Lirafugratinib NDA Seeks FDA Approval in Cholangiocarcinoma

A new drug application (NDA) has been submitted to the FDA seeking approval of lirafugratinib (RLY-4008), a selective FGFR2 inhibitor, for second-line treatment of patients with cholangiocarcinoma with FGFR2 fusion or rearrangement.¹

The NDA submission is underpinned by positive data from the phase 1/2 ReFocus trial (NCT04526106) presented earlier this month at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. Here, lirafugratinib was reported to have achieved a confirmed objective response rate of 47%.²

The clinical benefit was further evidenced by a median duration of response of 11.8 months, highlighting the durability of the treatment effect in a population that typically faces a poor prognosis. Furthermore, the disease control rate reached 96.5%, suggesting that a vast majority of patients experienced some degree of tumor stabilization or shrinkage. The median progression-free survival was 11.3 months (95% CI, 9.2-14.8), while the median overall survival was 22.8 months (95% CI, 18.1-27.2).

The safety profile observed was reported as consistent with the known class effects of FGFR inhibitors. The most common grade ≥3 treatment-related adverse events included palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). The toxicities were generally manageable with dose modifications or supportive care, and the rate of treatment discontinuation (4.3%) remained within acceptable limits for this patient population.

“This NDA reaffirms [our] mission of bringing life-changing medicines to cancer patients worldwide, including for rare indications and for advanced stages where treatment options are limited,” said Dong-Gun Kim, CEO of Elevar Therapeutics, in a news release.¹ “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.”

About Lirafugratinib

Lirafugratinib is an orally administered, potent, and highly selective small-molecule inhibitor of FGFR2.² In the context of cholangiocarcinoma, the drug specifically targets resistance mutations and aberrant signaling pathways driven by FGFR2 fusions, which is present in a number of intrahepatic cholangiocarcinoma cases.

Unlike multikinase inhibitors, lirafugratinib’s high selectivity for FGFR2 is designed to maximize target engagement while minimizing off-target toxicities. By binding to the ATP binding site of the FGFR protein, the agent inhibits the phosphorylation and subsequent downstream signaling that promotes tumor cell proliferation and survival. This precision-medicine approach allows for the exploitation of the "oncogene addiction" seen in FGFR2-rearranged tumors.

If approved, lirafugratinib would join a growing class of targeted therapies aimed at addressing the significant unmet need in this molecularly defined subset of patients who have progressed on standard platinum-based chemotherapy.

About the ReFocus Trial

The ReFocus trial is a global, open-label, first-in-human study of lirafugratinib in patients with advanced or metastatic cholangiocarcinoma and other solid tumors harboring FGFR2 alterations who had been previously treated with at least 1 systemic therapy.³ The study consisted of 4 parts: dose escalation, dose expansion, extension, and a rollover.

In the study, 116 patients received oral liraguratinib 70 mg once daily until disease progression or unacceptable toxicity.

REFERENCES

1. Elevar Therapeutics submits new drug application to FDA for lirafugratinib as second-line treatment option for cholangiocarcinoma. News release. Elevar Therapeutics. January 29, 2026. Accessed January 30, 2026. https://tinyurl.com/bdfxbx3f

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(2_suppl):476-476. doi:0.1200/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 30, 2026. https://clinicaltrials.gov/study/NCT04526106