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FDA approves lirafugratinib for FGFR2-altered cholangiocarcinoma

The oral agent adds a targeted option after chemotherapy for patients whose tumors carry an FGFR2 fusion or rearrangement.

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The FDA on Sept. 23 approved lirafugratinib (Lyrfigtu, Elevar Therapeutics), 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. The approved dose is 70 mg orally once daily, continued until disease progression or unacceptable toxicity.1

The FGFR inhibitors previously approved for this indication are pan-FGFR agents.2 Lirafugratinib, by contrast, is designed to selectively inhibit FGFR2 and to target FGFR2 resistance mutations that can arise with earlier agents.2,3

Efficacy in REFOCUS trial

Approval was based on REFOCUS, a multicenter, open-label, single-arm trial of 116 patients with unresectable or metastatic cholangiocarcinoma who had received chemotherapy or chemoimmunotherapy but no prior FGFR inhibitor. By independent review, the objective response rate was 46% (95% CI, 36%-55%), and median duration of response was 11.8 months (95% CI, 7.5-13.0 months).1

Elevar reported a median progression-free survival of 11.3 months (95% CI, 9.2-14.8 months),2 and median overall survival in the pivotal cohort was 22.8 months.4 REFOCUS had no comparator arm.1

Safety

The prescribing information carries warnings and precautions for ocular toxicity, hyperphosphatemia and soft tissue mineralization, and embryo-fetal toxicity.1 In the trial's pivotal safety population, any-grade hyperphosphatemia occurred in 20.7% of patients and diarrhea in 21.6%. The most common treatment-related adverse events were nail toxicities, palmar-plantar erythrodysesthesia, and stomatitis, and 4.3% of patients stopped treatment because of treatment-related adverse events.4 Andrew Ko, MD, of the University of California San Francisco, discussed the REFOCUS data at the 2026 ASCO Gastrointestinal Cancers Symposium. He said FGFR2 selectivity appeared to translate into lower rates of hyperphosphatemia and diarrhea than those reported with pan-FGFR inhibitors.5

The application received priority review, and lirafugratinib had breakthrough therapy and orphan drug designations.1 Elevar expects the drug to be available in the U.S. by the fourth quarter of 2026.2

Where it fits

FGFR2 fusions or rearrangements occur in up to 14% of intrahepatic cholangiocarcinomas.6 Pemigatinib received accelerated approval in 2020 as the first targeted therapy for previously treated disease with these alterations.7 Futibatinib followed with accelerated approval in September 2022 for intrahepatic cholangiocarcinoma.8

Earlier-line use is also being studied. In the phase 3 FIGHT-302 trial, presented at ASCO 2026, first-line pemigatinib extended median progression-free survival to 8.3 months vs 6.8 months with gemcitabine-cisplatin (HR, 0.58; 95% CI, 0.39-0.87). Overall survival did not improve (24.4 vs 25.0 months).9 First-line pemigatinib has not been approved by the FDA.7

Eligibility for any of these agents depends on detecting the alteration. In the futibatinib registration trial, FGFR2 status was determined by next-generation sequencing (NGS).8 Biliary specimens can make that difficult. Reported sensitivity for detecting malignant strictures is 45% to 56% for ERCP brushings and 48% to 67% for biopsies.10

A prospective study published this year in JHEP Reports enrolled 104 patients with extrahepatic biliary strictures, sampled through ERCP with single-operator cholangioscopy. DNA-based molecular profiling succeeded in 96.1% of patients with malignancy. However, exploratory RNA fusion analysis was noncontributory in 53.6% of samples, and the authors noted that FGFR2 fusions could not be analyzed in their study.10

EUS-guided biopsy offers another route. In a Japanese series of 94 patients with biliary tract cancer, 77.1% of EUS-guided samples were adequate for comprehensive genomic profiling. Adequacy with 22- or 19-gauge fine-needle biopsy was 85.7%, comparable with surgical specimens. The authors favored tissue-based over liquid-based profiling for detecting FGFR2 fusions.11

Full prescribing information will be posted on Drugs@FDA.1

References

  1. US Food and Drug Administration. FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. Published September 23, 2026. Accessed September 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lirafugratinib-previously-treated-unresectable-locally-advanced-or-metastatic

  2. Elevar Therapeutics. Elevar Therapeutics announces FDA approval of Lyrfigtu (lirafugratinib) as second-line cholangiocarcinoma with FGFR2 fusion or other rearrangement treatment option. GlobeNewswire. Published September 23, 2026. Accessed September 24, 2026. https://www.globenewswire.com/news-release/2026/09/23/3367897/0/en/elevar-therapeutics-announces-fda-approval-of-lyrfigtu-lirafugratinib-as-second-line-cholangiocarcinoma-with-fgfr2-fusion-or-other-rearrangement-treatment-option.html

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

  4. European approval is sought for lirafugratinib in FGFR2-altered metastatic cholangiocarcinoma. OncLive. Published September 2026. Accessed September 24, 2026. https://www.onclive.com/view/european-approval-is-sought-for-lirafugratinib-in-fgfr2-altered-metastatic-cholangiocarcinoma

  5. Lirafugratinib produces durable responses in FGFR2 fusion cholangiocarcinoma trial. Oncology News Central. Published January 15, 2026. Accessed September 24, 2026. https://www.oncologynewscentral.com/biliary-tract-cancer/lirafugratinib-produces-durable-responses-in-fgfr2-fusion-cholangiocarcinoma-trial

  6. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med. 2023;388(3):228-239. doi:10.1056/NEJMoa2206834

  7. Cholangiocarcinoma Foundation. Phase 3 FIGHT-302 results presented at ASCO 2026 evaluate pemigatinib as a potential first-line treatment approach for patients with FGFR2 fusion- or rearrangement-positive cholangiocarcinoma. Published June 12, 2026. Accessed September 24, 2026. https://www.cholangiocarcinoma.org/phase-3-fight-302-results-presented-at-asco-2026-evaluate-pemigatinib-as-a-potential-first-line-treatment-approach-for-patients-with-fgfr2-fusion-or-rearrangement-positive-cholangiocarcinoma/

  8. US Food and Drug Administration. FDA grants accelerated approval to futibatinib for cholangiocarcinoma. Published September 30, 2022. Accessed September 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-futibatinib-cholangiocarcinoma

  9. Bekaii-Saab TS, Melisi D, Wilmink JW, et al. Pemigatinib for untreated unresectable/metastatic cholangiocarcinoma (mCCA) with fibroblast growth factor receptor-2 (FGFR2) rearrangement: phase 3 FIGHT-302 results. J Clin Oncol. 2026;44(16 suppl):4017. doi:10.1200/JCO.2026.44.16_suppl.4017

  10. Brunac AC, Culetto A, Reboul H, et al. Molecular endoscopy with next-generation sequencing improves diagnosis of cholangiocarcinoma in patients with extrahepatic biliary strictures. JHEP Rep. 2026;8(5):101788. doi:10.1016/j.jhepr.2026.101788

  11. Yanaidani T, Hara K, Okuno N, et al. Clinical utility of endoscopic ultrasound-guided tissue acquisition for comprehensive genomic profiling of patients with biliary tract cancer, especially with intrahepatic cholangiocarcinoma. Clin Endosc. 2024;57(3):384-392. doi:10.5946/ce.2023.139