Treatment with pembrolizumab in programmed death ligand 1–positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE‐028 trial

Abstract

BACKGROUND: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. METHODS: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). RESULTS: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progressionfree survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion

“…In 2017, the FDA approved the anti-PD1 antibody pembrolizumab for patients with unresectable or metastatic dMMR and/or MSI-H solid cancers-the first tissue and/or site-agnostic drug approval. This approval was based on the results across five multicohort, multicenter, single-arm clinical trials (KEYNOTE-061, -164, -012, -028, and -158) [67][68][69][70][71] in 149 patients prospectively tested for dMMR and/or MSI-H using either PCR-or IHC-based testing. Although most patients across these five trials had CRC and experienced an objective response rate (ORR) of 36% (95% CI, 26 to 46), an ORR of 46% (95% CI, 33 to 59) was also observed across 14 other cancer types (eg, endometrial, gastric, and pancreatic cancers).…”

A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine

“…In line with these, the response rates of affected patients to a specific immune checkpoint inhibitor vary substantially, and the overall response rate of glioblastoma patients is not favorable. A phase I clinical trial has demonstrated that the overall response rate of glioblastoma patients with positive tumoral PD-L1 to pembrolizumab has been 8% ( 31 ).…”

Checkpoint Inhibitors as High-Grade Gliomas Treatment: State of the Art and Future Perspectives

“…Then, two PR, lasting 8.3 and 22.8 months, occurred. PFS (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at six months (PFS-6) was 37.7%, and the OS (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58% [32]. A total of 19 patients (73%) experienced TRAEs, of whom five were severe (one arthritis, one colitis, one lymphopenia, one syncope, one type 2 diabetes mellitus) [32].…”

“…PFS (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at six months (PFS-6) was 37.7%, and the OS (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58% [32]. A total of 19 patients (73%) experienced TRAEs, of whom five were severe (one arthritis, one colitis, one lymphopenia, one syncope, one type 2 diabetes mellitus) [32]. No correlation between the level of PD-L1 expression, gene expression profile score, or baseline steroid use and clinical benefit was found 32].…”