Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy

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.

Authors

Institutions

Publication Details

Journal
Cancer Immunology Research
Published
2024-11-11
DOI
https://doi.org/10.1158/2326-6066.cir-24-0561
Citations
4
Primary Topic
Gastric Cancer Management and Outcomes
Type
article
Field-Weighted Citation Impact
1.68

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy

Sylvie Lorenzen, Eray Goekkurt, Claudia Wickenhauser, Lisa Paschold et al.
4 citations
Cancer Immunology Research
Gastric Cancer Management and Outcomes
1.68
article

Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy

Sylvie Lorenzen, Eray Goekkurt, Claudia Wickenhauser, Lisa Paschold, Stefan Kubicka, Mariana Santos Cruz, Joseph Tintelnot, Anke Reinacher‐Schick, Lutz Jacobasch, Daniel Pink, Urte Matschl, Christoph Schultheiß, Jorge Riera‐Knorrenschild, Marcus Bauer, Thomas J. Ettrich, Salah‐Eddin Al‐Batran, Mascha Binder, Peter Thuss‐Patience, Carsten Bokemeyer, Udo Lindig, Axel Hinke, Alexander Stein, Marianne Sinn, Albrecht Kretzschmar, Susanna Hegewisch-Becker
article en
4 citations

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.

Cancer Immunology ResearchVol. 13(2)
Leibniz Institute of Virology (LIV) (DE), Universität Hamburg (DE), Philipps University of Marburg (DE), Heidelberg University (DE), Universitätsklinikum Gießen und Marburg (DE), Universitätsmedizin Greifswald (DE), Eppendorf (Germany) (DE), University Hospital of Basel (CH), TUM Klinikum (DE), Medizinische Hochschule Hannover (DE), Telstra (Australia) (AU), University Medical Center Hamburg-Eppendorf (DE), Helios Hospital Bad Saarow (DE), SmartPractice (United States) (US), Institute of Clinical Cancer Research (DE), University Cancer Center Hamburg (DE), Kreiskliniken Reutlingen (DE), Department of Biomedicine Basel (CH), Krankenhaus Nordwest (DE), Jena University Hospital (DE), Hamburg Institut (Germany) (DE), St. Josef-Hospital (DE), Bochum University of Applied Sciences (DE), Klinikum im Friedrichshain (DE), University Hospital Ulm (DE), Reutlingen University (DE), Martin Luther University Halle-Wittenberg (DE), Hochschule Düsseldorf University of Applied Sciences (DE), Charité - Universitätsmedizin Berlin (DE), Ruhr University Bochum (DE)
Amgen, Bristol-Myers Squibb, Eli Lilly and Company, AstraZeneca, Sanofi, Les Laboratories Pierre Fabre, BeiGene, Celltrion, Bayer HealthCare, Astellas Pharma, Servier, PharmaMar, Ipsen, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 14%
Gastric Cancer Management and Outcomes
1.68
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.