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.

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Journal
Cancers
Published
2026-09-09
DOI
https://doi.org/10.3390/cancers18182921
Primary Topic
Cholangiocarcinoma and Gallbladder Cancer Studies
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article
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article

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

Nuno Couto, Emanuela Dell’Aquila, David James Pinato, Lorenzo Antonuzzo et al.
Cancers
Cholangiocarcinoma and Gallbladder Cancer Studies
article

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

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

Abstract

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.

CancersVol. 18(18)
University of Pisa (IT), Champalimaud Foundation (PT), Goethe University Frankfurt (DE), University of Rome Tor Vergata (IT), Marche Polytechnic University (IT), Hebron University (PS), University of Parma (IT), Humanitas University (IT), Vita-Salute San Raffaele University (IT), National Health Research Institutes (TW), University of Cagliari (IT), Chinese University of Hong Kong (HK), University of Pavia (IT), Cardinal Health (Australia) (AU), Casa Sollievo della Sofferenza (IT), Policlinico Umberto I (IT), Beatson West of Scotland Cancer Centre (GB), Hammersmith Hospital (GB), WinnMed (US), Princess Margaret Cancer Centre (CA), Seoul National University Bundang Hospital (KR), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Medizinische Hochschule Hannover (DE), University of Ulsan (KR), Ospedali Riuniti di Foggia (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Hospital Universitario 12 De Octubre (ES), Urban Big Data Centre (GB), Inje University Haeundae Paik Hospital (KR), Istituto Oncologico Veneto (IT), Administração Regional de Saúde de Lisboa e Vale do Tejo (PT), University Hospitals Parma Medical Center (US), Prince of Wales Hospital (CN), Azienda Ospedaliero-Universitaria Careggi (IT), Algarve Biomedical Center (PT), Ospedale di Belcolle (IT), Hospital Universitario Fundación Jiménez Díaz (ES), University Hospital Frankfurt (DE), CHA University Bundang Medical Center (KR), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Campus Bio Medico University Hospital (IT), National Cancer Center Hospital East (JP), Tumori Foundation (US), Ospedale Policlinico San Martino (IT), Mayo Clinic in Florida (US), Oxford University Hospitals NHS Trust (GB), Fondazione Poliambulanza Istituto Ospedaliero (IT), Candiolo Cancer Institute (IT), Policlinico San Matteo Fondazione (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Ulm (DE), Ospedale San Luigi Gonzaga (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), National Cheng Kung University Hospital (TW), International Renal Research Institute of Vicenza (IT), IRCCS Humanitas Research Hospital (IT), Azienda Ospedaliera Universitaria Pisana (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), University of Florence (IT), University of Turin (IT), Universidad Autónoma de Madrid (ES), University of Algarve (PT), Medical University of Vienna (AT), University of Glasgow (GB), Sapienza University of Rome (IT), University of Bologna (IT), KU Leuven (BE)
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