FDA Approves Lirafugratinib for Pretreated, Locally Advanced or Metastatic Cholangiocarcinoma

The FDA has approved lirafugratinib (Lyrfigtu) for the treatment of adult patients with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma (CCA) harboring an FGFR2 gene fusion or other rearrangement.¹

This regulatory decision was backed by data from the phase 1/2 REFOCUS trial, (NCT04526106), in which lirafugratinib elicited an overall response rate (ORR) of 46% (95% CI, 36%, 55%) and a median duration of response (DOR) of 11.8 months (95% CI, 7.5, 13.0).

What was the design of the REFOCUS trial?

This multicenter, open-label, single-arm trial enrolled patients with advanced or metastatic solid tumors harboring FGFR2 alterations across dose-escalation (part 1), dose-expansion (part 2), extension (part 3), and rollover (part 4) parts.^2,3 Patients needed to be at least 18 years of age with histologically confirmed unresectable or metastatic solid tumors that had documented FGFR2 fusions, mutations, or amplifications. Patients also needed to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and disease that was refractory to or had not adequately responded to standard therapies, or for which no standard treatment options were available.

In part 2 of the trial, patients with CCA were treated with lirafugratinib at 70 mg once daily until disease progression or unacceptable toxicity.

The pivotal cohort had a primary end point of confirmed ORR per RECIST 1.1 criteria. Key secondary end points were DOR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life.

What additional efficacy data have been presented from REFOCUS?

Findings from the trial presented at the 2026 Gastrointestinal Cancers Symposium showed that among 114 evaluable patients, the ORR was 46.5% (95% CI, 37.1%-56.1%), including best overall responses of complete response (2.6%), partial response (43.9%), stable disease (50.0%), and progressive disease (2.6%); 1 patient was not evaluable.² The DCR was 96.5% (95% CI, 91.3%-99.0%), the median PFS was 1.3 months (95% CI, 9.2-14.8), and the median OS was 22.8 months (95% CI, 18.1-27.2).

Among chemotherapy-naive patients (n = 53), the ORR was 22.6% (95% CI, 12.3%-36.2%), the DCR was 77.4% (63.8%-87.7%), the median DOR was 5.6 months (3.8-not evaluable [NE]), the median PFS was 5.6 months (95% CI, 3.7-7.4), and the median OS was 10.9 months (95% CI, 6.6-18.2). Among patients naive to FGFR inhibition (n = 11), the ORR was 63.6% (95% CI, 30.8%-89.1%), the DCR was 100% (71.5%-100%), the median DOR was 9.2 months (5.6-NE), the median PFS was 11.0 months (95% CI, 3.7-NE), and the median OS was NE (95% CI, 12.6 months-NE).

What is the safety profile of lirafugratinib?

Among patients in the pivotal safety population, consisting of those with FGFR inhibitor–naive CCA (n = 116), any treatment-related adverse effects (TRAEs) occurred in 100%, and grade 3 or higher TRAEs occurred in 57.8%. The most common any-grade and grade 3 or higher treatment-emergent adverse effects were stomatitis (78.4%; 12.1%), palmar-plantar erythrodysesthesia syndrome (81.9%; 32.8%), nail toxicities (87.9%; 12.1%), and retinal pigment epithelial detachment (37.1%; 1.7%). TRAEs led to study drug dose reduction (75.9%), study drug interruption (82.8%), and study treatment discontinuation (4.3%). The most common TRAEs that led to dose interruption were stomatitis (21.6%) and palmar-plantar erythrodysesthesia syndrome (54.3%). The most common TRAEs that led to study discontinuation were stomatitis (0.9%), anaphylactic reaction (0.9%), and palmar-plantar erythrodysesthesia syndrome (2.6%). No TRAEs led to death.

The prescribing information for lirafugratinib includes warnings and precautions for ocular toxicity, embryo-fetal toxicity, and hyperphosphatemia and soft tissue mineralization.¹

References

1. FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. FDA. September 23, 2026. Accessed September 23, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lirafugratinib-previously-treated-unresectable-locally-advanced-or-metastatic
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://clinicaltrials.gov/study/NCT04526106