FDA approves Lyrfigtu, next-generation FGFR2-targeted therapy for previously treated cholangiocarcinoma

On September 23, 2026, FDA approved Lyrfigtu (lirafugratinib) for adults with previously treated unresectable, locally advanced, or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangement.

Cholangiocarcinoma is a rare bile duct cancer with limited treatment options once disease progresses after initial therapy. FGFR2 fusions or rearrangements occur in a subset of patients, making molecular testing critical to identify those who may benefit from FGFR inhibitors.

FDA's decision was based on findings from the phase 1/2 REFOCUS trial. Nearly half of treated patients experienced tumor shrinkage, with an objective response rate of 46%. Responses were durable, lasting a median of 11.8 months, suggesting that many patients can achieve prolonged disease control despite progression after prior systemic therapy.

The approval adds a third FGFR-directed treatment option for patients with previously treated cholangiocarcinoma harboring FGFR2 fusions or rearrangements, joining Pemazyre (pemigatinib) and Lytgobi (futibatinib). While all three agents target the same molecular driver, lirafugratinib was developed as a highly selective, irreversible FGFR2 inhibitor intended to minimize off-target FGFR effects. According to Lipika Goyal, MD, lead author of the REFOCUS study and director of gastrointestinal oncology at the Stanford Cancer Center, its "irreversible, covalent-binding mechanism enables potent and sustained inhibition of FGFR2, including many resistance mutations that can emerge with earlier FGFR inhibitors."

The safety profile was generally manageable with monitoring and dose modifications. Key warnings include ocular toxicity, hyperphosphatemia with potential soft tissue mineralization, and embryo-fetal toxicity. Common adverse reactions included nail toxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, alopecia, dry eye, fatigue, dysgeusia, rash, abdominal pain, diarrhea, nausea, decreased appetite, and visual disturbances.

Alison Schram, MD, gynecologic medical oncologist at Memorial Sloan Kettering Cancer Center, said, “These results represent a meaningful step forward for patients with FGFR2-fusion-positive CCA, a disease where treatment options have historically been limited and outcomes poor. Lyrfigtu demonstrated durable responses and a manageable safety profile, providing a much-needed treatment option for patients. The results also reinforce the importance of molecular testing at diagnosis so that patients can be matched to therapies most likely to benefit them.”

Sources: FDA. (2026 Sep 23). FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma; Elevar Therapeutics. (2026 Sep 23). Elevar Therapeutics announces FDA approval of Lyrfigtu (lirafugratinib) as second-line cholangiocarcinoma with FGFR2 fusion or other rearrangement treatment option