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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Prognostic Impact of Concomitant Genomic Alterations in FGFR2-Positive Cholangiocarcinoma Treated With Pemigatinib
Carolina Liguori1, Riccardo Giampieri1, Blandine Delaunay2
1Clinica Oncologica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy.
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.
Insights
Concomitant gene alterations (GAs) like BAP1 and CDKN2A negatively impact progression-free survival (PFS) in cholangiocarcinoma (CCA) patients treated with pemigatinib. This real-world study highlights GAs as key factors influencing treatment outcomes in FGFR2-positive CCA.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Anti-FGFR therapies have transformed cholangiocarcinoma (CCA) treatment for patients with FGFR2 alterations.
- Primary resistance to FGFR inhibitors remains a significant clinical challenge.
- Real-world data is crucial for understanding treatment nuances in advanced CCA.
Purpose of the Study:
- To evaluate the prognostic impact of concomitant gene alterations (GAs) in patients with FGFR2-positive CCA.
- To assess how specific GAs affect progression-free survival (PFS) and overall survival (OS) in patients treated with pemigatinib.
- To provide real-world evidence on resistance mechanisms in CCA.
Main Methods:
- Retrospective analysis of patients from the PEMIREAL-PEMIBIL study treated with pemigatinib.
- Inclusion of patients with evaluable next-generation sequencing (NGS) data.
- Kaplan-Meier and Cox-regression analyses to determine PFS and OS, with statistical significance set at p < 0.05.
Main Results:
- Among 63 patients with NGS data, 28 (44.4%) had concomitant GAs.
- BAP1 and CDKN2A mutations were most frequent (11.1% each).
- Patients with CDKN2A mutations had significantly shorter PFS (4.79 vs. 8.66 months; p=0.0011).
- Patients with BAP1 mutations also showed significantly shorter PFS (5.97 vs. 8.52 months; p=0.025).
Conclusions:
- BAP1 and CDKN2A GAs have a negative prognostic role on PFS in patients with advanced CCA and FGFR2 alterations treated with pemigatinib.
- These findings underscore the importance of comprehensive genomic profiling to predict treatment response.
- Real-world data confirms GAs as critical determinants of pemigatinib efficacy in CCA.