학술논문
Efficacy of pembrolizumab and biomarker analysis in patients with WGS-based intermediate to high tumor mutational load: results from the Drug Rediscovery Protocol.
Document Type
Academic Journal
Author
Geurts BS; Netherlands Cancer Institute, Netherlands.; Zeverijn LJ; Netherlands Cancer Institute, Amsterdam, Netherlands.; Leek LVM; Netherlands Cancer Institute, Amsterdam, Netherlands.; van Berge Henegouwen JM; Erasmus MC, Rotterdam, Netherlands.; Hoes LR; Netherlands Cancer Institute, Amsterdam, Netherlands.; van der Wijngaart H; Maastricht University Medical Centre, Netherlands.; van der Noort V; Netherlands Cancer Institute, Amsterdam, Netherlands.; van de Haar J; The Netherlands Cancer Institute, Amsterdam, Noord-Holland, Netherlands.; van Ommen-Nijhof A; The Netherlands Cancer Institute, Netherlands.; Kok M; Netherlands Cancer Institute, Amsterdam, Netherlands.; Roepman P; Hartwig Medical Foundation, Amsterdam, Netherlands.; Jansen AML; University Medical Center Utrecht, Utrecht, Utrecht, Netherlands.; de Leng WWJ; University Medical Center Utrecht, Utrecht, Utrecht, Netherlands.; de Jonge MJA; Erasmus MC Cancer Institute, Rotterdam, Netherlands.; Hoeben A; Maastricht University Medical Centre, Maastricht, Netherlands.; van Herpen CML; Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.; Westgeest HM; Amphia Ziekenhuis, Breda, Netherlands.; Wessels LFA; The Netherlands Cancer Institute, Amsterdam, NH, Netherlands.; Verheul HMW; Erasmus MC, Rotterdam, Netherlands.; Gelderblom H; Leiden University Medical Center, Leiden, Netherlands.; Voest EE; Netherlands Cancer Institute, Amsterdam, Netherlands.
Source
Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: To evaluate efficacy of pembrolizumab across multiple cancer types harboring different levels of Whole-Genome Sequencing (WGS)-based tumor mutational load (TML; total of non-synonymous 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 TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing.
Results: Seventy-two evaluable patients with 26 different histotypes were enrolled. 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 cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated.
Conclusion: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study's primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.
Patients and Methods: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing.
Results: Seventy-two evaluable patients with 26 different histotypes were enrolled. 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 cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated.
Conclusion: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study's primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.