With Bristol Myers Squibb’s (BMS) Phase III CheckMate-498 and CheckMate-143 Opdivo (nivolumab) studies both failing to meet primary or secondary endpoints, the use of single-agent PD-1 blockade for glioblastoma multiforme (GBM) remains unsatisfactory, says GlobalData. The leading data and analytics company notes; 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.

Alice Beckley, PhD, Senior Oncology and Haematology Analyst at GlobalData, comments: “BMS, Merck & Co, and Merck KGaA currently lead the PD-1/PD-L1 inhibitor space for GBM with Opdivo (nivolumab), Keytruda (pembrolizumab), and Bavencio (avelumab), respectively, with combination or monotherapy trials. However, the efficacy data for these drugs 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.”

Keytruda’s involvement in the promising phase II combination study with Istari’s PVSRIPO, having shown positive OS in phase I, possesses the opportunity to further improve the clinical efficacy of PD1-blockade combinations through the augmentation of tumor antigen-specific T cell activation and recruitment. However, severe and refractory immune-related adverse events (irAR) remain a challenge in combination studies due to the difficulty of adequately assessing the risk-benefit ratio.

Beckley continues: “More trials are exploring molecular markers, including PD-L1, microsatellite instability, tumor-infiltrating lymphocytes, and tumor mutational burden to aid clinical treatment and improve trial success by accurately screening sensitive populations. Combining this strategy with early recognition and prompt treatment of irARs will reduce patients’ adverse outcomes, thus focusing on improving OS. Though combination therapy increases the cost of treatment, the significant unmet therapeutic need in GBMs makes this approach a worthy candidate that can increase market traction 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 (*8MM) in 2020, according to GlobalData. GlobalData also valued the GBM market in the 8MM at $706m in 2020.

Beckley concludes: “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.”

*8MM: US, Japan, China, Germany, Italy, Spain, France, and the UK