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Clinical Trials: Immunotherapy| August 28 2024
Laurien J. Zeverijn
;
Laurien J. Zeverijn #
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
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Birgit S. Geurts
;
Birgit S. Geurts #
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
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Thomas W. Battaglia
;
Thomas W. Battaglia #
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
3
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Jade M. van Berge Henegouwen
;
Jade M. van Berge Henegouwen
4
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
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Gijs F. de Wit
;
Gijs F. de Wit
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
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Louisa R. Hoes
;
Louisa R. Hoes
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
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Hanneke van der Wijngaart
;
Hanneke van der Wijngaart
5
Department of Medical Oncology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
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Vincent van der Noort
;
Vincent van der Noort
6
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Paul Roepman
;
Paul Roepman
7
Hartwig Medical Foundation, Amsterdam, the Netherlands.
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Wendy W.J. de Leng
;
Wendy W.J. de Leng
8
Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
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Anne M.L. Jansen
;
Anne M.L. Jansen
8
Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
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Myriam Chalabi
;
Myriam Chalabi
9
Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Carla M.L. van Herpen
;
Carla M.L. van Herpen
10
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
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Lot A. Devriese
;
Lot A. Devriese
11
Division Beeld & Oncologie, Department of Medical Oncology, Utrecht University Medical Center, Utrecht, the Netherlands.
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Frans L.G. Erdkamp
;
Frans L.G. Erdkamp
12
Department of Medical Oncology, Zuyderland Hospital, Sittard-Geleen, the Netherlands.
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Mariette Labots
;
Mariette Labots
13
Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands.
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Maja J.A. de Jonge
;
Maja J.A. de Jonge
14
Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.
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Emile D. Kerver
;
Emile D. Kerver
15
Department of Medical Oncology, OLVG, Amsterdam, the Netherlands.
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Adriaan D. Bins
;
Adriaan D. Bins
13
Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands.
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Lindsay V.M. Leek
;
Lindsay V.M. Leek
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
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Jessica C.L. Notohardjo
;
Jessica C.L. Notohardjo
13
Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands.
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Alfonsus J.M. van den Eertwegh
;
Alfonsus J.M. van den Eertwegh
13
Department of Medical Oncology, Amsterdam University Medical Center, location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands.
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Lodewyk F.A. Wessels
;
Lodewyk F.A. Wessels
2
Oncode Institute, Utrecht, the Netherlands.
3
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Henk M.W. Verheul
;
Henk M.W. Verheul
14
Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.
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Hans Gelderblom
;
Hans Gelderblom
16
Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
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Joris van de Haar
;
Joris van de Haar
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
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Emile E. Voest
Emile E. Voest *
1
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Oncode Institute, Utrecht, the Netherlands.
17
Center for Personalized Cancer Treatment, Rotterdam, the Netherlands.
*Corresponding Author: Emile E. Voest, Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands. E-mail: e.voest@nki.nl
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Author & Article Information
*Corresponding Author: Emile E. Voest, Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands. E-mail: e.voest@nki.nl
Clin Cancer Res 2024;XX:XX–XX
#
L.J. Zeverijn, B.S. Geurts, and T.W. Battaglia contributed equally to this article.
Received: February 12 2024
Revision Received: April 24 2024
Accepted: July 16 2024
Online ISSN: 1557-3265
Print ISSN: 1078-0432
Funding
Funding Group:
Award Group:
- Funder(s):
Stelvio for Life Foundation
- Principal Award Recipient(s):
E.E.
Voest
- Funder(s):
Award Group:
- Funder(s):
KWF Kankerbestrijding (DCS)
- Award Id(s):
10015
- Principal Award Recipient(s):
E.E.
Voest
- Funder(s):
©2024 American Association for Cancer Research
2024
American Association for Cancer Research
Clin Cancer Res OF1–OF13.
Article history
Received:
February 12 2024
Revision Received:
April 24 2024
Accepted:
July 16 2024
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- Proof August 28 2024
- Accepted Manuscript July 18 2024
Citation
Laurien J. Zeverijn, Birgit S. Geurts, Thomas W. Battaglia, Jade M. van Berge Henegouwen, Gijs F. de Wit, Louisa R. Hoes, Hanneke van der Wijngaart, Vincent van der Noort, Paul Roepman, Wendy W.J. de Leng, Anne M.L. Jansen, Myriam Chalabi, Carla M.L. van Herpen, Lot A. Devriese, Frans L.G. Erdkamp, Mariette Labots, Maja J.A. de Jonge, Emile D. Kerver, Adriaan D. Bins, Lindsay V.M. Leek, Jessica C.L. Notohardjo, Alfonsus J.M. van den Eertwegh, Lodewyk F.A. Wessels, Henk M.W. Verheul, Hans Gelderblom, Joris van de Haar, Emile E. Voest; The Innate Immune Landscape of dMMR/MSI Cancers Predicts the Outcome of Nivolumab Treatment: Results from the Drug Rediscovery Protocol. Clin Cancer Res 2024; https://doi.org/10.1158/1078-0432.CCR-24-0480
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Abstract
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.
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©2024 American Association for Cancer Research
2024
American Association for Cancer Research
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