Dexamethasone Decreases the Efficacy of Immune Checkpoint Inhibitors in Patients With Glioblastoma

Results of a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) demonstrated that glioblastoma (GBM) patients being treated with an immune checkpoint inhibitor and who had received the potent corticosteroid dexamethasone at baseline for cerebral edema had significantly worse overall survival.[1]

The study was funded by the National Institutes of Health (NIH) and sponsored by The Jennifer Oppenheimer Cancer Research Initiative, The Ben and Catherine Ivy Foundation, Hope It’s A Beach Thing, and the Pan-Mass Challenge.

“Dexamethasone is a potent corticosteroid that is often prescribed to patients with glioblastoma to treat symptoms related to cerebral edema, or swelling in the brain,” noted  David A. Reardon, M.D., clinical director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute in Boston.

“Cerebral edema is a common yet potentially life-threatening complication for patients with glioblastoma, and treatment with corticosteroids can help to suppress the inflammation in the brain,” Reardon added.

Empirical treatment
“Historically, patients with glioblastoma have been empirically treated with dexamethasone, even without symptoms, with many clinicians prescribing steroids for prolonged periods of time, out of a concern that patients may start to develop edema,” Reardon continued.

“Our study was designed to look at that paradigm of clinical practice, particularly in the immunotherapy era, and determine if there could be negative consequences associated with dexamethasone use among patients with glioblastoma treated with immune checkpoint inhibitors.”

Effects of dexamethasone
Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.

Reardon and colleagues evaluated the dose-dependent effects of concurrent dexamethasone administration with an immune checkpoint inhibitor (anti-PD-1 therapy).

In an immune-sensitive mouse model, which included in syngeneic murine glioblastoma models, including programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors, which is inherently responsive to immune checkpoint blockade, the researchers found that the addition of dexamethasone to anti-PD-1 therapy resulted in reduced survival in a dose-dependent manner.[1]

Additionally, in an immune-resistant mouse model, which Reardon noted is more representative of human glioblastoma, the addition of dexamethasone to anti-PD-1 therapy or anti-PD-1 therapy plus radiotherapy also resulted in reduced survival.

A significant detrimental effect
The study results showed that dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses.

“In our preclinical studies, we found that steroids had a significant detrimental effect on the efficacy of anti-PD-1 therapy, even in an immuno-sensitive model, which over-predicts the benefit of immune checkpoint blockade in glioblastoma patients,” Reardon concluded.

Analysis of survival data
The researchers next analyzed overall survival data from 181 patients with glioblastoma treated with either anti-PD-1 or anti-PD-L1 therapy at Dana-Farber Cancer Institute who were diagnosed before April 1, 2019. This patient population was heterogeneous, with patients receiving treatment through a clinical trial or on a compassionate use basis; roughly 76% were treated for recurrence, and roughly 24% were treated for a new diagnosis. Of these 181 patients, around 35% were taking dexamethasone at baseline.[1]

Reardon and colleagues evaluated the potentially detrimental effect of dexamethasone using multivariable analysis, where they adjusted for a variety of factors, including disease setting (newly diagnosed versus recurrent), tumor volume at treatment initiation, age, and extent of resection, among the 163 patients that had complete annotated data for relevant prognostic factors.

Following multivariable adjustment with the relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival.

Compared with patients who were not taking dexamethasone at baseline, patients treated with dexamethasone had roughly twice the risk of death.

The study showed that baseline use of dexamethasone was the strongest identified negative risk factor for overall survival.[reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30–3.68; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23–3.16; P = 0.005].[1]

Clinical strategy
“Our results suggest that we should try to avoid dexamethasone among patients with glioblastoma who are treated with immunotherapy, and if corticosteroids are clinically required, we should use these drugs judiciously,” Reardon said.

“Further, our results highlight that other strategies for the treatment of cerebral edema that do not have such a broad anti-inflammatory effect critically need to be investigated,” he added.

Study limitations
Limitations of the study include the retrospective nature of the clinical analyses. Further, in their preclinical studies, the researchers solely evaluated the effect of dexamethasone on the efficacy of anti-PD-1 treatment.

“Whether the same observations would occur with other immunomodulatory checkpoint targeting agents, or even other immunotherapy treatments—such as vaccines, adoptive cellular therapies, or genetically engineered oncolytic viruses—remains to be evaluated,” Reardon concluded.

Reference
[1] Iorgulescu JB, Gokhale PC, Speranza MC, Eschle BK, Poitras MJ, Wilkens MK, Soroko KM, Chhoeu C, et al. Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291. Epub ahead of print. PMID: 33239433.

Featured image: Glioblastoma with extreme nuclear enlargement. Photo courtesy: © 2016 – 2020 Fotolia/Adobe. Used with permission.