Lirafugratinib (Lyrfigtu)

Lirafugratinib is an oral, covalent, FGFR2-selective kinase inhibitor with approximately 250-fold selectivity over FGFR1 and 5,000-fold selectivity over FGFR4 in vitro. The FDA approved it on 23 September 2026, after priority review, at 70 mg once daily for adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement. The product had received orphan drug designation in 2022 and breakthrough therapy designation in 2023.

Approval rests on REFOCUS (NCT04526106), a multicenter, open-label, single-arm phase 1/2 trial, in 116 participants who had received prior chemotherapy or chemoimmunotherapy and no FGFR inhibitor. The FDA reports an objective response rate of 46% (95% CI 36 to 55) and a median duration of response of 11.8 months (95% CI 7.5 to 13.0). In the primary efficacy analysis set of 114 participants, the objective response rate by independent review committee was 46.5% (53 of 114; 95% CI 37.1 to 56.1), with 3 complete responses (2.6%), and the disease control rate was 96.5%. Responses lasted more than 6 months in 76.2% of responders. Median progression-free survival was 11.3 months (95% CI 9.2 to 14.8) with a 12-month rate of 49.2%, and median overall survival was 22.8 months with a 12-month rate of 74.6%; the 95% CI for overall survival is reported as 17.3 to 27.2 months in the congress abstract and 18.1 to 27.2 months in the presentation. Of the 114 participants, 72 (63.2%) had received one prior line of systemic therapy.

In supportive cohorts, the objective response rate was 22.6% (12 of 53) with median progression-free survival of 5.6 months in participants previously treated with an FGFR inhibitor, and 63.6% (7 of 11) in chemotherapy-naive participants. In participants with other FGFR2 fusion- or rearrangement-positive solid tumors (Group 3, 46 participants), the objective response rate was 33.3%.

The safety population comprised 385 participants with advanced solid tumors, including 232 with cholangiocarcinoma. In the 116-participant pivotal cohort, grade 3 or higher treatment-related adverse events occurred in 67 participants (57.8%), and treatment-related adverse events led to dose reduction in 75.9%, dose interruption in 82.8%, and discontinuation in 4.3%; the prescribing information reports dose reduction for an adverse reaction in 81%, dosage interruption in 88%, and permanent discontinuation in 5%. The most frequent adverse reactions in the prescribing information were nail toxicity (89%, grade 3 or 4 in 12%), palmar-plantar erythrodysesthesia syndrome (82%, grade 3 or 4 in 33%), stomatitis (80%, grade 3 or 4 in 12%), and alopecia (66%). Serious adverse reactions occurred in 32%, and a fatal adverse reaction of hemorrhage occurred in one participant. Among the 385 participants, retinal pigment epithelial detachment occurred in 31% (grade 3 in 1.8%) at a median of 57 days and hyperphosphatemia in 21%, which led to dose interruption in one participant (0.3%). The label requires ophthalmological examination including optical coherence tomography before treatment, every 2 months for the first 13 months, and every 4 months thereafter. The FDA required a randomized trial comparing 70 mg once daily with a lower dosage and a drug interaction trial with a sensitive P-gp and BCRP substrate.