PD-1/PD-L1 inhibition may work synergistically with radiation.
November 19, 2020—Houston, Texas—Atezolizumab + radiation and temozolomide has been shown to be tolerable and demonstrated efficacy in line with published trials for newly diagnosed glioblastoma.
This outcome of a phase I/II study was reported at the 2020 Society for Neuro-Oncology (SNO) Virtual Meeting.
Shiao-Pei Weathers, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues set out to evaluate concurrent atezolizumab (anti-programmed death ligand 1 therapy, anti–PD-1/PD-L1) with radiation and temozolomide followed by adjuvant atezolizumab and temozolomide in newly diagnosed glioblastoma.
Dr. Weathers explained to Elsevier’s PracticeUpdate, “Immunotherapy has helped revolutionize the treatment of many types of cancer. In neuro-oncology, we are trying different types of immunotherapy strategies to treat glioblastoma in hopes that we can improve the outcomes for our patients who desperately need better therapies.”
She continued, “We were excited for the opportunity to partner with Genentech for this clinical trial as we work together to try and learn more about the role of checkpoint inhibitors such as atezolizumab in the treatment of glioblastoma.”
Subjects were unselected for O(6)-methylguanine-DNA methyltransferase (MGMT) status. Eligible patients were >18 years of age and had undergone surgery only.
The primary endpoint was safety in phase I (n = 10) and overall survival in phase II (n = 50). Secondary endpoints included progression-free survival, overall response rate, and duration of response.
All 60 enrolled patients were evaluated for efficacy. Correlative endpoints include profiling tumor immune cell populations, peripheral blood for circulating chemokines/cytokines, and stool for gut microbiome.
After a median of 22 months (data cutoff October 2020), 37 patients had progressed, 30 of whom died. Median overall survival was 19 (95% CI, 14.2-24.8) months. Median progression-free survival was 10.6 (95% CI, 8.2-16.7) months.
Median overall survival in MGMT-methylated patients (n = 18) was 29.9 (95% CI, 11.37 to not reached) and 14.9 (95% CI, 13.6-24.8) months in MGMT-unmethylated patients (n = 33).
Treatment-related adverse events of maximum Common Terminology Criteria for Adverse Events grade >3 occurred in 33 patients. The most common were elevation liver enzymes (n = 5) and lymphopenia (n = 23).
To date, 20 of the 60 enrolled patients have undergone reresection post atezolizumab treatment. Matched paired tumor analysis of pre- and post-treatment tissue will provide valuable insights into mechanisms of resistance to anti–PD-L1 therapy. Tumor immunocorrelative studies are pending.
Dr. Weathers explained that immunotherapeutic strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation. The latter is known to increase antigen presentation and to promote a pro-inflammatory tumor microenvironment.
The majority of patients with GBM (61%) harbor tumors with 1% or more PD-L1–positive cells. Of these tumors, 38% exhibit at least 5% PD-L1 expression. PD-L1 is commonly expressed on GBM-infiltrating T cells as well.
Dr. Weathers concluded that concurrent use of atezolizumab with radiation and temozolomide has been shown to be tolerable and demonstrated efficacy in line with published trials for newly diagnosed glioblastoma.
“Though our trial demonstrated modest efficacy,” she added, “we are hopeful that the correlative analysis of pre- and post-atezolizumab–treated tissue will provide valuable insight into better understanding mechanisms underlying resistance to anti–PD-L1 therapy and ultimately inform the design of future checkpoint inhibitor trials in glioblastoma.”
She continued, “We will profile tumor immune cell populations, tumor DNA, mRNA, microRNA, and DNA methylation. We will perform whole exome sequencing, RNA sequencing, and microRNA sequencing. We will assess circulating tumor DNA and peripheral blood for circulating chemokines/cytokines, as well as stool for gut microbiome profiling. We also plan to examine the immune effector function of atezolizumab on the GBM microenvironment.”