First-line treatment options are limited to gemcitabine/cisplatin (GemCis) for patients with advanced cholangiocarcinoma (CCA). Infigratinib (BGJ398) is a selective, orally bioavailable, ATP-competitive, small-molecule fibroblast growth factor receptor (FGFR)1-3 inhibitor that is approved for use in previously treated patients with unresectable locally advanced/metastatic CCA bearing FGFR2 alterations. The ongoing, randomized, multicenter, open-label, phase 3 PROOF trial (NCT03773302) is evaluating the efficacy and safety of infigratinib versus GemCis as frontline therapy in patients with advanced/metastatic or inoperable CCA harboring FGFR2 gene rearrangements; the study design of the PROOF 301 trial was presented at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer 2022.
The study will enroll patients aged ≥18 years with histologically or cytologically confirmed locally advanced nonresectable or metastatic CCA, documented FGFR2 gene fusions/rearrangements (by central or local laboratory), no prior systemic therapy, and ECOG performance status ≤1. Eligible patients will be randomly assigned 2:1 to receive oral infigratinib 125 mg once daily for the first 21 days of a 28-day treatment cycle or intravenous standard GemCis (1000 mg/m2 + 25 mg/m2, respectively) on days 1 and 8 of a 21-day cycle until disease progression, intolerance, withdrawal of informed consent, or death. Patients will be stratified by unresectable locally advanced versus metastatic disease, geographic region, prior neoadjuvant/adjuvant treatment versus none, and prior treatment with 1 cycle of gemcitabine-based chemotherapy for unresectable locally advanced/metastatic disease prior to randomization versus none. The study design will permit patients on the GemCis arm to cross over to receive infigratinib on disease progression.
The primary end point is progression-free survival (PFS) as determined by blinded independent central review (BICR). Secondary end points include overall survival, PFS (investigator assessed), overall response rate, disease control rate, duration of response (BICR and investigator assessed), and safety. Exploratory end points include quality of life, pharmacokinetics, and correlative genetic alterations/biomarker assessments.
Abou-Alfa and colleagues plan to enroll approximately 300 patients with tumors bearing FGFR2 gene fusions/rearrangements. Assuming a PFS hazard ratio of 0.67 comparing infigratinib with GemCis, the study will provide approximately 80% power to demonstrate that infigratinib improves PFS assessed by BICR compared with treatment with GemCis at a 2-sided significance level of .05. The primary analysis for PFS will be conducted after approximately 228 PFS events have been observed.
Trial enrollment started in December 2019, with an estimated completion date of January 2026. The data monitoring committee last reviewed the trial in December 2021.
Source: Abou-Alfa GK, Borbath I, Goyal L, et al. PROOF 301: a multicenter, open-label, randomized, phase 3 trial of infigratinib vs gemcitabine + cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement. Abstract P-16.
To sign up for our newsletter or print publications, please enter your contact information below.
