Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study

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.

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Results were comparable to historical data on bevacizumab monotherapy; indeed, in the combination arm, the 6 month-PFS rate was 26.0% (95% CI, 16.3–41.5) while for pembrolizumab alone it was 6.7% (95% CI, 1.8–25–4); the median OS was 8.8ms in the combination arm (95% CI, 7.7–14.2) and 10.3ms with pembrolizumab alone (95% CI, 8.5–12–5). Moreover, as reported in a recent paper [ 171 ], pembrolizumab showed no benefit in a subgroup of recurrent high-grade gliomas with immunohistochemical loss of mismatch repair protein expression, although most of them reported a high tumor mutational burden. Pembrolizumab was also evaluated as a neoadjuvant treatment: the Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized clinical trial to evaluate the immune response and survival obtained from neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with surgically resectable rGBM [ 116 ].…”

Molecular Profiling of 22 Primary Atypical Meningiomas Shows the Prognostic Significance of 18q Heterozygous Loss and CDKN2A/B Homozygous Deletion on Recurrence-Free Survival

“…The formal proof that the MMR machinery is not functioning is the detection of MSI by molecular assays testing mononucleotide microsatellites; however, immunohistochemistry to detect the loss of MMR proteins is routinely used as a surrogate [ 39 ]. The absence of MSI in the MSH2 mutated meningioma of our series indicates that, in meningiomas, the immunohistochemical loss of MMR proteins is not a good alternative to MSI testing and should not be used to select patients for treatment with immune check-point inhibitors, as already suggested in gliomas [ 40 ]. Of note, MSI was found in only one of 771 progressive meningiomas in a recent study, showing that this is a rare event in these tumors [ 9 ].…”

Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?

“…Individuals with germline mismatch repair (MMR) defects (Lynch Syndrome) are at increased risk of CNS tumors, and these patients also respond to nivolumab (27). On the other hand, several series have shown disappointing results in patients with TMB-H glioblastoma without germline MMR defects (28,29).. In these patients, chemotherapy may increase TMB without promoting a response to PD-1 inhibitors.…”