P3.02b-117 Phase Ib Results from a Study of Capmatinib (INC280) + EGF816 in Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC): Topic: EGFR RES

Abstract

Among patients with EGFR-mutant NSCLC who progress on EGFR tyrosine kinase inhibitors (EGFR-TKIs), the most common (50%) resistance mechanism is secondary T790M mutation. cMET dysregulation is the second most common mechanism, with amplification occurring in 5‒22% of resistant patients. This study evaluates targeting these two mechanisms to overcome acquired resistance to EGFR-TKIs. Capmatinib (INC280) is a highly selective, potent cMET inhibitor with clinical activity in patients with cMET dysregulation. EGF816 is an irreversible EGFR-TKI that selectively inhibits T790M and EGFR-activating mutations, with antitumor activity in EGFRT790M-mutated NSCLC. In this open-label Phase Ib/II study, capmatinib was combined with EGF816 in patients with EGFR-mutated, EGFR-TKI resistant NSCLC. The Phase Ib primary objective is estimation of the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of the combination using an adaptive Bayesian logistic regression model. Eligible patients (≥18 years; ECOG PS ≤2) must have documented EGFR-mutated (exon19del and/or L858R) NSCLC and documented progression (RECIST v1.1) while on EGFR-TKI treatment. Patients received capmatinib (starting dose 200 mg BID) plus EGF816 (starting dose 50 mg QD). At the data cut-off (Aug 1, 2016), 33 patients were enrolled at five capmatinib BID/EGF816 QD mg dose levels (200/50 [n=4]; 200/100 [n=5]; 400/75 [n=3]; 400/100 [n=16]; 400/150 mg [n=5]); 18/33 (55%) patients discontinued treatment, mainly (13 [39%] patients) due to disease progression. Dose-limiting toxicities (DLTs) occurred in 4 patients: in 1 patient at the 200/50 dose level (increased alanine aminotransferase), 1 patient at the 400/100 dose level (anaphylactic reaction), and 2 patients at the 400/150 dose level (pyrexia, maculopapular rash, and allergic dermatitis). The most frequent (≥30%) any-grade adverse events (AEs), regardless of causality, were nausea (55%), peripheral edema (45%), increased amylase (42%), increased blood creatinine (36%), decreased appetite and diarrhea (both 30%). The most frequent (>10%) Grade ≥3 AEs were maculopapular rash (18% [mainly in the 400/150 cohort]) and increased amylase (12%). Capmatinib and EGF816 exposure increased with dose; preliminary data indicate a ∼35% increase in EGF816 exposure (AUC) at steady state when co-administered with the capmatinib RP2D, compared with single-agent exposure. The investigator-assessed overall response rate was 42% (2/33 complete responses; 12/33 partial responses) across all dose levels and 50% (8/16 patients) at the 400/100 dose level, regardless of molecular status of resistance. The RP2D of the combination was declared as capmatinib 400 mg BID + EGF816 100 mg QD. Preliminary antitumor activity was observed across dose levels, independent of T790M status.