RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Oncogenic fibroblast growth factor receptor 2 (FGFR2) activation drives various cancers, presenting a therapeutic target.
• Current pan-FGFR inhibitors (pan-FGFRi) show efficacy but are limited by FGFR1/FGFR4-mediated toxicities and acquired resistance mutations.

Purpose of the Study:

• To evaluate RLY-4008, a novel, highly selective, irreversible FGFR2 inhibitor, designed to overcome limitations of existing therapies.
• To assess RLY-4008's efficacy against primary FGFR2 alterations and resistance mutations in preclinical models and early clinical testing.

Main Methods:

• In vitro assessment of RLY-4008 selectivity against FGFR1 and FGFR4, and its activity against FGFR2 alterations.
• In vivo evaluation of RLY-4008 in xenograft models, including those with resistance mutations.
• Analysis of early clinical data for treatment responses and off-isoform toxicities.

Main Results:

• RLY-4008 demonstrated high selectivity (>250-fold for FGFR1, >5,000-fold for FGFR4) in vitro.
• RLY-4008 induced tumor regression in xenograft models, including those with resistance mutations, while sparing FGFR1 and FGFR4.
• Early clinical trials showed responses without significant off-isoform FGFR toxicities.

Conclusions:

• RLY-4008 is a highly selective FGFR2 inhibitor effective against primary alterations and resistance mutations.
• Selective FGFR2 inhibition with RLY-4008 may overcome limitations of pan-FGFRi, offering a potential new therapeutic strategy.
• RLY-4008 demonstrates broad therapeutic potential for FGFR2-driven cancers with an improved safety profile.