Lirafugratinib

Cholangiocarcinoma is a malignancy of the biliary epithelium classified by anatomic site as intrahepatic, perihilar, or distal, and biliary tract cancer accounts for less than 1% of all cancers worldwide. The American Cancer Society estimates that about 8,000 people in the United States are diagnosed with bile duct cancer each year. In the Surveillance, Epidemiology, and End Results program, the incidence of intrahepatic cholangiocarcinoma increased 148.8% from 2001 to 2017, from 0.80 to 1.99 per 100 000 person-years. FGFR2 fusions or rearrangements are reported in 10% to 16% of intrahepatic cholangiocarcinomas; central prescreening for FIGHT-202 identified them in 107 of 1,206 participants (9%), and a genomic profiling dataset identified FGFR2 rearrangements in 9.2% of 6,802 cholangiocarcinoma samples. Only part of the incident population reaches later-line therapy: 46% of 413 participants in a United States commercial-claims cohort with advanced biliary tract cancer received second-line treatment.

Five-year relative survival for liver and intrahepatic bile duct cancer is 37.4% for localized, 13.4% for regional, and 3.6% for distant disease. In first-line advanced disease, median overall survival was 12.9 months with durvalumab plus gemcitabine and cisplatin in the TOPAZ-1 three-year update and 12.7 months with pembrolizumab plus gemcitabine and cisplatin in KEYNOTE-966. After first-line progression, ABC-06 reported median overall survival of 6.2 months with FOLFOX plus active symptom control and 5.3 months with active symptom control alone, with an objective response in four of 81 participants (5%) receiving FOLFOX. FGFR genetic aberrations were associated with longer overall survival in an institutional series (37 versus 20 months).

The approved FGFR inhibitors pemigatinib and futibatinib produced objective response rates of 37.0% and 42% in their pivotal single-arm trials, with median progression-free survival of 7.0 and 9.0 months. Their labels report hyperphosphatemia from laboratory values in 93% and 88% of participants, and 49 of 82 participants (60%) had one or more secondary FGFR2 kinase domain mutations at acquired resistance to an FGFR inhibitor. The United States approval of infigratinib was withdrawn in 2024.

In the ABC-06 quality-of-life analysis, the EQ-5D utility value in the active symptom control arm fell from 0.75 at baseline to 0.62 at month 4. In a United States commercially insured cohort with advanced biliary tract cancer, mean all-cause costs were $18,274 per patient per month overall and $22,617 per patient per month during second-line therapy. The Canadian drug agency estimated that testing costs $38,000 to identify a single patient eligible for pemigatinib.

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.

No wholesale acquisition cost or average sales price for lirafugratinib had been published as of September 2026, and no budget impact model, cost-effectiveness analysis, or health technology assessment of lirafugratinib was identified. Elevar Therapeutics expects the product to be available in the United States by the fourth quarter of 2026.

Comparator prices are partly public. An average monthly United States price of $44,000 has been reported for futibatinib. Canada's Drug Agency estimated that pemigatinib costs $15,499 per 28 days, projected a 3-year budget impact of $63,606,331, and estimated incremental cost-effectiveness ratios of $252,718 and $261,226 per quality-adjusted life-year relative to active symptom control alone and mFOLFOX plus active symptom control. In England, NICE reports list prices of £7,159.04 for a pack of 14 pemigatinib 13.5 mg tablets (an annual cost of £124,430) and £2,386.33 per pack of futibatinib, each supplied to the NHS at a confidential discount. NICE recommended pemigatinib as a life-extending treatment at the end of life, with committee-preferred incremental cost-effectiveness ratios between £45,051 and £45,808 per quality-adjusted life-year compared with mFOLFOX plus active symptom control, and recommended futibatinib as an alternative to pemigatinib after a cost comparison found similar costs.

The inputs a payer model would use are available in part: about 8,000 people in the United States are diagnosed with bile duct cancer each year, FGFR2 fusions or rearrangements occur in 10% to 16% of intrahepatic cholangiocarcinomas, and 46% of 413 participants with advanced biliary tract cancer in one United States claims cohort received second-line treatment. Relay Therapeutics estimated that FGFR2-mediated cancers of all tumor types affect approximately 11,000 late-line patients annually in the United States. Mean all-cause health care costs during second-line therapy for advanced biliary tract cancer were $22,617 per patient per month.

Three features of lirafugratinib bear on its budget effect. Treatment continues until disease progression or unacceptable toxicity, and median progression-free survival in the pivotal cohort was 11.3 months. Ophthalmological examination with optical coherence tomography is required every 2 months for the first 13 months and every 4 months thereafter. Eligibility depends on FGFR2 testing, for which the Canadian agency estimated a cost of $38,000 to identify a single patient eligible for pemigatinib; NICE estimated that adding FGFR2 as a target to the NHS panel test would cost an additional £34, or £340 for each additional person identified who is FGFR2-positive.

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.