Efficacy of derazantinib (DZB) in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) expressing FGFR2-fusion or FGFR2 mutations/amplifications

Abstract

Background FGFR2 gene aberrations (GA) include fusions and mutations/amplifications, with an estimated prevalence of approximately 15% and 5% in iCCA, respectively. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 mutations and amplifications is less well defined, due to ambiguous available preclinical and clinical data. In a non-comparative Phase 2a study (NCT01752920), the potent pan-FGFR inhibitor DZB was administered to iCCA pts expressing either FGFR2-fusion (N = 29), FGFR2 mutations/amplifications (N = 6) or no FGFR gene aberration (N = 9). Here, we present a post-hoc analysis of outcomes of iCCA pts expressing FGFR mutations/amplifications (N = 6) or no FGFR GA (N = 9) as compared to previously reported data of iCCA pts (N = 29) expressing FGFR2 fusions (Mazzaferro et al. 2018 BJC). Methods Pts received 300 mg DZB QD PO. Eligibility criteria included a locally confirmed (FISH or NGS) testing of FGFR2 GA (fusions vs mutations/amplifications or no aberrations). Objective responses were determined per RECIST 1.1. Disease control rate (DCR) was defined by the summation of CR, PR and SD, and PFS, calculated from treatment initiation until disease progression or death. Results The table shows the efficacy outcomes in the 3 patient groups. Types of drug-related adverse events were similar across groups. No new safety signals were identified.Table: 721P iCCA patient group FGFR2 fusion N = 29 FGFR2 mutation/ amplification N = 6 No FGFR2 genomic aberration N = 9 Objective response rate (RECIST 1.1) 6 (21%) 0 (0%) 0 (0%) DCR (PR or SD) 24 (83%) 4 (67%) 2 (22%) Any target lesion diameter reduction 18 (62%) 4 (67%) 0 (0%) Median (95% CI) Progression free survival (PFS), months 5.7 6.7 1.5 (4.0-9.2) (1.0-14.7) (0.7 – NA) % PFS at 3 months 83% 67% 0% % PFS at 6 months 47% 50% 0% Conclusions Anti-tumor efficacy of DZB as measured by DCR and PFS in iCCA patients harboring an FGFR2 GA seems to be similar for patients with FGFR2 fusions and FGFR2 mutations/amplifications, while patients without any detectable FGFR GA appear to derive no benefit from DZB treatment. While the influence of prognostic variables still has to be confirmed, the anti-tumor efficacy of DZB seen in pts with FGFR2 GA other than fusions warrant further clinical investigation.