Prognostic Role of Adverse Events in a Worldwide Population of Patients with Biliary Tract Cancer Treated with Chemo-Immunotherapy.

BACKGROUND

Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment options. The addition of durvalumab or pembrolizumab to cisplatin-gemcitabine improves overall survival (OS), but validated biomarkers of benefit remain limited. Immune-mediated adverse events (imAEs) have been proposed as treatment-emergent clinical correlates of immune activation.

METHODS

We retrospectively analyzed an international cohort of patients with locally advanced or metastatic BTC treated with first-line cisplatin-gemcitabine plus durvalumab. Primary endpoints were OS and progression-free survival (PFS). The principal exposure was the occurrence of any imAE. A post hoc complete-case Cox model was adjusted for age, sex, primary tumor site, prior surgery, ECOG performance status, disease stage, albumin, bilirubin, and neutrophil-to-lymphocyte ratio (NLR); analyses of individual AEs were exploratory. Exact AE onset dates were not consistently available, precluding a reliable formal time-dependent exposure analysis.

RESULTS

A total of 1358 patients were included; all received durvalumab, and 276 (20.3%) developed at least one imAE. In the fully baseline-adjusted model, any imAE remained associated with a lower risk of death (adjusted HR 0.72, 95% CI 0.57-0.92; p = 0.008) and progression or death (adjusted HR 0.63, 95% CI 0.52-0.77; p < 0.001). In exploratory baseline-adjusted analyses of individual imAEs, other imAEs remained associated with OS (HR 0.39, 95% CI 0.24-0.62; p < 0.001) and PFS (HR 0.56, 95% CI 0.40-0.77; p < 0.001), while hypothyroidism remained associated with PFS only (HR 0.65, 95% CI 0.43-0.97; p = 0.034); rash and hyperthyroidism were not independently associated after full baseline adjustment. In AE-focused exploratory models, decreased appetite and hyponatremia were associated with worse outcomes, neutropenia with better outcomes, and ALT elevation with worse PFS. Baseline corticosteroid use was uncommon (n = 21), and all steroid analyses are vulnerable to confounding by indication and exposure-timing bias.

CONCLUSIONS

Treatment-emergent imAEs may represent potential prognostic markers or clinical correlates of benefit, but they are not validated surrogate endpoints. Prospective studies with precise AE-onset capture are required.