The Innate Immune Landscape of dMMR/MSI Cancers Predicts the Outcome of Nivolumab Treatment: Results from the Drug Rediscovery Protocol.

Autor:	Zeverijn LJ; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Geurts BS; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Battaglia TW; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands.; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands., van Berge Henegouwen JM; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands., de Wit GF; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Hoes LR; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., van der Wijngaart H; Department of Medical Oncology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands., van der Noort V; Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands., Roepman P; Hartwig Medical Foundation, Amsterdam, the Netherlands., de Leng WWJ; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands., Jansen AML; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands., Chalabi M; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands., van Herpen CML; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Devriese LA; Division Beeld & Oncologie, Department of Medical Oncology, Utrecht University Medical Center, Utrecht, the Netherlands., Erdkamp FLG; Department of Medical Oncology, Zuyderland Hospital, Sittard-Geleen, the Netherlands., Labots M; Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands., de Jonge MJA; Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands., Kerver ED; Department of Medical Oncology, OLVG, Amsterdam, the Netherlands., Bins AD; Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands., Leek LVM; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Notohardjo JCL; Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands., van den Eertwegh AJM; Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands., Wessels LFA; Oncode Institute, Utrecht, the Netherlands.; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands., Verheul HMW; Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands., Gelderblom H; Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands., van de Haar J; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Voest EE; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands.; Center for Personalized Cancer Treatment, Rotterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Oct 01; Vol. 30 (19), pp. 4339-4351.
DOI:	10.1158/1078-0432.CCR-24-0480
Abstrakt:	Purpose: The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. Patients and Methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response or stable disease ≥16 weeks). Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. Results: A total of 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% [95% confidence interval (CI), 53-70], with an objective response in 45% (95% CI, 36-54). After a median follow-up of 14.5 months (95% CI, 13-19), the median progression-free survival was 18 months (95% CI, 9-not reached), and the median overall survival was not reached. Whereas CB was not, or only weakly, associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, in which markers of adaptive immunity dominated the biomarker landscape. Conclusions: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of a good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor type-specific biomarkers for guiding immunotherapy. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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