Lirafugratinib sequencing with futibatinib shows feasibility in FGFR2-driven cancers based on early-phase trial data
This Phase I/II clinical trial with preclinical validation assessed the feasibility of treatment sequencing in patients with FGFR2-driven cancers. The study population included 30 patients, of whom 18 (60%) had intrahepatic cholangiocarcinoma and 12 (40%) had other tumor types. Twenty-two patients (73%) were FGFR inhibitor-naïve at enrollment. The setting involved the ReFocus trial (NCT04526106) and UNLOCK program at Gustave Roussy.
The primary outcome focused on identifying resistance mutations to lirafugratinib. Potential resistance mechanisms were identified in 5 of 6 pretreatment samples. Upon progression, FGFR2 mutations in M538 and/or L618 residues emerged in 11 of 16 cases. In contrast, FGFR2 molecular brake (N550) and gatekeeper (V565) mutations were rare compared with futibatinib resistance, though specific rates were not reported.
Regarding treatment response after progression on lirafugratinib, three patients received futibatinib and experienced prolonged disease response. Safety data, including adverse events, serious adverse events, discontinuations, and tolerability, were not reported. The study design relied on preclinical validation based on viability assays and xenografts, including Ba/F3 and patient-derived xenografts models.
Key limitations include the small sample size (n=30) and the reliance on preclinical models for sequencing proposals. The association between resistance mutations and treatment sequencing is proposed based on preclinical and clinical data rather than established causality. Generalizability beyond FGFR2-driven tumors and long-term efficacy beyond the prolonged disease response in 3 patients remain uncertain. Practice relevance supports sequential use of lirafugratinib and futibatinib when precise resistance mutations are detected.
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