HM61713, an EGFR-mutant selective inhibitor

Abstract

EGFR tyrosine kinase inhibitors (TKIs) are effective for EGFR mutation positive non-small cell lung cancer (NSCLC) patients. However, acquired resistance occurs in most cases and EGFR T790M mutation is a major (>50%) resistance mechanism of first-generation EGFR TKIs. HM61713 is an orally active, EGFR-mutant selective inhibitor showed strong anti-cancer activity in EGFR mutant lung cancer cell lines including T790M mutation positive one. In addition, lower activity to wild-type EGFR inhibition suggested the possibility of decreased clinical toxicities such as skin rash and diarrhea. A phase 1/2 trial is ongoing to evaluate the safety, pharmacokinetics, and efficacy of HM61713 in patients with advanced EGFR mutation positive NSCLC who had failed to previous EGFR-TKIs (NCT01588145). In dose escalation part, the 3 + 3 dose-escalation scheme was used and the maximum tolerated dose was determined as 800 mg qd. An early expansion cohort was implemented at the dose 300 mg qd (N = 83) and the preliminary result was reported in ASCO 2014; the objective response rate was 29.2% in T790M positive patients (N = 48) and 11.8% in T790M negative population (N = 34). The disease control rate was 75.0% and 55.9%, respectively. Commonly reported adverse events (AEs) included skin exfoliation, nausea, diarrhea, rash, decreased appetite and pruritus. Most AEs were typically Gr 1/2, easily manageable and reversible without interruption of dosing. HM61713 showed good safety profile and promising anti-tumor activity in pts with EGFR mutated NSCLC who failed to EGFR-TKIs, especially in patients with T790M mutation. The phase 2 part is ongoing at the dose of 800 mg qd.