Abstract 106P
Background
The TOPAZ-1 trial showed improved overall survival (OS) and progression-free survival (PFS) for pts with advanced BTC. However, we still lack predictive biomarkers for immunotherapy benefits and have limited data on the clinical significance of genomic features.
Methods
The study involved pts with unresectable, locally advanced, or metastatic BTC receiving CGD at 39 clinical sites in 11 countries from July 2021 to December 2023. Genomic analyses of primary tumors were conducted locally using various next-generation sequencing assays. Additionally, to test the impact of the prognostic index, outcomes from the CGD cohort were compared to a historical cohort receiving only CG. The data was collected prospectively from 17 centers in Italy between March 2006 and December 2022.
Results
The study comprised 666 pts with advanced BTC treated with CGD. Gene alteration analysis was conducted on tumor tissue samples from 513 pts (77%). In the whole population, multivariate analysis revealed that SMAD4 was positively associated with both PFS and OS (HR 0.49; p=0.018; HR 0.11; p=0.023) while TP53 mutation harmed PFS (HR 1.62; p=0.0047) and TERT mutation negatively affected OS (HR 8.92; p=0.001). In pts with intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), multivariate analysis for PFS indicated a negative prognostic role of TP53 mutation, while for OS this was significant only in pts with iCCA. A prognostic model based on SMAD4 and TERT status, disease stage, and ECOG performance status stratified pts into four risk groups: very low-risk (59 pts), low-risk (154), intermediate-risk (121), and high-risk (8). Significant differences in PFS and OS were found among the groups (p < 0.001), as well as differences in overall response rates (very low-risk 42.9%, low-risk 38.5%, intermediate-risk 30.2%, high-risk 0%) (p < 0.0001).
Conclusions
Our analysis suggests that SMAD4 mutations positively influence PFS and OS, while TP53 mutations negatively affect PFS, and TERT mutations lower OS. Additionally, CGD showed an advantage across all four subclasses of the prognostic index.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
T. Pressiani: Financial Interests, Personal, Invited Speaker: Bayer, Ipsen, AstraZeneca. L. Rimassa: Financial Interests, Personal, Invited Speaker: AbbVie, AstraZeneca, Basilea, Bayer, BMS, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, Iqvia, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier. A. Casadei Gardini: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Eisai; Financial Interests, Personal, Invited Speaker: Bayer, BMS, Incyte, Ipsen, Iqvia, MSD, Roche, Servier. All other authors have declared no conflicts of interest.