KEYNOTE-158 evaluates the role of pembrolizumab monotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) recurrent gliomas, a rare subgroup with limited treatment options. Recurrent gliomas are associated with poor prognosis, and while immunotherapy has shown success in several malignancies, its benefit in neuro-oncology remains uncertain. Given the high mutational burden of MSI-H/dMMR tumors, pembrolizumab offers a biologically rational approach, and this study explores whether such molecular selection can translate into meaningful clinical outcomes in this difficult-to-treat population.
Tilte: Pembrolizumab monotherapy for microsatellite instability-high or mismatch repair deficient recurrent gliomas: results from the multicohort KEYNOTE-158 study
Authors: Capucine Baldini, Philippe A. Cassier, Jean-Pierre Delord, Matteo Simonelli, Mehdi Touat, Lili Yao, J. Paul Duic, Alexander Gozman, Aurelien Marabelle
Background
Recurrent gliomas represent a clinically challenging disease with limited therapeutic options and poor prognosis. Standard treatments, including surgery, radiotherapy, and chemotherapy, often fail to provide durable disease control, particularly in advanced or recurrent settings. The emergence of immunotherapy, especially immune checkpoint inhibitors targeting the programmed cell death protein-1 (PD-1) pathway, has transformed outcomes in several malignancies. However, gliomas have historically shown limited responsiveness to immunotherapy, likely due to their immunosuppressive tumor microenvironment.
Microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors are characterized by high mutational burden, which may increase neoantigen presentation and sensitivity to immune checkpoint blockade. Pembrolizumab, a monoclonal antibody targeting PD-1, has demonstrated efficacy across multiple MSI-H/dMMR tumor types in a tumor-agnostic manner. The KEYNOTE-158 study aimed to evaluate whether this biological rationale translates into clinical benefit in patients with MSI-H/dMMR recurrent gliomas, a rare but molecularly distinct subgroup.
Methods
KEYNOTE-158 is a multicohort, phase II clinical trial designed to assess the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers. This specific analysis focused on patients with recurrent gliomas harboring MSI-H or dMMR molecular alterations.
Eligible patients were aged 18 years or older, had measurable disease according to RECIST v1.1 criteria, and had previously treated recurrent glioma. All participants received pembrolizumab at a fixed dose of 200 mg administered intravenously every three weeks. Treatment was continued for up to 35 cycles or until disease progression, unacceptable toxicity, or withdrawal of consent.
The primary endpoint was objective response rate (ORR), as determined by independent central radiologic review using RECIST v1.1 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety outcomes.
Study Design
This was a non-randomized, open-label, multicohort phase II study. The glioma cohort included a small subset of patients within a broader basket trial evaluating pembrolizumab across multiple rare tumor types with MSI-H/dMMR status.
A total of 21 patients with recurrent glioma were enrolled in this cohort. The median follow-up duration was 50.0 months, with a range of 15.4 to 65.5 months, allowing for a relatively long-term assessment of clinical outcomes in this population.
Tumor responses were categorized as complete response, partial response, stable disease, or progressive disease based on standardized radiologic criteria. Safety assessments included monitoring of treatment-related adverse events (AEs), graded according to established toxicity criteria.
Results
Among the 21 enrolled patients, clinical responses to pembrolizumab were limited but notable in a subset. The objective response rate was 5% (95% CI: 0.1%–24%), corresponding to one patient achieving a partial response.
Stable disease was observed in 3 patients (14%), while the majority of patients (76%) experienced disease progression as their best overall response. One patient (5%) did not have a post-baseline assessment.
Despite the low response rate, durability of benefit was observed in patients achieving disease control. Among the four patients with stable disease or better, the median duration of response was 27.8 months. The patient with partial response achieved a progression-free survival of 29.2 months and overall survival of 32.7 months.
In the three patients with stable disease, progression-free survival ranged from 3.3 to 23.2 months, and overall survival ranged from 9.1 to 23.2 months, indicating that a subset of patients may derive meaningful long-term benefit.
Regarding safety, treatment-related adverse events were reported in 33% of patients (7 out of 21). Grade 3–4 adverse events occurred in only one patient (5%), suggesting a favorable safety profile consistent with prior pembrolizumab studies.
Key Findings
Pembrolizumab demonstrated limited overall activity in MSI-H/dMMR recurrent gliomas, with an objective response rate of only 5%. However, durable clinical benefit was observed in a small subset of patients, including prolonged progression-free and overall survival exceeding two years in responders.
Stable disease was achieved in 14% of patients, and when combined with the partial response rate, disease control was observed in approximately 19% of the cohort. Importantly, responses and disease stabilization were associated with prolonged durations, highlighting the potential for meaningful clinical benefit despite low response rates.
The safety profile of pembrolizumab remained manageable, with low incidence of severe treatment-related toxicity. Only one patient experienced grade 3–4 adverse events, reinforcing the tolerability of immunotherapy in this population.
These findings suggest that MSI-H/dMMR status may identify a small subgroup of glioma patients who could benefit from immune checkpoint inhibition, although the overall response remains limited.
Conclusion
The KEYNOTE-158 study demonstrates that pembrolizumab monotherapy has limited but clinically meaningful activity in a small subset of patients with MSI-H/dMMR recurrent gliomas. While the objective response rate is low, the durability of responses and favorable safety profile highlight the importance of biomarker-driven treatment strategies.
These findings reinforce the need for further research to better identify predictive biomarkers, optimize patient selection, and explore combination strategies that may enhance immunotherapy efficacy in gliomas.