Lenvatinib after progression on pemigatinib and futibatinib in FGFR2 fusion-positive biliary tract cancer with an acquired kinase point mutation.

Biliary tract cancers (BTC) represent a heterogeneous group of malignancies with a poor prognosis and rising incidence. Oncogenic FGFR2 fusions are one of several actionable molecular alterations. In this context, selective FGFR tyrosine kinase inhibitors have demonstrated promising and durable response rates and are now approved and included in clinical guidelines. However, secondary kinase mutations frequently arise over time, leading to resistance against these drugs. We present the case of a 41-year-old male patient with metastatic BTC who underwent molecular analysis after disease progression to various established chemotherapy combinations. Testing identified an oncogenic FGFR2 fusion (FGFR2::BICC1). The patient was treated with pemigatinib for 14 months. Upon disease progression, the resistance-associated FGFR2 p. E565A variant was detected in a follow-up biopsy. Treatment was switched to futibatinib, resulting in rapid disease progression. Lacking other therapeutic options, the patient was treated with lenvatinib, supported by previously published data suggesting a potential benefit in similar settings. The treatment was well tolerated, with only a mild increase in transaminases, and the patient remained on treatment with noteworthy effects for 15 months to date. With a growing incidence of BTC and growing use of targeted therapies for FGFR2 alterations, the emergence of secondary resistance-causing point mutations following treatment with approved inhibitors is becoming increasingly challenging. Beyond selective inhibitors, lenvatinib may represent a viable therapeutic option.