Exploratory genomic stratification of benefit from first-line immunotherapy-based combination in advanced biliary tract cancer: a biomarker analysis of a randomized phase 2 trial.

Authors

Yatong He, Zeyu Ruan, Xiaoqing Xu, Yue Han, Junrong Yan, Jiaojiao Ni, Qi Xu, Jieer Ying, Shurui Zhou

Published in

Frontiers in immunology. Volume 17. Pages 1878780. Epub Jul 27, 2026.

Abstract

Benefit from first-line immunotherapy-based treatment in advanced biliary tract cancer (BTC) is heterogeneous, and selection biomarkers are lacking. We investigated whether genomic features could stratify benefit from intensified immunotherapy-based treatment versus chemotherapy.
This exploratory biomarker analysis included 58 patients from a randomized phase 2 trial of sintilimab, anlotinib, gemcitabine, and cisplatin (SAGC) versus gemcitabine plus cisplatin (GC) with baseline tumor tissue available for 425-gene targeted next-generation sequencing. Treatment-by-biomarker interactions for progression-free survival (PFS) were evaluated using Cox models. A genomic classifier was developed, and its feature selection robustness and internal stability were assessed by leave-one-out cross-validation (LOOCV) and bootstrap resampling.
Among 58 biomarker-evaluable patients, SAGC improved overall PFS versus GC (median 7.7 vs 6.3 months; HR 0.48, 95% CI 0.27-0.86; P = 0.011), with no overall survival (OS) difference (HR 0.98; P = 0.946). Evaluating these interactions identified DNA damage response (DDR) alteration and high tumor mutation burden (TMB-H) as the most robust predictors. Applied to both endpoints, the classifier stratified patients into SAGC-predominant (SP; either feature, n=40) and GC-predominant (GP; neither feature, n=18) subgroups, revealing diametrically opposed clinical trajectories (interaction P = 0.001 for PFS; P = 0.004 for OS). In SP, SAGC markedly prolonged PFS (10.7 vs 4.5 months; HR 0.26, 95% CI 0.12-0.55; P = 0.0002) and showed a favorable OS trend (16.9 vs 10.3 months; HR 0.55; P = 0.113). Conversely, in GP, SAGC yielded shorter PFS (5.8 vs 8.0 months; HR 2.70; P = 0.078) and significantly shorter OS (8.2 vs 13.9 months; HR 3.73, 95% CI 1.18-11.77; P = 0.017) compared to GC. LOOCV supported the reproducibility of feature prioritization and the internal stability of the final classifier, while bootstrap resampling supported the robustness of subgroup-specific treatment effects.
An exploratory genomic classifier based on DDR alteration and TMB-H may help identify patients with advanced BTC more likely to benefit from the intensified first-line SAGC regimen, pending external validation.

PMID:
42577326
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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