-finding (Part A) and dose expansion (Part B) portions of this study. Adults with advanced EGFRm NSCLC and disease progression on prior EGFR-TKI, including third-generation agents, were eligible regardless of T790M or KRAS status. In Part A, pts received osimertinib 80 mg QD plus intermittent or continuous selumetinib. Asian pts received continuous selumetinib 25/50 mg BID, while other pts received continuous selumetinib 50/75 mg BID, or intermittent selumetinib 75 mg BID 4 days on/3 days off (4/3), or on days 1 and 4 of each week of treatment. In Part B, pts received osimertinib plus intermittent selumetinib 75 mg BID 4/3. Primary objectives were safety, tolerability and preliminary efficacy (objective response rate [ORR]). Secondary objectives included duration of response (DoR) and pharmacokinetics (PK). At data cut-off (Feb 2018), 36 and 47 pts received treatment in Parts A and B, respectively. In Part A, most pts were white (18, 50%) or Asian (17, 47%), and 26 (72%) had a baseline exon 19 deletion. In Part B, 44 (94%) pts were Asian, and 30 (64%) had a baseline exon 19 deletion. The most common treatment-related adverse events (TRAEs) in Part A were diarrhea (27, 75%), nausea (14, 39%) and fatigue (12, 33%). Six pts had dose-limiting toxicities (DLTs) with continuous selumetinib (all Grade 3): ALT and AST increase (50 mg); diarrhea, asthenia and dizziness (50 mg); diarrhea (n=2, 75 mg); diarrhea and nausea (75 mg); and pneumonitis (75 mg). No DLTs were reported with intermittent dosing, so the selumetinib 4/3 schedule was selected for Part B. The most common TRAEs in Part B were diarrhea (38, 81%), stomatitis (15, 32%), and paronychia (14, 30%). In Part A, 15 (42%) pts had confirmed partial response (PR); 14 (39%) had stable disease at 6 weeks (SD); 3 (8%) had progressive disease (PD); 2 (6%) died; and 2 (6%) were not evaluable (NE). Median DoR was 16.6 months; 77% remained in response at 12 months. In Part B, 16 (34%) pts had confirmed PR; 16 (34%) had SD; 11 (23%) had PD; 2 (4%) died; and 2 (4%) were NE. Median DoR was 9.1 months; 31% remained in response at 12 months. Osimertinib and selumetinib PK parameters were similar to those previously observed with monotherapy. Osimertinib plus intermittent selumetinib had an acceptable safety profile and demonstrated preliminary anti-tumor activity in pts with disease progression on a prior EGFR-TKI. Responses were durable and this combination warrants further investigation. Citation Format: Suresh S. Ramalingam, Hideo Saka, Myung-Ju Ahn, Helena Yu, Helena Yu, Leora Horn, Toyoaki Hida, Mireille Cantarini, Remy Verheijen, Jonathan Wessen, Geoffrey Oxnard, Yuichiro Ohe. Osimertinib plus selumetinib for patients (pts) with EGFR-mutant (EGFRm) NSCLC following disease progression on an EGFR-TKI: Results from the Phase Ib TATTON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT034.