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Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol.
- Source :
-
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. - Publication Year :
- 2024
-
Abstract
- 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).<br />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.<br />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.<br />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.<br /> (©2024 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Female
Humans
Male
Middle Aged
Antineoplastic Agents, Immunological therapeutic use
Treatment Outcome
Antibodies, Monoclonal, Humanized therapeutic use
Antibodies, Monoclonal, Humanized administration & dosage
Biomarkers, Tumor genetics
Mutation
Neoplasms drug therapy
Neoplasms genetics
Neoplasms pathology
Neoplasms immunology
Whole Genome Sequencing
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 30
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 38630551
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-24-0011