Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol.

Autor:	Geurts BS; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Zeverijn LJ; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Leek LVM; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., van Berge Henegouwen JM; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands., Hoes LR; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., van der Wijngaart H; Department of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.; 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., van de Haar J; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., van Ommen-Nijhof A; Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands., Kok M; Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands., Roepman P; Hartwig Medical Foundation, Amsterdam, the Netherlands., Jansen AML; Department of Pathology, University Medical Cancer Center Utrecht, Utrecht, the Netherlands., de Leng WWJ; Department of Pathology, University Medical Cancer Center Utrecht, Utrecht, the Netherlands., de Jonge MJA; Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands., Hoeben A; Department of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.; Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands., van Herpen CML; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Westgeest HM; Department of Internal Medicine, Amphia Hospital, Breda, 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., Voest EE; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Oncode Institute, Utrecht, the Netherlands.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Sep 03; Vol. 30 (17), pp. 3735-3746.
DOI:	10.1158/1078-0432.CCR-24-0011
Abstrakt:	Purpose: To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing-based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234). Patients and Methods: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint was clinical benefit [CB; objective response or stable disease (SD) ≥16 weeks]. Pretreatment tumor biopsies were obtained for whole-genome sequencing and RNA sequencing. Results: Seventy-two evaluable patients with 26 different histotypes were enrolled. The CB rate was 13% in cohort A [3/24 with partial response (PR)], 21% in cohort B (3/24 with SD; 2/24 with PR), and 42% in cohort C (4/24 with SD; 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohorts A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, whereas in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated. Conclusions: Although pembrolizumab lacked activity in cohort A, cohorts B and C met the study's primary endpoint. Further research is warranted to refine the selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity. See related commentary by Hsu and Yen, p. 3652. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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