Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy
Year: 2024
Type: article
Abstract: Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma, but long-term survival remains limited. In this study, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison with a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% confidence interval, 41%-71%) in the Ipi arm and 70% OS (95% confidence interval, 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analyses demonstrated elevated levels of normetanephrine, cortisol, and IL6 in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil to lymphocyte ratio that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low neutrophil to lymphocyte ratio characterized patients benefiting from immunotherapy and targeted therapy without the need for additional chemotherapy. These data suggest that patient selection based on inflammatory stress-driven immune changes could help customize first-line treatment in patients with advanced HER2-positive esophagogastric adenocarcinoma to potentially improve long-term survival.
Source: Cancer Immunology Research
Authors: Joseph Tintelnot, Lisa Paschold, Eray Goekkurt, Christoph Schultheiss, Urte Matschl, Mariana Santos Cruz, Marcus Bauer, Claudia Wickenhauser, Peter Thuss-Patience, Sylvie Lorenzen, Thomas J. Ettrich, Jorge Riera-Knorrenschild, Lutz Jacobasch, Albrecht Kretzschmar, Stefan Kubicka, Salah-Eddin Al-Batran, Anke Reinacher-Schick, Daniel Pink, Carsten Bokemeyer, Marianne Sinn, Udo Lindig, Axel Hinke, Susanna Hegewisch-Becker, Alexander Stein, Mascha Binder
Institutions: University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, University Hospital in Halle, Martin Luther University Halle-Wittenberg, University of Basel, University Hospital of Basel, Leibniz Institute of Virology (LIV), Klinikum im Friedrichshain, Charité - Universitätsmedizin Berlin, Heidelberg University, TUM Klinikum, Technical University of Munich, University Hospital Ulm, Philipps University of Marburg, Universitätsklinikum Gießen und Marburg, Medizinische Hochschule Hannover, Kreiskliniken Reutlingen, Institute of Clinical Cancer Research, Krankenhaus Nordwest, St. Josef-Hospital, Ruhr University Bochum, Universitätsmedizin Greifswald, Universität Greifswald, Helios Hospital Bad Saarow, Jena University Hospital
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404241482