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
{"title":"炎症压力决定了接受靶向和免疫疗法的 HER2 阳性食管胃腺癌患者是否需要化疗。","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","doi":"10.1158/2326-6066.CIR-24-0561","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"200-209"},"PeriodicalIF":8.1000,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy.\",\"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\",\"doi\":\"10.1158/2326-6066.CIR-24-0561\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":9474,\"journal\":{\"name\":\"Cancer immunology research\",\"volume\":\" \",\"pages\":\"200-209\"},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2025-02-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer immunology research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/2326-6066.CIR-24-0561\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer immunology research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2326-6066.CIR-24-0561","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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.
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.