Lirafugratinib (Lyrfigtu)

In 116 participants with previously treated, FGFR inhibitor-naive FGFR2 fusion- or rearrangement-positive cholangiocarcinoma, lirafugratinib produced an objective response rate of 46% (95% CI 36 to 55) with a median duration of response of 11.8 months, a median progression-free survival of 11.3 months, and a median overall survival of 22.8 months. The corresponding values reported in the pivotal single-arm trials of pemigatinib and futibatinib were objective response rates of 37.0% and 42% and median progression-free survival of 7.0 and 9.0 months. Hyperphosphatemia occurred in 21% of the 385 participants in the lirafugratinib safety population, and retinal pigment epithelial detachment in 31%.

The evidence has the following limitations. REFOCUS is a single-arm trial with no randomized comparison against chemotherapy or another FGFR inhibitor, and no head-to-head or indirect treatment comparison has been published; the FDA endpoint guidance states that single-arm trials do not adequately characterize time-to-event endpoints. The pivotal results are available as a congress abstract, a sponsor presentation, sponsor announcements, the FDA approval notice, and the prescribing information, and no peer-reviewed full publication of the pivotal cohort was located. Quality of life was a registered secondary endpoint, and the only reported result is the abstract statement that quality of life was maintained. Treatment-related adverse events led to dose reduction in 75.9% of the pivotal cohort, the prescribing information reports dose reduction for an adverse reaction in 81% and dosage interruption in 88%, and the FDA required a randomized postmarketing trial comparing 70 mg once daily with a lower dosage, with trial completion scheduled for November 2031. FGFR2 status in the trial was determined by local testing, and no FDA-authorized companion diagnostic is specified in the labeling; the FDA postmarketing commitment to validate one has a final report due in September 2029. Efficacy was lower in participants previously treated with an FGFR inhibitor (objective response rate 22.6%), who are outside the population in which approval efficacy was established; in an institutional cohort in which the second FGFR inhibitor was lirafugratinib in 12 participants and futibatinib in 10, all 3 partial responses (13.6%) occurred with lirafugratinib.