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By targeting primary alterations and resistance mutations, the highly selective, irreversible FGFR2 inhibitor RLY4008 shows a broad therapeutic potential in multiple tumors
A new study recently published on Cancer Discovery shows that RLY 4008, a highly selective, irreversible FGFR2 inhibitor, targets FGFR2 primary alterations and resistance mutations inducing regression in multiple xenograft models, thus confirming the broad therapeutic potential of selective FGFR2 targeting.
Oncogenic activation of FGFR2 drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved and patients with FGFR2-driven cancers derive limited benefit from pan-FGFR inhibitors due to multiple FGFR1–4 mediated toxicities and acquired FGFR2 resistance mutations. The new study describes RLY-4008, the first highly selective, irreversible, small-molecule FGFR2 inhibitor specifically designed to overcome the limitations of pan-FGFR inhibitors via targeting of oncogenic FGFR2 alterations and resistance mutations. Preclinical characterization in biochemical assays, cell-based assays and in vivo cancer models validate RLY4008 mechanism of action; moreover, three case studies from the ongoing phase 1/2, first-in-human study of RLY-4008 (ReFocus) shows high response rates with RLY-4008 in patients with FGFR inhibitors-naïve cholangiocarcinoma harboring an FGFR2 fusion or rearrangement as well as responses in patients with other FGFR2-altered tumors and activity against common FGFR2 resistance mutations. The case studies demonstrate that RLY- 4008 induces durable radiographic response in pan-FGFR inhibitors-naive and pre-treated patients without clinically significant off-isoform toxicity. Taken together, these data demonstrate that RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential.