Prognostic Impact of Concomitant Genomic Alterations in FGFR2 ‐Positive Cholangiocarcinoma Treated With Pemigatinib

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BACKGROUND & AIMS: Anti-FGFR therapies changed the treatment landscape for patients with previously treated, advanced, or metastatic cholangiocarcinoma (CCA) harbouring FGFR2 fusions/rearrangements. However, primary resistance to FGFR inhibitors remains a key challenge. In the present real-world study, we aimed to evaluate the prognostic impact of concomitant GAs in patients with FGFR2-positive CCA treated with pemigatinib. METHODS: This study included PEMIREAL-PEMIBIL patients treated with pemigatinib in second or later lines. Only patients who underwent extensive DNA- and/or RNA-based next-generation sequencing (NGS) analysis were considered. Primary endpoint was progression-free survival (PFS), with overall response rate, disease control rate and overall survival (OS) as secondary endpoint. OS and PFS were calculated by Kaplan-Meier and log-rank test. Multivariate analysis used cox-regression model. Level of statistical significance p was 0.05. RESULTS: Of 72 patients of PEMIREAL-PEMIBIL, 63 patients had evaluable NGS data, with concomitant GAs identified in 28 patients (44.4%). The most frequently observed concomitant GAs involved BAP1 (7/63, 11.1%), CDKN2A (7/63, 11.1%), TP53 (6/63, 9.5%), CDKN2B (5/63, 7.9%), PTEN (3/63, 4.7%) and IDH1 (1/63, 1.5%). A significantly shorter PFS was observed in patients with CDKN2A mutations compared to CDKN2A wild-type tumours (4.79 vs. 8.66 months, p = 0.0011, HR: 3.48 95% CI: 0.91-13.24), and similarly in patients with BAP1 mutations compared to BAP1 wild-type tumours (5.97 vs. 8.52 months, p = 0.025, HR:2.55 95% CI: 0.72-9.00). No significant differences in OS were observed. CONCLUSIONS: Our results support the negative prognostic role of BAP1 and CDKN2A GAs on PFS in patients with locally advanced or metastatic CCA with FGFR2 gene fusion/rearrangement treated with pemigatinib in a real-world setting.

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