Abstract
Radiation therapy may enhance anti-tumor immune responses by several mechanisms including induction of immunogenic cell death. We performed a phase 2 study of pembrolizumab with re-irradiation in patients with recurrent glioblastoma. Sixty recurrent glioblastoma patients received pembrolizumab with re-irradiation alone (cohort A, bevacizumab-naïve; n=30) or with bevacizumab continuation (cohort B, n=30). Dual primary endpoints including overall response rate (ORR) and overall survival at either 12 (OS-12; cohort A) or six months (OS-6; cohort B) were assessed per cohort relative to historical benchmarks. Paired paraffin-embedded formalin-fixed tumor samples were assessed for immunologic biomarkers by immunohistochemistry using digital quantification and Co-Detection-by-InDEXing (CODEX). Study therapy was well tolerated with most toxicities being grade ≤ 3. For cohort B, the primary endpoint of OS-6 was achieved (57%), however survival was not improved for cohort A patients. The ORR was 3.3% and 6.7% for cohorts A and B, respectively. CODEX analysis of paired tumor samples from 5 patients revealed an increase of activated T cells in the tumor microenvironment after study therapy. Compared to historical controls, re-irradiation plus pembrolizumab appeared to improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. CODEX revealed evidence of intratumoral infiltration of activated immune effector cells. A randomized, properly controlled trial of PD-1 blockade plus re-irradiation is warranted to further evaluate this regimen for bevacizumab refractory patients, but alternative approaches are needed for bevacizumab-naïve patients.
Overview
- The study aims to investigate the efficacy of pembrolizumab with re-irradiation in patients with recurrent glioblastoma. The hypothesis being tested is that the combination of pembrolizumab with re-irradiation will enhance anti-tumor immune responses and improve survival in patients with recurrent glioblastoma. The study used a phase 2 design with 60 patients receiving pembrolizumab with re-irradiation alone (cohort A) or with bevacizumab continuation (cohort B). The primary objective of the study was to assess the overall response rate (ORR) and overall survival at either 12 months (OS-12; cohort A) or six months (OS-6; cohort B) relative to historical benchmarks. The study also assessed immunologic biomarkers by immunohistochemistry using digital quantification and Co-Detection-by-InDEXing (CODEX) in paired paraffin-embedded formalin-fixed tumor samples from 5 patients. The study was well tolerated with most toxicities being grade ≤ 3. The study found that the primary endpoint of OS-6 was achieved in cohort B, but survival was not improved for cohort A patients. The ORR was 3.3% and 6.7% for cohorts A and B, respectively. CODEX analysis of paired tumor samples from 5 patients revealed an increase of activated T cells in the tumor microenvironment after study therapy. The study suggests that re-irradiation plus pembrolizumab may improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. The study also provides evidence of intratumoral infiltration of activated immune effector cells. The study highlights the potential of combining radiation therapy with immunotherapy to enhance anti-tumor immune responses and improve survival in patients with recurrent glioblastoma.
Comparative Analysis & Findings
- The study compared the outcomes observed under two experimental conditions: pembrolizumab with re-irradiation alone (cohort A) and with bevacizumab continuation (cohort B). The study found that the primary endpoint of OS-6 was achieved in cohort B, but survival was not improved for cohort A patients. The ORR was 3.3% and 6.7% for cohorts A and B, respectively. CODEX analysis of paired tumor samples from 5 patients revealed an increase of activated T cells in the tumor microenvironment after study therapy. The study suggests that re-irradiation plus pembrolizumab may improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. The study also provides evidence of intratumoral infiltration of activated immune effector cells.
Implications and Future Directions
- The study's findings suggest that re-irradiation plus pembrolizumab may improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. The study highlights the potential of combining radiation therapy with immunotherapy to enhance anti-tumor immune responses and improve survival in patients with recurrent glioblastoma. The study also provides evidence of intratumoral infiltration of activated immune effector cells. The study's limitations include the small sample size and the lack of a control group. Future research should focus on increasing the sample size and incorporating a control group to further evaluate the efficacy of re-irradiation plus pembrolizumab in patients with recurrent glioblastoma. Alternative approaches are needed for bevacizumab-naïve patients. The study also suggests that further research is needed to identify the optimal combination of radiation therapy and immunotherapy for patients with recurrent glioblastoma.