PD-17 Multicentric prospective study assessing clinical benefit of targeted treatment for patients with biliary tract cancers

Biliary Tract Cancers (BTC) patients (pts) have poor prognosis and limited therapeutic options, but there is increasing evidence for biomarker-directed therapy, with several potentially actionable molecular targets and FDA-approved drugs. ESMO and ASCO recommends the use of tumour multigene next generation sequencing (NGS) for BTC. This was a multicentric study assessing real-life clinical actionability of molecular alterations identified with comprehensive NGS for patients (pts) affected by advanced BTCs treated at five Italian referral centers. NGS was performed either via the “Hotspot Cancer Panel, Ion Torrent®”, the “Oncomine Comprehensive Assay Plus” or the FoundationOne®CDx panel; FGFR2 testing was also performed via fluorescence in situ hybridisation and Archer®FusionPlex®Oncology Research Panel. Molecular alterations were correlated with targeted treatments administered and efficacy endpoints. Benefit from targeted treatment was evaluated by means of progression-free survival (PFS) ratio, as defined as the ratio of each patient’s PFS2 (i.e. PFS on molecularly informed therapy) to the PFS1 (PFS on his/her most recent previous treatment), with delta for efficacy equal to 1. Out of 587 pts with adequate tissue for NGS, 397 (68%) were affected by intrahepatic (iCCA), 58 (10%) by perihilar (pCCA) and 63 (11%) by distal (dCCA) cholangiocarcinoma, with 64 (11%) gallbladder and 5 (1%) ampullary cancers. Targeted therapy was actually started for 95 pts (16%), with 15 (16%) pts treated with ivosidenib for IDH1 mutations, 63 (66%) with FGFR2 inhibitors for FGFR2 alterations, 3 (3%) with immune checkpoint inhibitors (ICIs) for MSI-H, 9 (10%) with BRAF+MEK inhibitors for BRAFV600E mutations and 4 (4%) with HER2 inhibitors for HER2 amplification. Overall response rate and disease control rate were 20% and 61%, respectively. Median PFS was 5.5 months (95% CI 4.1-7.3) overall and 3.0 months on ivosidenib, 5.8 months on FGFR2 inhibitors, 9.5 months on ICIs and 7.3 months on BRAF+MEK inhibitors. Median PFSratio was 1.02 (95%CI 0.75-1.34), with benefit rate of 52%. Of note, 34 (36%) of pts received targeted therapy as ≥ III line. Median overall survival from start of targeted therapy was 11.4 (95%CI 9.4-15.2) months. NGS is feasible in daily clinical practice and it should be performed, as recommended, for all pts affected by advanced BTC, since biomarker-directed treatment for BTCs has clinically meaningful benefit in pretreated patients.