Association of genomic and clinical factors with outcomes with front-line chemoimmunotherapy in patients with advanced biliary tract cancer.

Abstract

4135 Background: Anti-PD1/L1 therapy plus gemcitabine/cisplatin is standard first-line therapy in advanced biliary tract cancer (BTC), yet outcomes remain heterogeneous and prognostic biomarkers are poorly defined. We aimed to identify genomic and clinical factors associated with outcomes in advanced BTC patients (pts) treated with first-line gemcitabine, cisplatin and durvalumab (GCD). Methods: All pts with advanced BTC treated with first-line GCD at Memorial Sloan Kettering who underwent pre-treatment tumor genomic profiling (NCT01775072) were included. The primary objective was to study the association between genomic and clinical features and investigator-assessed progression free survival (PFS); evaluation of overall survival (OS) was a secondary objective. Cox regression analyses evaluated associations with PFS/OS. A multivariable Cox PFS model used variables selected by LASSO-based stability selection and was stratified by tumor subtype. Results: 236 pts were eligible for analysis. Tumor subtypes included intrahepatic cholangiocarcinoma (CCA) (56%), gallbladder cancer (23%), extrahepatic CCA (16%), and BTCs not otherwise specified (5%). Common genomic alterations were TP53 (36%), ARID1A (24%), CDKN2A (23%), KRAS (17%), IDH1 (13%), SMAD4 (12%), MTAP (11%) and ERBB2 (7.6%). With a median follow up of 23 months (mo), median PFS for the cohort was 9.1 mo (95% CI 7.7–11.0). OS at 12 and 24 mo was 68% (95% CI: 62–74) and 45% (95% CI, 38–53), respectively. On univariable analysis, KRAS and FGFR2 alterations were associated with shorter PFS (Table). KRAS alterations were also associated with an increased risk for all-cause mortality on univariable analysis (HR 1.81, 95% CI: 1.17–2.81, p=0.008). Median PFS and OS for the KRAS -altered group were 5.6 (95% CI: 3.6-7.8) and 11 (95% CI: 7.8-42) mo respectively, compared to 11 (95% CI: 8.1-12) and 21 (95% CI: 19-28) mo for KRAS -WT patients. On multivariable analysis, KRAS alterations and liver metastases were independently associated with shorter PFS; higher baseline albumin was protective (Table). Conclusions: Among pts with advanced BTC treated with front-line GCD, KRAS alterations were independently associated with poor PFS. These findings highlight the heterogeneity of benefit from GCD and support development of biomarker-informed strategies to refine patient selection and incorporation of KRAS-targeted strategies to improve outcomes in patients with KRAS -mutant BTCs. Factors associated with PFS with GCD. Analysis (95% CI), p Factor Univariable HR Multivariable HR Alteration KRAS 2.17 (1.48–3.19), <0.001 2.06 (1.36–3.12), <0.001 FGFR2 1.85 (1.02–3.34), 0.042 - Baseline CA19-9 1.14 (1.05–1.23), 0.002 - Metastases Liver 1.78 (1.25–2.54), 0.001 2.06 (1.41–3.01), <0.001 Bone 1.9 (1.05–3.43), 0.034 - Baseline albumin (per 1-unit increase) 0.43 (0.29–0.64), <0.001 0.44 (0.30–0.66), <0.001