Pembrolizumab, Temozolomide and HSPPC-96 Vaccine in Newly Diagnosed Glioblastoma Post-Chemoradiation: Results from a Multi-institutional, Phase 2, Randomized, Placebo-Controlled Trial

Abstract Background GBM is one of the most common and most aggressive brain tumors in adults, and upfront standard of care treatment has limited efficacy. Immune checkpoint inhibitor strategies have significantly improved outcomes in various solid tumors but have not proven effective in GBM, suggesting other strategies may be needed to realize their full potential. Methods GBM patients were treated with upfront standard of care chemoradiation with temozolomide and pembrolizumab, followed by adjuvant temozolomide and pembrolizumab for six nine-week cycles. Depending on production of sufficient vaccine, patients were randomized into HSPPC-96 vaccine or placebo group (q4 weeks) while those with failed vaccine production continued on study unblinded as an ancillary group. The primary objective was overall survival at one year, and secondary endpoints were progression-free survival at six months, overall and progression-free survival, radiographic response, and tolerability by patient-reported outcomes and adverse event documentation. Results 90 patients were screened, 32 were treated (8 vaccine, 9 placebo, 15 ancillary), and 26 were evaluable for radiographic responses prior to accrual termination. The study did not meet its primary endpoint of overall survival at one year (65.5% in vaccine group, 75% in placebo). Progression-free endpoints were mildly improved in the vaccine group but were not significant, and response rates were not significantly different. The regimen was well-tolerated and safe. Conclusions Though limited by early discontinuation, these findings do not support the combination of pembrolizumab and HSPPC-96 vaccine with standard of care therapy. Trials Registration ClinicalTrials.gov identifier: NCT03018288 Key Points Newly diagnosed glioblastoma (GBM) has one standard of care treatment option with known limitations. Combination of standard of care therapy with immunotherapeutics consisting of pembrolizumab and the personalized cancer-derived HSPPC-96 vaccine is safe and well-tolerated in newly diagnosed GBM This regimen demonstrated no survival benefit, but the vaccine safety profile recommends consideration of alternative combinatorial strategies Importance of the Study In this phase 2, multicenter, placebo-controlled, double-blinded trial of newly diagnosed GBM patients, the addition of pembrolizumab and patient tumor-derived HSPPC-96 vaccine to standard of care chemoradiation and adjuvant temozolomide was not effective even accounting for early termination due to accrual issues during the Covid pandemic. However, with good safety profile and tolerability, HSPPC-96 vaccine could be considered in combination with other immunotherapeutic strategies in future GBM trials.