OA02.1. Radiation-Induced Lymphopenia During Neoadjuvant Chemoradiotherapy as Predictive Biomarker for Nivolumab Benefit in Esophageal Cancer

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ID: 325763
2026
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Ranked #153 of 453 articles by views in diseases of the esophagus : official journal of the international society for diseases of the esophagus

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Abstract
Abstract Topic Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies Background Radiation-induced lymphopenia (RIL) is an established prognostic factor associated with poorer pathologic response, disease-free survival (DFS), and overall survival (OS) in locally advanced esophageal cancer patients undergoing concurrent chemoradiotherapy (CRT). In resectable patients, standard treatment can consist of neoadjuvant CRT followed by surgery, with adjuvant nivolumab indicated (since 2022) for incomplete pathologic response. As immunotherapy efficacy relies on lymphocyte function, we hypothesize that RIL may attenuate nivolumab benefit. This study evaluates whether RIL during neoadjuvant CRT predicts nivolumab efficacy in esophageal cancer. Methods In this multicenter retrospective cohort study (2020–2024), patients from six hospitals with esophageal cancer showing incomplete pathologic response after neoadjuvant CRT and esophagectomy and available absolute lymphocyte counts (ALCs) at baseline and during CRT, were analyzed. To avoid immortal time bias, only patients surviving ≥90 days post-surgery were included. Severe RIL was predefined as grade ≥3 lymphopenia (ALC <0.5K/μL) in week 3 of CRT; the threshold best distinguishing survival in the largest series to date. Baseline characteristics were compared between groups with versus without severe RIL, and subsequent survival analyses for patients with nivolumab versus without nivolumab were analyzed within each group. DFS and OS were calculated from esophagectomy using Kaplan-Meier analyses, and compared between nivolumab and no nivolumab using Cox regression analyses. Baseline differences between nivolumab and no nivolumab groups were primarily driven by diagnosis year (i.e. reimbursement), but residual imbalances were adjusted via inverse-probability-of-treatment-weighting (IPTW). Results Among 264 patients, those with severe RIL (n=117 [44%]) had significantly higher cN- and overall clinical stage, and lower baseline ALC. In the 147 patients without severe RIL, significantly better outcomes were observed with nivolumab (n=63; DFS: hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.20-0.90; OS: HR 0.20, 95%CI 0.08-0.53; Figure 1), even after IPTW-adjustment (DFS: HR 0.44, 95%CI 0.19-1.01; OS: HR 0.19, 95%CI 0.07-0.54). In the 117 patients with severe RIL, no significant outcome advantages were observed with nivolumab (n=55; DFS: HR 0.92, 95%CI 0.47-1.82; OS: HR 0.67, 95%CI 0.34-1.32; Figure 2), also not after IPTW-adjustment (DFS: HR 0.64, 95%CI 0.41-1.74; OS: HR 0.56, 95%CI 0.27-1.15). Conclusion Patients with severe RIL during neoadjuvant CRT do not seem to benefit from adjuvant nivolumab for esophageal cancer. The DFS and OS benefit of adjuvant nivolumab appears confined to patients without severe RIL. How this relates to PD-L1-status is under investigation. This hypothesis-generating study indicates RIL might serve as predictive biomarker for nivolumab benefit in esophageal cancer.
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Authors Pim Damen, Gulsah Ozden, Maaike Berbée, Jacco de Haan, Sarah Derks, N Haj Mohammad, Erik Korevaar, Hanneke van Laarhoven, Marlinde de Leede, Radhe Mohan, Bianca Mostert, Stella Mook, Remi Nout, Barbara Stam, Famke Schneiders, Mathijs Tomassen, J. Verhoeff, Rob Verhoeven, Fabienne Warmerdam, Christina Muijs, Steven Lin, Peter van Rossum
Journal diseases of the esophagus : official journal of the international society for diseases of the esophagus
Year 2026
DOI
10.1093/dote/doag077.013
URL
https://doi.org/10.1093/dote/doag077.013
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