Improving the survival of glioblastoma multiforme (GBM) patients remains a challenge, with over 90% of newly diagnosed patients expected to recur within the first two years of receiving first-line treatment. Although population-level genomics and proteomic approaches have improved therapeutic options and identified single protein targets, in most cases, the targeted compounds, having shown high preclinical efficacy, failed expensive Phase III clinical trials in humans. PD-1 blockade has transformed the landscape in several cancers; however, its effectiveness in eliciting a clinical benefit for GBM patients is still in question. With Bristol Myers Squibb’s (BMS) Phase III CheckMate-498 and CheckMate-143 Opdivo (nivolumab) studies both failing to meet primary (overall survival: OS) or secondary endpoints, the use of single-agent PD-1 blockade remains unsatisfactory.
Considering that multiple immunosuppressive mechanisms and low immunogenic responses are observed in GBM, combining several immunomodulators may be the most promising method for GBM patients. However, several Phase I/II studies still focus on using single-agent PD-1 blockade, likely due to barriers such as increased toxicity, challenges with combination trial designs, and the interpretation of endpoints.
The open-label LUMINOS-101 study is a promising Phase II trial exploring Istari’s PVSRIPO, an investigational immunotherapy based on the live attenuated Sabin type 1 poliovirus vaccine combined with Merck’s pembrolizumab to generate an anti-tumor response in patients with recurrent GBM (rGBM). LUMINOS-101 follows the Phase I trial of PVSRIPO monotherapy in rGBM, which found that survival rates were significantly higher in rGBM patients who received an intratumoral infusion of PVSRIPO (21% of patients achieving 36–60 months) compared to similar patients receiving standard treatment (4% of patients achieving 36 months; 2%, 60 months). Since GBM patients are known to have significant deficits in cell-mediated immunity, specifically the CD4 cells, PVSRIPO combination with PD-1 blockade is anticipated to augment tumor antigen-specific T cell activation and recruitment, thereby increasing overall survival. Another prospect of PD-1 inhibitors is in the neoadjuvant setting, since surgery dampens cellular immunity as a surgical stress response by the host. Interim data from the pilot Phase I trial (Table 1) involving Merck & Co’s Keytruda (pembrolizumab) revealed a better survival together with an upregulation of T-cell and interferon-γ-related gene expression in the presurgical-surgical PD-1-treated patients compared to control.
Although BMS, Merck & Co, and Merck KGaA currently lead the PD-1/PD-L1 inhibitor space for GBM with Opdivo, Keytruda (pembrolizumab), and Bavencio (avelumab), respectively, as combination trial therapies or singular, their efficacy data are still not validated, leaving ample opportunities for Regeneron Pharmaceuticals’ Libtayo (cemiplimab), Roche/Genentech’s Tecentriq (atezolizumab), and AstraZeneca’s Imfinzi (durvalumab) to contend for the GBM space. While the interest in using checkpoint modulators may start to wane due to the recent failures of Opdivo Phase III studies, the upcoming promising trials involving Keytruda place the drug as a potential favorite to reach the GBM market if successful.
In general, the GBM market is dominated by the sales of Avastin and chemotherapy (temozolomide and the PCV regimen, primarily) for patients with newly diagnosed GBM and rGBM, which make up approximately 81% of sales across the eight major markets (United States, Japan, China, Germany, Italy, Spain, France, United Kingdom) in 2020, according to GlobalData patient-based forecasts; GlobalData also valued the GBM market in the 8MM at $706M in 2020. To tap into this market, the efficacy of PD-1 blockade in GBM still needs to be demonstrated in comparative clinical studies and replicate promising Phase I/II results in Phase III.