T790M mutation mediates resistance to first- and second-generation EGFR-targeting agents, including gefitinib, erlotinib and afatinib. BI1482694 (HM61713) is an oral, third-generation EGFR mutant-specific TKI active against mutant EGFR isoforms, including T790M, while sparing wild-type EGFR. A Phase I/II trial was conducted to evaluate the safety and tolerability of BI1482694 and assess its clinical activity at the recommended Phase II dose (RP2D).
Pts with advanced EGFR mutation-positive NSCLC, previously treated with an EGFR TKI were included. Once-daily doses of 75–1200 mg were explored in the dose escalation part. Following confirmation of the maximum tolerated dose in the expansion cohorts of Phase I, a Phase II part recruited additional pts at the RP2D (800 mg). T790M positivity in the tumor had to be confirmed for all pts treated at the RP2D.
As of 30/06/2015, 203 pts received BI1482694 once-daily, including 76 pts treated at the RP2D of 800 mg. Of these 76 pts, 44 (58%) were female, 61 (80%) had ECOG PS ≤1 and 15 (20%) ECOG PS 2. Pts received between 1 and 9 prior chemotherapy regimens (median 2) and 46 (61%) received an EGFR TKI immediately prior to the study. Treatment duration ranged between 0.3–9.9 months with 38 pts continuing therapy at cut-off. The most common treatment-related AEs included (total/grade ≥3) diarrhea (58%/0), nausea (41%/0), rash (37%/4%), pruritus (36%/1%). Among 70 pts evaluable for response, 54% had partial response (PR) and 94% achieved disease control. PFS data are immature; 43 out of 70 pts (61%) are ongoing without progression, including 28 pts with ongoing PR. Updated PFS, objective response rate and overall survival, as well as subgroup data, will be presented at the meeting.
At the RP2D, BI1482694 showed meaningful clinical activity in EGFR TKI-resistant NSCLC harboring T790M mutations with a favorable safety profile. A broader program of trials evaluating efficacy and safety of this agent in various NSCLC settings has been initiated.
Clinical trial identification
K. Park: employment by Samsung Medical Center, and advisory board participation for Boehringer Ingelheim (uncompensated). J.-Y. Han: advisory board participation for AstraZeneca, Boehringer Ingelheim and Pfizer; corporate-sponsored research for AstraZeneca, Roche and Boehringer Ingelheim; and honoraria from AstraZeneca, Roche and Boehringer Ingelheim. B.-S. Kim: Hanmi advisory board participation. J. Jung: employment by Hanmi Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.