Abstract
Introduction: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed. Methods: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages. Results: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity. Conclusions: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.
Highlights
IntroductionAnti-programmed death 1 (PD-1) immune checkpoint inhibitors have shown efficacy in patients with several different cancer types
Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin
high-grade gliomas (HGG) were screened by IHC for MMR protein expression
Summary
Anti-programmed death 1 (PD-1) immune checkpoint inhibitors have shown efficacy in patients with several different cancer types These new drugs can overcome T cell inhibition and promote an immune response against the tumor [1]. Nivolumab and Pembrolizumab, two anti PD1 immune checkpoint inhibitors, demonstrated therapeutic efficacy in solid tumors with MMRd [2,9,10,11,12]. Based on these results, the US Food and Drug. In a phase 1b trial (KEYNOTE-028), pembrolizumab showed poor results in patients with recurrent PD-L1 positive glioblastoma [15] In these studies, neither MMR status nor TMB were analyzed. To better clarify the role of MMR status as a potential biomarker of pembrolizumab activity, we performed an observational pilot study, in which pembrolizumab was administered in recurrent HGG patients with loss of expression of MMR proteins, used as a surrogate marker for hypermutation
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.