FDA Approval Sought for Lirafugratinib in Second-Line, FGFR2-Altered Cholangiocarcinoma

A new drug application (NDA) seeking the approval of lirafugratinib (RLY-4008) as a second-line treatment option for patients with cholangiocarcinoma (CCA) harboring FGFR2 fusions or rearrangements has been submitted to the FDA.¹

The NDA is supported by data from the phase 1/2 ReFocus trial (NCT04526106), in which lirafugratinib demonstrated clinically meaningful antitumor activity and a manageable safety profile in patients with unresectable, locally advanced or metastatic cholangiocarcinoma (CCA) harboring FGFR2 fusions or rearrangements who progressed on standard therapies but were not previously exposed to FGFR inhibitors.^1,2

Following a meeting with Relay Therapeutics in early 2024, the FDA recommended that the company file an NDA for FGFR2-altered CCA, followed by a supplemental NDA for other FGFR2-altered solid tumors.¹

“This NDA reaffirms Elevar’s mission of bringing life-changing medicines to cancer patients worldwide, including for rare indications and for advanced stages where treatment options are limited,” Dong-Gun Kim, chief executive officer of Elevar Therapeutics, stated in a news release. “We are excited to work with the FDA as it reviews the submission while simultaneously preparing for a potential commercial launch. We could not be more appreciative of the patients who participated in lirafugratinib-focused clinical trials and everyone who brought us to this crucial point in its development.”

What Is Unique About Lirafugratinib?

Lirafugratinib is a highly selective, oral small molecule inhibitor of FGFR2 designed to have minimal off-target activity against other FGFR family receptors, thereby potentially reducing class-specific toxicities such as hyperphosphatemia and retinopathy that have been observed with less selective inhibitors.² Preclinical data suggest the agent also retains activity against known on-target resistance mutations, which may influence durability of response relative to first-generation FGFR inhibitors.

What Was the Design of the ReFocus Trial?

ReFocu is an open-label, first-in-human, phase 1/2 study evaluating the safety and efficacy of lirafugratinib in advanced or metastatic solid tumors with FGFR2 alterations.³ The study comprised 4 parts: a dose-escalation phase (Part 1), a dose-expansion phase (Part 2), an extension phase (Part 3) and a rollover portion (Part 4).

Across all parts, patients were required to be at least 18 years of age and have histologically or cytologically confirmed unresectable or metastatic solid tumors with documented FGFR2 gene fusions, mutations, or amplifications; measurable disease per RECIST 1.1 criteria; and an ECOG performance status of 0 or 1.² Patients were also required to have disease that was either refractory or had not adequately responded to standard therapy, or for which no standard therapy exists.

In part 1, patients with solid tumors received multiple ascending doses of oral lirafugratinib to determine the recommended phase 2 dose (RP2D).^2,3 In part 2, patients with CCA were divided into 4 groups according to FGFR alteration type and prior exposure to chemotherapy or FGFR inhibitors. Patients were then treated with a continuous, daily dose of lirafugratinib at the RP2D of 70 mg.

The primary end point in the pivotal cohort was confirmed overall response rate (ORR) per RECIST 1.1 criteria by independent review committee (IRC).² Key secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life per the EORTC QLQ-C30 questionnaire.

What Prior Data from ReFocus Supported This NDA?

Data from an efficacy analysis of the pivotal cohort (n = 116) in ReFocus, as conducted by an IRC, were presented at the 2026 ASCO Gastrointestinal Cancers Symposium.²This cohort comprised patients who were FGFR inhibitor–naive but had previously received chemotherapy (n = 114). In this cohort, the objective response rate (ORR) was 46.5% (95% CI, 37.1%-56.1%). Best overall responses included a complete response (CR) rate of 2.6%, partial response (PR) rate of 43.9%, and stable disease (SD) rate of 50.0%. Moreover, the DCR was 96.5% (95% CI, 91.3%-99.0%), the median DOR was 11.8 months (95% CI, 7.5-13.0), the median PFS was 11.3 months (95% CI, 9.2-14.8), and the median OS was 22.8 months (95% CI, 18.1-27.2).

Regarding safety, the most common any-grade and grade 3 or higher treatment-related adverse effects (TRAEs) were nail toxicities (87.9%, 12.1%), Palmar-plantar erythrodysesthesia (81.9%; 32.8%), stomatitis (78.4%; 12.1%), and retinal pigment epithelial detachment (37.1%, 1.7%). TRAEs led to dose reduction, dose interruption, and treatment discontinuation in 75.9%, 82.8%, and 4.3% of patients, respectively.

References

1. Elevar Therapeutics submits new drug application to FDA for lirafugratinib as second-line treatment option for cholangiocarcinoma. Elevar. January 29, 2026. Accessed January 29, 2026. https://elevartx.com/2026/01/28/elevar-therapeutics-new-drug-application-lirafugratinib/
2. Hollebecque A, Borad MJ, Lu P, 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(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 May 7, 2025. Accessed January 29, 2026.https://clinicaltrials.gov/study/NCT04526106