Linda Bartalini, Margherita Rimini, Masafumi Ikeda, Oluseyi Abidoye, Jessica Lucchetti, Lorenzo Antonuzzo, Jin Won Kim, Arndt Vogel, Angela Lamarca, Federico Nichetti, Anna Saborowski, Tiziana Pressiani, Caterina Vivaldi, Ilario Giovanni Rapposelli, Jeroen Dekervel, Chiara Braconi, David James Pinato, Emiliano Tamburini, Chiara Carlotta Pircher, Stefano Tamberi, Florian Castet, Monica Verrico, Alessandro Parisi, Nuno Couto, Hong Jae Chon, Andrea Martirena, Matteo Landriscina, Fabian Finkelmeier, Ester Oneda, Antonio Avallone, Emanuela Dell'Aquila, Lukas Perkhofer, Il Hwan Kim, Vincenzo Formica, Cidalia Maria de Sousa Pinto, Ingrid Garajova, Beodeul Kang, Salvatore Corallo, Elisabetta Fenocchio, Giovanni Farinea, Alessandro Pastorino, Anna Diana, Changhoon Yoo, Marta Schirripa, Maria Grazia Rodriquenz, Mario Scartozzi, Lucrezia Zumstein, Michele Ghidini, Gerald W Prager, Giuseppe Aprile, Gian Paolo Spinelli, Yung-Yeh Su, Stephen L Chan, Emily Warmington, Alessia Lancianese, Tomoyuki Satake, Tanios Bekaii-Saab, Daniele Lavacchi, Laura Passeri, Michele Ferrara, Minsu Kang, Alessandra Anna Prete, Silvia Bozzarelli, Mara Persano, Andrea Pretta, Gianluca Masi, Rita Balsano, Monica Niger, Sara Lonardi, Francesca Salani, Silvia Camera, Lorenzo Fornaro, Andrea Casadei-Gardini, Lorenza Rimassa
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.
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.