Targeting FGFR3 Alterations: The Efficacy of LY3076226 in Tumor Models with Mutations or Fusions

The fibroblast growth factor receptor 3 (FGFR3) is frequently activated in various cancers, including bladder cancer, through mechanisms such as overexpression and genetic alterations. Approximately 48% of bladder cancer cases exhibit FGFR3 mutations like S249 and Y373C or fusions with genes such as TACC3 and BAIAP2L1. LY3076226 is an antibody-drug conjugate (ADC) that targets FGFR3, utilizing a human anti-FGFR3 antibody linked to the cytotoxic agent DM4. This conjugate has shown high affinity binding to FGFR3 and can induce cell cycle arrest and death in tumor cells.

In vivo studies have shown that LY3076226 can effectively halt or reduce tumor growth in bladder cancer cell lines with FGFR3 mutations or fusions after four weekly doses. Over 90 patient-derived xenograft (PDX) models were assessed for FGFR3 mutations and expression, revealing several models with specific mutations. LY3076226 demonstrated significant antitumor activity in these models, including a lung PDX model with an FGFR3-TACC3 fusion and bladder PDX models with various FGFR3 mutations.

The findings suggest that LY3076226 could be a potential therapy for FGFR3-positive patients with FGFR3 mutations or fusions. The study was presented at the American Association for Cancer Research Annual Meeting in 2019.