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

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Abstract
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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  • Incyte

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