Cancer Discovery · 31 authors, 8 centres
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RLY-4008 is a small-molecule FGFR2-selective inhibitor that is >250-fold selective over FGFR1 and >5,000-fold selective over FGFR4, designed to avoid pan-FGFR inhibitor toxicities. In preclinical models, it induces tumor regression in FGFR2-fusion-positive, FGFR2-amplified, and FGFR2-mutant xenografts, retains activity against resistance mutations such as FGFR2 V564F, and early patient case vignettes show clinical responses.
RLY-4008 demonstrates >250-fold selectivity over FGFR1 and >5,000-fold selectivity over FGFR4. In xenograft models bearing FGFR2 fusions, amplifications, or mutations, RLY-4008 induces tumor regression. Notably, RLY-4008 retains potency against FGFR2 resistance mutations that confer resistance to pan-FGFR inhibitors, including FGFR2 N549K and the gatekeeper mutation FGFR2 V564F, on which RLY-4008 is more potent than on wild-type FGFR2. Brief clinical case vignettes from an ongoing phase I/II study showed a near-complete tumor regression in a pan-FGFR inhibitor–naïve intrahepatic cholangiocarcinoma patient and a confirmed partial response with clearance of polyclonal FGFR2 resistance mutations in a pan-FGFR inhibitor–pretreated patient with disease stabilization for greater than 7 months.
