A Modified Phase 1 Clinical Trial of Abivertinib (Ac0010), a Third-Generation EGFR Tyrosine Kinase Inhibitor, in Chinese Patients with EGFR-T790M-positive Non-Small Cell Lung Cancer

Abstract

Background: Abivertinib is a novel, third-generation EGFR tyrosine kinase inhibitor. We investigated the safety and efficacy of abivertinib in Chinese patients with EGFR T790Mpositive non-small cell lung cancer (NSCLC) and determined the recommended Phase II dose (RP2D). Methods: This open-label, single-arm, dose-escalation study enrolled patients (18–75 years) with disease progression on prior EGFR TKIs from 8 centers in China. Patients received abivertinib 50–350 mg BID in sequential cohorts using a dose escalation/expansion protocol which determined dose-limiting toxicities (DLTs) in Cycle 1 and evaluated the clinical activity of abivertinib. RP2D (primary endpoint) was based on DLTs along with available safety, efficacy and pharmacokinetic data. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. This study is registered with ClinicalTrials.gov (NCT02330367). Findings: Between January 2015 and March 2018, 140 patients received abivertinib for a median (range) of 21·7 (1·3–148) weeks. Median relative dose intensity was 99%. Maximum tolerated dose was not reached with only 3 DLTs observed across all doses. RP2D was 300 mg BID based on a median (range) PFS of 6·9 (3·0, 9·0) months, ORR of 40% and broadly comparable safety profile to the 50–300 mg BID doses. Grade 3/4 treatment-related adverse events were more frequent with abivertinib 350 mg BID (4/6 patients, 67%) versus 300 mg BID (12/45, 27%) and lower doses. Minimal accumulation of abivertinib was observed at steady state across the studied doses and exposure rose proportionally with increasing dose. Interpretation: Abivertinib 150–300 mg BID represented the efficacious range while 350 mg BID dose had the least favorable safety profile, suggesting 300 mg BID as the RP2D. This novel study design which considered efficacy, pharmacokinetics, and safety beyond Cycle 1 in addition to DLTs may facilitate RP2D determination for drugs with favorable toxicity profiles. Clinical Trial Number: This study is registered with ClinicalTrials.gov (NCT02330367). Funding Statement: This study was funded by ACEA Therapeutics Inc. Declaration of Interests: W-HX is an employee of ACEA Pharmaceutical Research, Hangzhou, China. FL, LX and XX are employees of ACEA Therapeutics Inc. QZ declares speaker fees from AstraZeneca and Roche. LW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. YLW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. X-QL, PH, J-YZ, LZ, T-TA, YC, JJ, Z-HC, and BG declare no competing interests. Ethics Approval Statement: The study was conducted according to the ethical principles established in the Declaration of Helsinki and was consistent with the Chinese Good Clinical Practice Guidelines. The study protocol was approved by the institutional review board or independent ethics committee at each study center.