Phase III trial of infigratinib versus gemcitabine/cisplatin in adults with advanced cholangiocarcinoma with FGFR2 gene fusion or rearrangement: results and reflections on early termination of PROOF 301.

BACKGROUND

Infigratinib, an oral fibroblast growth factor receptor (FGFR) 1-3 inhibitor, showed clinical activity and manageable adverse events in the P2 CBGJ398X2204 study and was conditionally approved for adults with previously treated, unresectable, or metastatic cholangiocarcinoma (CCA) with FGFR2 fusion or other rearrangement. PROOF 301, reported in this article, is the confirmatory phase III trial of infigratinib versus gemcitabine plus cisplatin as first-line treatment of FGFR2-rearranged CCA.

PATIENTS AND

METHODS

Eligible adult patients were randomly assigned in a 2 : 1 ratio to infigratinib 125 mg on days 1-21 of a 28-day treatment cycle versus gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, investigator-determined PFS, overall response rate (ORR), best overall response, disease control rate, duration of response, and safety.

RESULTS

Over 40 months, 1127 patients were pre-screened at 120 sites, and 48 patients were randomly allocated to the study in a 2 : 1 ratio (29 to infigratinib, 19 to chemotherapy). With a target accrual of ∼300 patients, this study was terminated early due to poor accrual. Median PFS (95% confidence interval) by blinded independent central review (BICR) was 7.4 and 8.0 months with infigratinib and chemotherapy, respectively. The ORRs by BICR were 37.9% with infigratinib and 15.8% with chemotherapy. Grade 3-4 adverse events occurred in 79.3% and 58.8% patients treated with infigratinib and chemotherapy, respectively.

CONCLUSION

Early termination limited the ability to draw definitive conclusions on the efficacy of infigratinib as first-line treatment of FGFR2-rearranged CCA. This study illustrates the challenges of powering confirmatory studies in biomarker-selected subpopulations of rare tumors and highlights the need for regulatory collaboration to develop pragmatic frameworks for assessing novel therapies in ultra-rare malignancies.