European Approval Is Sought for Lirafugratinib in FGFR2-Altered Metastatic Cholangiocarcinoma

A marketing authorization application (MAA) has been submitted to the European Medicines Agency (EMA) seeking the approval of lirafugratinib (RLY-4008), an oral, potent, selective small molecule inhibitor of FGFR2, as a second-line treatment for patients with advanced or metastatic cholangiocarcinoma (CCA) harboring FGFR2 fusions or rearrangements.¹

The MAA submission is based on results from the phase 1/2 ReFocus trial (NCT04526106). Data presented at the 2026 Gastrointestinal Cancers Symposium showed that among evaluable patients with FGFR inhibitor–naive CCA who had previously received chemotherapy (n = 114), lirafugratinib produced an independent review committee (IRC)–assessed overall response rate (ORR) of 46.5% (95% CI, 37.1%-56.1%), consisting of a complete response rate of 2.6% and a partial response rate of 43.9%; an additional 50.0% of patients had stable disease.^1,2 The median progression-free survival (PFS) was 11.3 months (95% CI, 9.2-14.8), and the median overall survival (OS) was 22.8 months (95% CI, 18.1-27.2). The disease control rate (DCR) was 96.5% (95% CI, 91.3%-99.0%), and the median duration of response (DOR) was 11.8 months (95% CI, 7.5-13.0).

“Most of the FGFR inhibitors that are currently approved for CCA, such as pemigatinib [Pemazyre] or futibatinib [Lytgobi], and then erdafitinib [Balversa] for urothelial cancers, target multiple FGFR family members,” Lipika Goyal, MD, said in an exclusive interview with OncLive^®. “However, lirafugratinib was designed to preferentially inhibit FGFR2, which leads to high potency at this receptor and decreases some of the adverse effects [AEs] we see from inhibiting other FGFRs. The second characteristic of lirafugratinib is that it’s an irreversible inhibitor. One of the benefits of that is that it forms a covalent bond with the target kinase. That means that once the drug binds to the receptor, the inhibition persists even after the circulating drug levels decline. That’s different from the reversible inhibitors, such as pemigatinib, that bind and unbind dynamically, [where] the activity is more dependent on maintaining certain drug levels for those drugs to be effective. Irreversible inhibitors are also potentially able to have more durable and sustained inhibition through the receptor, and that can help overcome resistance mutations.”

Goyal is an associate professor of medicine (oncology) at Stanford Medicine and the director of Gastrointestinal Oncology at Stanford Cancer Institute in Palo Alto, California.

How was the ReFocus trial designed?

ReFocus is an open-label study evaluating lirafugratinib in patients with advanced or metastatic solid tumors harboring FGFR2 alterations. Eligible patients were at least 18 years of age with histologically or cytologically confirmed unresectable or metastatic solid tumors with documented FGFR2 fusions, mutations, or amplifications; measurable disease by RECIST 1.1 criteria; and an ECOG performance status of 0 or 1. Patients were also required to have disease that was refractory to or inadequately responsive to standard therapies, or for which no standard options existed.

In the dose-expansion portion, patients with CCA were stratified into cohorts based on FGFR alteration type and prior exposure to chemotherapy or FGFR inhibitors. Confirmed ORR by RECIST 1.1 criteria per IRC served as the primary end point for the pivotal cohort, with key secondary end points including DOR, DCR, PFS, OS, safety, and quality of life.

What is the safety profile of lirafugratinib in FGFR2-altered CCA?

Lirafugratinib selectively targets FGFR2, making it distinct from pan-FGFR inhibitors that also inhibit FGFR1, FGFR3, and/or FGFR4.¹ Consistent with this selectivity, the rates of any-grade hyperphosphatemia and diarrhea (AEs that are associated with nonselective FGFR inhibitors) were 20.7% and 21.6%, respectively.^1,2 In the ReFocus pivotal safety population (n = 116), the most common any-grade treatment-related AEs included nail toxicities (87.9%), palmar-plantar erythrodysesthesia (81.9%), and stomatitis (78.4%).² Additionally, treatment-related AEs led to discontinuation in 4.3% of patients.

What is the regulatory status of lirafugratinib?

Lirafugratinib received orphan drug designation from the FDA in 2022 and FDA breakthrough therapy designation in 2023.¹ A new drug application seeking the approval of second-line lirafugratinib for the treatment of patients with pretreated CCA harboring FGFR2 fusions or rearrangements was granted priority review by the FDA in March 2026.^1,3

“Lirafugratinib is a novel drug candidate that has demonstrated meaningful clinical activity and a differentiated safety profile consistent with its high selectivity for FGFR2 and sustained inhibitory mechanism,” Dong-Gun Kim, chief executive officer of Elevar, stated in a news release.¹

Beyond CCA, lirafugratinib is being evaluated in the global phase 2 ReFocus202 trial in patients with various solid tumors harboring FGFR2 fusions or rearrangements, with enrollment underway at sites in the European Union, United Kingdom, Korea, and the United States.

References

1. Elevar Therapeutics submits marketing authorization application to European Medicines Agency for lirafugratinib as a treatment for patients with advanced/metastatic cholangiocarcinoma (CCA) harboring FGFR2 fusions or rearrangements. News release. Elevar Therapeutics, Inc. September 15, 2026. Accessed September 16, 2026. https://elevartx.com/2026/09/15/elevar-ema-authorization-application-1/
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. Elevar Therapeutics announces FDA acceptance for review of new drug application for lirafugratinib as second-line cholangiocarcinoma treatment. News release. Elevar. March 30, 2026. Accessed September 16, 2026. https://www.globenewswire.com/news-release/2026/03/30/3264531/0/en/Elevar-Therapeutics-Announces-FDA-Acceptance-for-Review-of-New-Drug-Application-for-Lirafugratinib-as-Second-line-Cholangiocarcinoma-Treatment.html