The prognosis for patients with advanced or metastatic cholangiocarcinoma (CCA) remains poor, even with first-line gemcitabine and cisplatin ± anti–programmed death-(ligand) 1 therapy. FGFR2 is a well-established oncogenic driver in many tumor types and occurs as gene fusion or amplification. Pan-FGFR inhibitors are approved for previously treated patients with locally advanced or metastatic CCA harboring FGFR2 fusions; however, their benefit is limited by resistance from polyclonal FGFR2 fusions and by off-isoform toxicity. Lirafugratinib is the first, highly selective, irreversible FGFR2 inhibitor with the potential to target oncogenic FGFR2 driver alterations as well as resistance mutations.
ReFocus (NCT04526106) is a phase 1/2, open-label, multicohort, multicenter study evaluating the efficacy and safety of lirafugratinib in patients with FGFR2-driven unresectable or metastatic CCA or other solid tumors. The trial included a dose-escalation phase (part 1), which identified a recommended phase 2 dose of 70 mg once daily. Part 2 consisted of CCA and non-CCA expansion cohorts, and part 3 consisted of extensions for patients with CCA. The reported data focused on the pivotal cohort, which included patients with FGFR2 fusion/rearrangement–positive, FGFR inhibitor–naïve advanced, or metastatic CCA who had received at least 1 prior systemic therapy. In addition, efficacy results were reported for group 1A, which included patients with FGFR2 fusion/rearrangement–positive CCA who had received prior chemotherapy and FGFR inhibitor treatment, and for group 6, which included patients with FGFR2 fusion/rearrangement–positive CCA who were chemotherapy- and FGFR inhibitor–naïve. Patients received oral lirafugratinib 70 mg daily until disease progression or unacceptable toxicity. The primary endpoint was confirmed objective response rate (ORR), with secondary endpoints including duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life.
As of September 27, 2024, the pivotal cohort and primary analysis included 114 patients, whereas secondary analyses included 116 patients. In the primary analysis, the median age was 57 years and 61.4% of patients were female. All patients had received prior chemotherapy, and 36.8% had been treated with immune checkpoint inhibitors. In the pivotal cohort, the ORR was 46.5% (95% CI, 37.1-56.1), with a DCR of 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). Efficacy analysis in group 6 (FGFR fusion/rearrangement-positive, chemotherapy and FGFR inhibitor-naïve) showed a higher ORR (63.6% vs 22.6%), DCR (100% vs 77.4%), as well as a longer median DOR (9.2 vs 5.6 months) and median PFS (11.0 vs 5.6 months), compared with group 1A (FGFR2 fusion/rearrangement–positive and received prior chemotherapy and an FGFR inhibitor). Among the patients in the pivotal cohort, most showed some tumor shrinkage. The median duration of treatment in the pivotal cohort was 41 weeks.
In the pivotal safety population (n=116), lirafugratinib demonstrated a manageable safety profile. All patients had at least 1 treatment-related adverse event (TRAE), and grade ≥3 TRAEs were observed among 57.8% of patients. Dose reductions and dose interruptions due to TRAEs occurred in 75.9% and 82.8% of the patients, respectively. Treatment discontinuation due to adverse events occurred in 5 patients, and no treatment-related deaths were observed. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were stomatitis (12.1%), palmar–plantar erythrodysesthesia (32.8%), and nail toxicity (12.1%); these TEAEs were on-target and reversible. Off-isoform toxicities in the pivotal cohort included hyperphosphatemia and diarrhea (any grade; 20.7% and 21.6%, respectively). Overall, these results show that lirafugratinib is a potential therapeutic option for patients with FGFR2 fusion/rearrangement CCA who have progressed on standard therapies.
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