On September 23, 2026, the U.S. Food and Drug Administration (FDA) approved lirafugratinib (Lyrfigtu, Elevar Therapeutics, Inc.), a kinase inhibitor, for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangement.
Efficacy was evaluated in REFOCUS (NCT04526106), an open-label, multicenter phase 1/2 study of lirafugratinib in patients with advanced or metastatic cholangiocarcinoma and other solid tumors with FGFR2 alterations.
Why FGFR2 Matters in Cholangiocarcinoma
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases involved in signaling pathways that regulate cell growth, proliferation, and survival. FGFR2 is one member of this family. In intrahepatic cholangiocarcinoma, FGFR2 gene fusions or other rearrangements can lead to constitutive FGFR2 activation, driving oncogenic signaling and providing a target for FGFR-directed therapy. Lirafugratinib is a highly selective, irreversible FGFR2 inhibitor designed to target oncogenic FGFR2 driver alterations and resistance mutations.
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REFOCUS Trial
For the FDA efficacy assessment, REFOCUS included a cohort of 116 patients with unresectable or metastatic cholangiocarcinoma who had received prior chemotherapy or chemoimmunotherapy and were naïve to FGFR inhibitor treatment. Patients received lirafugratinib 70 mg orally once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR), assessed by an independent review committee according to RECIST v1.1. The FDA reported an ORR of 46% (95% CI, 36–55) and a median DOR of 11.8 months (95% CI, 7.5–13.0).
REFOCUS at ASCO GI 2026
Earlier this year, during the 2026 ASCO Gastrointestinal Cancers Symposium, Antoine Hollebecque, MD, presented results from the pivotal REFOCUS cohort in patients with advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements who had received at least one prior systemic therapy and were FGFR inhibitor-naïve.
The abstract, “Efficacy and safety of lirafugratinib in FGFRi-naïve cholangiocarcinoma (CCA) patients harboring FGFR2 fusions/rearrangements (FGFR2 f/r),” was authored by Antoine Hollebecque, Mitesh J. Borad, Peter Lu, Xianzhang Meng, Kristin Ryan, Laura Alexander, Jia Liu, Do-Youn Oh, and Richard D. Kim and was published in the Journal of Clinical Oncology as abstract 476.
As of September 27, 2024, the primary IRC-assessed efficacy analysis included 114 patients, while the secondary investigator-assessed analysis included 116 patients; two patients were not available for the primary efficacy analysis.
In the primary efficacy analysis, the confirmed IRC-assessed ORR was 46.5% (95% CI, 37.1–56.1), corresponding to 53 responses, including 3 complete responses and 50 partial responses. The disease control rate was 96.5% (95% CI, 91.3–99.0).
Median DOR was 11.8 months (95% CI, 7.5–13.0), and 76.2% of responses lasted more than 6 months. Median progression-free survival was 11.3 months (95% CI, 9.2–14.8), with a 12-month PFS rate of 49.2%. Median overall survival was 22.8 months (95% CI, 17.3–27.2), with a 12-month OS rate of 74.6%.
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Safety
At ASCO GI 2026, common grade ≥3 on-target, off-tumor treatment-related adverse events included palmar-plantar erythrodysesthesia in 32.8% of patients and stomatitis in 12.1%. Treatment-related adverse events led to dose reductions in 75.9%, dose interruptions in 82.8%, and treatment discontinuation in 4.3% of patients. Quality of life was reported as maintained.
According to the FDA announcement, the prescribing information for lirafugratinib includes warnings and precautions for ocular toxicity, hyperphosphatemia and soft tissue mineralization, and embryo-fetal toxicity.
Recommended Dose
The FDA-recommended dose of lirafugratinib is 70 mg orally once daily until disease progression or unacceptable toxicity.
Regulatory Review
The lirafugratinib application was granted priority review, and the drug received breakthrough therapy and orphan drug designations. The FDA review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, as well as the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
Takeaway
Lirafugratinib is FDA-approved for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement. In the FDA efficacy analysis of REFOCUS, the objective response rate was 46%, and median duration of response was 11.8 months by independent review.
Find full information about approval on official FDA website.
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