Lirafugratinib (Lyrfigtu)

Three other FGFR inhibitors have been approved by the FDA for previously treated FGFR2 fusion- or rearrangement-positive cholangiocarcinoma, each under accelerated approval based on response rate and duration of response: pemigatinib (Pemazyre, 2020), infigratinib (Truseltiq, 2021; withdrawn 16 May 2024, with United States distribution discontinued), and futibatinib (Lytgobi, 2022). Their pivotal single-arm trials reported objective response rates of 36% (pemigatinib, N=107), 23% (infigratinib, N=108), and 42% (futibatinib, N=103), with median durations of response of 9.1, 5.0, and 9.7 months; the FIGHT-202 final analysis reported an objective response rate of 37.0% for pemigatinib. In REFOCUS, lirafugratinib produced an objective response rate of 46% (N=116) with a median duration of response of 11.8 months. The labels differ in dosing (lirafugratinib 70 mg and futibatinib 20 mg once daily continuously; pemigatinib 13.5 mg for 14 of 21 days; infigratinib 125 mg for 21 of 28 days on an empty stomach). Hyperphosphatemia was reported in 93%, 82%, and 88% of participants receiving pemigatinib, infigratinib, and futibatinib across clinical trials, with phosphate-lowering therapy or binders in 33%, 83%, and 77%, compared with 21% for lirafugratinib, consistent with its preclinical selectivity over FGFR1. Retinal pigment epithelial detachment was reported in 31% of participants receiving lirafugratinib, with monitoring that included optical coherence tomography, and in 9% to 11% of participants receiving the other agents, whose trials did not routinely include optical coherence tomography; lirafugratinib labeling requires examination every 2 months for 13 months, compared with every 2 months for 6 months for pemigatinib and futibatinib. Pemigatinib and infigratinib were approved with an FDA-approved test, whereas no FDA-authorized test is available for lirafugratinib. Preclinically, lirafugratinib retained potency against the FGFR2 V564F gatekeeper mutation, against which pan-FGFR inhibitors showed a more than 55-fold loss of potency. No head-to-head or indirect treatment comparison of lirafugratinib with another FGFR inhibitor has been published. In an institutional cohort in which the second FGFR inhibitor after progression was lirafugratinib in 12 participants and futibatinib in 10, all 3 partial responses (13.6%) occurred with lirafugratinib, and the authors state that differences in clinical activity across FGFR inhibitors may reflect confounding factors. For the comparators, a matching-adjusted indirect comparison reviewed by NICE gave hazard ratios for futibatinib compared with pemigatinib of 0.95 (95% CI 0.72 to 1.21) for overall survival and 1.07 (95% CI 0.86 to 1.30) for progression-free survival. A reported average monthly United States price of $44,000 for futibatinib was identified, and NICE reports list prices in England of £7,159.04 for a pack of 14 pemigatinib 13.5 mg tablets and £2,386.33 per pack of futibatinib; no lirafugratinib price has been published.