Lirafugratinib Shows Antitumor Activity, Manageable Safety Profile in Pretreated, FGFR2-Altered Cholangiocarcinoma

The FGFR2 inhibitor lirafugratinib (RLY-4008) demonstrated strong antitumor activity and a manageable, predictable 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, according to data from the phase 1/2 ReFocus trial (NCT04526106), which were presented at the 2026 ASCO Gastrointestinal Cancers Symposium.¹

In an efficacy analysis conducted by an independent review committee (IRC) of the pivotal cohort consisting of those who were fibroblast growth factor receptor inhibitor naive (FN) but chemotherapy pretreated (CP; n = 114), the objective response rate (ORR) was 46.5% (95% CI, 37.1%-56.1%), with 2.6% of patients achieving a complete response (CR), 43.9% achieving a partial response (PR), and 50.0% attaining stable disease (SD) as best response. The disease control rate (DCR) was 96.5% (95% CI, 91.3%-99.0%). Additionally, in this cohort, the median duration of response (DOR) was 11.8 months (95% CI, 7.5-13.0), 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).

In groups 1A (n = 53) and 6 (n = 11), which consisted of patients who were fibroblast growth factor receptor inhibitor pretreated (FP) plus CP and FN plus chemotherapy naive (CN), respectively, the ORR was 22.6% (95% CI, 12.3%-36.2%) and 63.6% (95% CI, 30.8%-89.1%). Additionally, 22.6% vs 54.5% achieved a PR, 54.7% vs 36.4% attained SD, and 9.1% of group 6 achieved a CR; the DCR in the respective cohorts was 77.4% (95% CI, 63.8%-87.7%) and 100% (95% CI, 71.5%-100%). Furthermore, the median DOR was 5.6 months (95% CI, 3.8-not evaluable [NE]) vs 9.2 months (95% CI, 5.6-NE), the median PFS was 5.6 months (95% CI, 3.7-7.4) vs 11.0 months (95% CI, 3.7-NE), and the median OS was 10.9 months (95% CI, 6.6-18.2) vs NE (95% CI, 12.6-NE) in groups 1A and 6, respectively.

Additional efficacy data revealed that among patients treated in the pivotal cohort, group 1A, and group 6, respectively, the median duration of treatment with lirafugratinib was 41 weeks (range, 4-138), 27 weeks (range, 2-96), and 36 weeks (range, 16-55).

“Lirafugratinib at the proposed dose regimen of 70 mg [once daily] demonstrated positive antitumor activity in patients with previously treated, unresectable, locally advanced or metastatic [CCA] harboring FGFR2 fusions or rearrangements,” lead author Antoine Hollebecque, MD, senior medical oncologist at the Gustave Roussy Cancer Institute in Paris, France, stated in the presentation. “The safety profile of lirafugratinib is consistent with FGFR2 inhibition and is predictable and manageable. The most common adverse effects [AEs] were stomatitis and palmar-plantar erythrodysesthesia [PPE]; they were on target and reversible.”

What was the design of ReFocus?

Patients 18 years and older with histologically confirmed unresectable/metastatic CCA per RECIST v1.1 criteria that was refractory or relapsed from standard therapy, or for which no standard therapy exists, were enrolled on the trial. Patients must also have had an ECOG performance status of no more than 1 and documented FGFR2 genomic alterations per local assessment of blood and/or tumor tissue.

In part 1, or the dose-escalation portion, of the study, 58 and 41 patients with solid tumors underwent dosing on continuous and discontinuous dosing schedule, and 17 patients underwent dosing every other day. Then, patients with CCA were treated with continuous daily lirafugratinib at the recommended phase 2 dose of 70 mg. Patients were broken into 4 cohorts based on prior receipt of chemotherapy and FGFR inhibition.

A part 3 extension cohort included 86 patients with FN CP FGFR2-fused or rearranged disease.

The median age of the pivotal cohort was 57 years (range, 29-81), and most patients were female (61.4%) and White (54.4%). A total of 41.2%, 35.1%, and 23.7% were treated in North America, Europe, and the Asia-Pacific region, respectively, and an equal number of patients had an ECOG status of 0 or 1. The median prior lines of systemic therapy was 1 (range, 1-5), with 63.2% of patients treated with 1 line of therapy.

All patients received prior chemotherapy, with the most common regimens including gemcitabine-containing treatment with (33.3%) and without (57.9%) immune checkpoint inhibition, followed by fluoropyrimidine-based regimens (32.5%). A total of 36.8% of patients received prior immune checkpoint inhibition, 3.5% of whom received it without gemcitabine.

The primary end point of the study was confirmed ORR per RECIST v1.1 criteria. The key secondary end points included DOR, DCR, PFS, OS, safety, and quality of life per EORTC QLC-C30.

What were the safety data from the trial?

Any-grade treatment-related AEs (TRAEs) occurred in all patients included in the FN CP pivotal safety population (n = 116) compared with 98.4% of patients with all solid tumors (n = 385). Grade 3 or higher TRAEs occurred in 57.8% vs 43.4% of the respective groups, and no TRAEs led to death. TRAEs leading to dose reduction, dose interruption, and treatment discontinuation occurred in 75.9% vs 55.3%, 82.8% vs 68.1%, and 4.3% vs 2.6% of the respective groups.

The most common any-grade and grade 3 or higher TRAEs in the pivotal safety population included nail toxicities (87.9%, 12.1%), PPE syndrome (81.9%, 32.8%), stomatitis (78.4% vs 12.1%), and retinal pigment epithelial detachment (37.1%, 1.7%). Stomatitis and PPE syndrome led to dose interruption in 21.6% and 54.3% of patients. Three cases of PPE syndrome, and single cases of stomatitis and anaphylactic reaction, led to study discontinuation in this group.

Hollebecque disclosed relationships with the following: Abbvie, Agios, Amgen, Argenx, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca/MedImmune, AVEO, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgen, Chugai Pharma, Clovis Oncology, Daiichi Sankyo, Debiopharm Group, Eisai, Exelixis, Forma Therapeutics, GamaMabs Pharma, Genentech, GlaxoSmithKline, H3 Biomedicine, Incyte, Innate Pharma, Jassen-Cilag, Kyowa Hakko Kirin, Lilly, Loxo, Lytix Biopharma, Menarini, Merck Sharp & Dohme, Merrimack, Merus, Millenium Pharmaceuticals, Nanobiotix, Nektar, Novartis, Octimet, Oncoethix, Onyx, Orion, Oryzon Genomics, Pfizer, Pierre Fabre, QED Therapeutics, Relay Therapeutics, Roche, Sanofi/Aventis, SERVIER, Spectrum Pharmaceuticals, Taiho Pharmaceuticals, Tesaro, and Xencor.

Reference

1. 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