Osimertinib plus Selumetinib in EGFR-Mutated Non–Small Cell Lung Cancer After Progression on EGFR-TKIs: A Phase Ib, Open-Label, Multicenter Trial (TATTON Part B)

MEK/ERK inhibition can overcome acquired resistance to osimertinib in preclinical models. Osimertinib (epidermal growth factor receptor [EGFR]-tyrosine kinase inhibitor [TKI]) plus selumetinib (mitogen-activated protein kinase [MEK]1/2 inhibitor) was assessed in the global TATTON study.This multicenter, open-label, Phase 1b study expansion cohort enrolled patients (aged {greater than or equal to}18 years) with advanced MET-negative, EGFRm NSCLC who had progressed on EGFR-TKIs. Patients were assigned to one of two cohorts by prior first-/second-generation [1G/2G] or T790M-directed EGFR-TKI and received osimertinib 80 mg QD and intermittent selumetinib 75 mg BID PO. Safety and tolerability (primary objective) and antitumor activity determined by objective response rate (ORR), and progression-free survival (PFS) using RECIST version 1.1 were assessed. Data cutoff: March 4, 2020.Forty-seven patients received treatment (prior 1G/2G EGFR-TKI, n=12; prior 3G EGFR-TKI, n=35). Forty-four (94%) patients were Asian; 30 (64%) had baseline exon 19 deletion. Most common AEs were diarrhea (89%), decreased appetite (40%), and stomatitis (32%); 11/47 patients (23%) had an AE Grade {greater than or equal to}3 possibly causally selumetinib-related. ORR was 66.7% (95% confidence interval: 34.9-90.1) in the prior 1G/2G EGFR-TKI group, 22.9% (10.4-40.1) in the prior 3G EGFR-TKI group, and 34.0% (2.7-7.2) overall; median PFS was 15.0 (2.7-33.0), 2.8 (1.6-5.5), and 4.2 months (2.7-7.2), respectively.In this small study, AEs and tolerability of osimertinib plus selumetinib were as expected, based on previous studies. The combination demonstrated antitumor activity supportive of further investigation in patients with MET-negative, EGFRm advanced NSCLC, who had progressed on a previous EGFR-TKI.