Intramuscular INO-5401 + INO-9012 With Cemiplimab in Newly Diagnosed Glioblastoma
Study rationale
Dr. Ahluwalia: This study was interesting because it looked at novel T cell enabling therapies in addition to checkpoint inhibition to potentially increase overall survival in glioblastoma. As we all know, the first three large randomized trials in glioblastoma looking at the single checkpoint blockade were negative for any improvements in survival. This included CheckMate 143, which looked at nivolumab, compared it to bevacizumab, did not result in any survival benefit in recurrent glioblastoma setting. CheckMate 498 looked at nivolumab plus radiation and compared it to temozolomide and radiation and did not show any survival benefit.
Similarly, when CheckMate 548 tried to add nivolumab to radiation and temozolomide in MGMT hypermethylated glioblastoma, there was no survival benefit seen as well.
Study design
In this study, the investigators looked at synthetic DNA plasmids encoding either the third alteration of Wilms tumor or PSMA, which was called the INO-5401 plasmid and combined that with INO-9012, which was a synthetic DNA plasmid that encodes for interferon 12. They combined that with cemiplimab, which is an anti-PD1 inhibitor and gave it to patients with newly diagnosed glioblastoma with minimal residual disease to look at the tolerability, efficacy, and the immunogenicity of this approach. The primary endpoints were looking at median overall survival at 18 months. So essentially, there was a phase I/II single arm, two cohort study. Cohort A was unmethylated patients. Cohort B was those patients who had methylated MGMT.
All in all, 32 patients were treated in the cohort A, and 20 patients were treated in the cohort B. Around 35% of the patients were women. Median age was around 60 years. This was very comparable than what we have seen in other trials. The adverse event profile was consistent with the single agent adverse events seen with the combinatorial approach of INO-5401, INO-9012, or cemiplimab.
Study results
What was interesting was the median overall survival, duration in cohort A was around 18 months and cohort B was around 32.5 months. This basically appeared promising when we look at those what we have seen with the historical benchmarks where those patients who have unmethylated MGMT, we see survival benefits in the ballpark of 13 to 16 months in this patient population. When you look at those patients who have MGMT methylated glioblastoma, the survival in those patients, at least in the recent trials, have been in the ballpark of 24 to 28 months. 24 months was seen in the veliparib standard of care arm as presented at ASCO 2022.
So essentially, these are initially hypotheses generating benefit, which is seen in this novel approach of using DNA plasmids in addition to anti-PD1 checkpoint blockade. In addition, the investigators performed a number of translational studies, which basically revealed that there was additional benefit seen in those patient populations that had activated antigen specific CD4+ or CD8+ T cells with increasing benefit with increase in the components of these subtypes.
Summary
So in summary, this trial basically showed that the combinatorial approach of using DNA plasmid with anti-PD1, in addition to standard of care treatment of these patients, had an acceptable safety profile. It did elicit robust immune responses, which at least in a small group of patients correlated with enhanced survival. This, we think, is worthy of exploration in a randomized setting to see if there is any efficacy with this approach going forward.
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