The FDA has accepted and granted priority review to a new drug application (NDA) seeking the approval of lirafugratinib (RLY-4008) as a second-line treatment option for patients with pretreated cholangiocarcinoma (CCA) harboring FGFR2 fusions or rearrangements.1
The regulatory agency has assigned a Prescription Drug User Fee Act target action date of September 27, 2026.
The NDA submission was supported by findings from the phase 1/2 REFOCUS trial (NCT04526106).1,2 Among evaluable patients in the pivotal cohort, patients with FGFR inhibitor–naive CCA who had previously received chemotherapy (n = 114) achieved an objective response rate (ORR) of 46.5% (95% CI, 37.1%-56.1%) with lirafugratinib per independent review committee (IRC) assessment. Best overall response rates included a complete response rate of 2.6%, a partial response rate of 43.9%, and a stable disease rate of 50.0%.2 Moreover, the disease control rate (DCR) was 96.5% (95% CI, 91.3%-99.0%), with a median duration of response (DOR) of 11.8 months (95% CI, 7.5-13.0). The median progression-free survival (PFS) and overall survival (OS) were 11.3 months (95% CI, 9.2-14.8) and 22.8 months (95% CI, 18.1-27.2), respectively. Of note, these data were shared during the 2026 Gastrointestinal Cancers Symposium.
“Lirafugratinib has established a compelling clinical profile that differentiates it from existing treatment options,” Dong-Gun Kim, chief executive officer of Elevar Therapeutics, stated in a news release.1 “We are very pleased with the FDA’s priority review designation and focused on advancing the review process efficiently to bring this therapy to patients as quickly as possible.”
What Prior Data From ReFocus Supported the NDA?
- Data from an efficacy analysis of the pivotal cohort in ReFocus were shared at the 2026 Gastrointestinal Cancers Symposium; this cohort comprised patients who were FGFR inhibitor–naive but had previously received chemotherapy.
- Lirafugratinib achieved an IRC-assessed ORR of 46.5% (95% CI, 37.1%-56.1%), a DCR of 96.5% (95% CI, 91.3%-99.0%), and a median DOR of 11.8 months (95% CI, 7.5-13.0).
- The safety profile of lirafugratinib was consistent with those commonly associated with on-target FGFR2 inhibition; the most common grade 3 or higher treatment-related AEs were nail toxicities, palmar-plantar erythrodysesthesia, and stomatitis.
What was the design of the ReFocus trial?
The ReFocus study is an open-label, first-in-human trial evaluating the safety and efficacy of lirafugratinib, a potent, selective, oral small molecule inhibitor of FGFR2, in patients with advanced or metastatic solid tumors harboring FGFR2 alterations.3 The trial includes dose-escalation (part 1), dose-expansion (part 2), extension (part 3), and rollover (part 4) components.
Eligible patients across all 4 parts 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 per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1.2,3 Patients were also required to have disease that was refractory to or had not adequately responded to standard therapies, or for which no standard treatment options were available.
In part 1, patients received escalating doses of oral lirafugratinib to establish the recommended phase 2 dose (RP2D). In part 2, patients with CCA were stratified into 4 cohorts based on FGFR alteration type and prior exposure to chemotherapy or FGFR inhibitors and were treated with continuous daily lirafugratinib at the RP2D of 70 mg.
The primary end point for the pivotal cohort was confirmed ORR per RECIST 1.1 criteria by IRC.2 Key secondary end points included DOR, DCR, PFS, OS, safety, and quality of life (QOL) as assessed by the EORTC Core QOL questionnaire.
What should be known about lirafugratinib’s safety profile?
Lirafugratinib demonstrated a predictable and manageable safety profile, with adverse effects (AEs) mitigated through dose modifications.1 The most common any-grade and grade 3 or higher treatment-related AEs (TRAEs) in the ReFocus pivotal safety population (n = 116) 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%).2 TRAEs leading to dose reduction, dose interruption, and treatment discontinuation were reported in 75.9%, 82.8%, and 4.3% of these patients, respectively.
References
- 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 March 30, 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
- 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
- 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 March 30, 2026. https://clinicaltrials.gov/study/NCT04526106
