Nivolumab Plus Bevacizumab for Recurrent Glioblastoma
PracticeUpdate: What is the rationale behind combining nivolumab and bevacizumab at different dose levels, for patients with recurrent glioblastoma?
Dr. Ahluwalia: We were excited to present our findings from a randomized phase 2, open-label study of nivolumab plus standard-dose bevacizumab vs nivolumab plus low-dose bevacizumab in recurrent glioblastoma at the Society for Neuro-Oncology meeting in 2021, that was held in Boston. This was a multi-center collaboration between Cleveland Clinic and Dana-Farber Cancer Institute, and was conducted during my time at Cleveland Clinic. As we all know, outcomes from recurrent glioblastoma remain dismal. Most patients with recurrent glioblastoma survive 9-12 months; therefore, there is a desperate need for finding novel treatments for these patient populations.
We also know that blockade of programmed death 1 (PD1)-mediated immunosuppression has resulted in clinical benefit across multiple tumor types. The early trials that we and several others participated in was included in CheckMate 143, which was a randomized trial of nivolumab versus bevacizumab in patients with recurrent glioblastoma. However, what we found out in that trial was that those patients who were treated with nivolumab required higher doses of steroids. We also do know that steroids are immunosuppressive, so in a patient population where you're trying to use immunotherapy, if you use an agent that leads to immunosuppression, that'll hinder the benefit of immunotherapy that you use. Hence, this was the basis for our trial, where we combined nivolumab and bevacizumab in patients with recurrent glioblastoma.
PracticeUpdate: What prompted the decision to investigate bevacizumab at different dose levels?
Dr. Ahluwalia: We actually decided to go with two various doses of bevacizumab. One was the standard-dose bevacizumab that was defined as 10 mg per kg, given every two weeks, as is the FDA label. We also decided to use a low-dose of bevacizumab with 3 mg per kg, every two weeks. This was based on work from Dr. Rakesh Jain's lab at Harvard Medical School, where we thought that maybe using a lower dose of bevacizumab would lead to less mesenchymal phenotype in the tumor.
PracticeUpdate: What was the trial design?
Dr. Ahluwalia: This was a randomized trial where we used a standard-dose of nivolumab (240 mg) every two weeks. We used the two doses of bevacizumab that I described. One was arm one, with the standard-dose of bev, and the second was arm two with a low-dose bevacizumab. The study population was pretty standard: more than 18 years of age, first recurrence of glioblastoma, normal organ function, performance status of more than 70%. We only allowed patients who were in their first recurrence of glioblastoma. Exclusion criteria included active, known, or suspected autoimmune diseases, and Decadron usage of 4 mg or greater.
This was a 90-patient study when there was one-to-one randomization. The primary objective was to evaluate the efficacy of nivolumab, either with standard-dose or low-dose bevacizumab, as measured by overall survival at 12 months.
PracticeUpdate: What were the findings?
Dr. Ahluwalia: What we found out with the study was that the overall survival at 12 months was very comparable in both the arms. There was no difference. Overall survival at one year was 41% in arm A (that was the standard-dose of bevacizumab) and 38% in arm B. Progression-free survival was 5.6 months for arm A, and 4.6 months for arm B. Both of these, progression-free survival and overall survival, were very comparable to what we have seen with bevacizumab monotherapy or nivolumab monotherapy.
However, what was interesting in our study: when we looked at patients who were less than 60 years of age or more than 60 years of age, we found out that patients who are more than 60 years of age actually derived greater benefit with use of standard-dose of bevacizumab along with nivolumab. That is that they were treated in arm A. Obviously, this was not the primary endpoint of the study, and is post-hoc analysis, and is intriguing.
PracticeUpdate: What kind of further investigations and implications can be drawn from this study's results?
Dr. Ahluwalia: What we also did was number of translation work with this trial. We looked at single cell RNA sequencing with CITE-Seq to analyze blood cell samples for 16 patients, at a baseline and eight weeks post-treatment. We found a number of intriguing translational outcomes, which we are exploring further, looking at myloid-derived suppressor cell levels and inflammatory response gene signature. What we found out was standard-dose-bev-treated patients had decreased MDSCs and inflammatory response gene signature at eight weeks. This correlated with responses seen in this patient population. Hence, we are exploring further translation studies with this cohort to see if we can find any hypothesis to explore the combination of nivolumab and standard-dose bevacizumab further, especially in patients more than 60 years of age. However, on the basis of our trial, for the whole patient population, we found no difference in outcomes of combination of nivolumab with bevacizumab compared to either single agent nivolumab or single agent bevacizumab. Thank you so much for your kind attention.
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