Abstract P02-02: First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors

作者：Lipika Goyal, Mitesh J. Borad, Vivek Subbiah, Amit Mahipal, Suneel D. Kamath, Kabir Mody, Robin Katie Kelley, Richard D. Kim, Vaibhav Sahai, Anthony B. El-Khoueiry, Efrat Dotan, Oleg Schmidt‐Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh V. Padval, Cori Ann Sherwin, Charles Ferté, Beni B. Wolf, Alison M. Schram · 发表于：Molecular Cancer Therapeutics · 年份：2021 · DOI：10.1158/1535-7163.targ-21-p02-02 · 被引用次数：11 · 研究领域：Fibroblast Growth Factor Research、Cholangiocarcinoma and Gallbladder Cancer Studies、Epigenetics and DNA Methylation

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy >85% across dose levels. The ...