Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol.
Clin Cancer Res
; 30(17): 3735-3746, 2024 Sep 03.
Article
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| MEDLINE
| ID: mdl-38630551
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). PATIENTS ANDMETHODS:
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Biomarcadores de Tumor
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Anticuerpos Monoclonales Humanizados
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Secuenciación Completa del Genoma
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Mutación
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Neoplasias
Límite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Países Bajos