FDA Approves Lirafugratinib for FGFR2-Altered Cholangiocarcinoma

The FDA has approved the kinase inhibitor lirafugratinib (Lyrfigtu) for adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma (CCA) harboring an FGFR2 gene fusion or other rearrangement.

The approval was supported by efficacy and safety data from the phase 1/2 REFOCUS trial (NCT04526106).^1,2 In the CCA cohort of the trial, which comprised FGFR inhibitor-naive patients who had previously received chemotherapy (n = 114), lirafugratinib achieved a confirmed objective response rate (ORR) of 46% (95% CI, 36%-55%) per independent review committee (IRC) assessment, a disease control rate of 96.5% (95% CI, 91.3%-99.0%), and a median duration of response of 11.8 months (95% CI, 7.5-13.0). The median progression-free survival was 11.3 months (95% CI, 9.2-14.8) and the median overall survival was 22.8 months (95% CI, 18.1-27.2).²

REFOCUS Trial

Lirafugratinib is a potent, selective, and irreversible small molecule inhibitor of FGFR2 distinguished by its high selectivity relative to other members of the FGFR family. The ongoing open-label, first-in-human, multi-part REFOCUS study is exploring lirafugratinib in patients with advanced or metastatic solid tumors harboring FGFR2 alterations.

Patients in the CCA cohort received a continuous oral dose of 70 mg once daily. Eligibility required histologically or cytologically confirmed locally advanced or metastatic CCA, prior failure or intolerance of standard therapy, and an ECOG performance status of 0 or 1. The primary endpoint was confirmed ORR per RECIST v1.1 criteria; key secondary endpoints included duration of response, disease control rate, progression-free survival, overall survival, safety, and quality of life.³

The primary end point for the CCA cohort was confirmed ORR per RECIST 1.1 criteria by IRC.² Key secondary end points included DOR, DCR, PFS, OS, safety, and quality of life (QOL) as assessed by the EORTC Core QOL questionnaire.

The most common any-grade treatment-related adverse effects in the pivotal cohort included nail toxicities (87.9%), palmar-plantar erythrodysesthesia (81.9%), stomatitis (78.4%), and retinal pigment epithelial detachment (37.1%). Grade 3 or higher events for these toxicities occurred in 12.1%, 32.8%, 12.1%, and 1.7% of patients, respectively. Elevar has characterized this safety profile as predictable and manageable through dose modifications.²

CCA Treatment Paradigm

The current standard first-line treatment for advanced biliary tract cancer, including CCA, is gemcitabine/cisplatin-based chemotherapy combined with an immune checkpoint inhibitor. For patients with CCA harboring an FGFR2 gene fusion or other rearrangement who progress after first-line therapy, 2 FGFR inhibitors—pemigatinib and futibatinib—are FDA-approved in the previously treated setting. Lirafugratinib is now another FDA-approved treatment option for this population. Randomized data directly comparing lirafugratinib with pemigatinib or futibatinib are not available.

REFERENCES

1. FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. Published online and accessed September 23, 2026. https://tinyurl.com/yfnmu6vu

2. Hollebecque A, Borad MJ, Lu P, et al. Efficacy and safety of lirafugratinib in FGFRi-naive cholangiocarcinoma (CCA) patients harboring FGFR2 fusions/rearrangements (FGFR2 f/r). J Clin Oncol. 2026;44(suppl 2):476. doi:10.1200/JCO.2026.44.2_suppl.476

3. REFOCUS: a first-in-human study of highly selective FGFR2 inhibitor, RLY-4008, in patients with ICC and other advanced solid tumors ClinicalTrials.gov. Updated February 27, 2026. Accessed September 23, 2026. https://tinyurl.com/ty6xm7kh