Inovio's DNA Vaccine Combo Plus Cemiplimab Shows Promise in Glioblastoma

Amid the progress seen with checkpoint inhibitors in other cancers, glioblastoma stands out as the last frontier—immunotherapies as a group have not worked well in this disease.

But a new method for delivering the treatment offers promising overall survival (OS) results and merits further study, according to a leading glioblastoma investigator who presented findings on June 6, during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

The results involve a pair of DNA medicines combined with the checkpoint inhibitor cemiplimab, which is approved as Libtayo to treat other solid tumors. The regimen is designed to prime a T-cell response before a patient receives radiation.

David A. Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute in Boston, Massachusetts, offered the first look at median survival findings involving Inovio’s DNA medicines, INO-5401 and INO-9012, which were administered with cemiplimab. Reardon explained the concept of the combination and its mechanism of action: “We rationalized that utilizing a robust vaccine platform with checkpoint blockade may be able to generate antitumor immune responses that could migrate the T cells into the immunologically cold tumor microenvironment, which could translate into a survival benefit.”

This is no simple regimen. INO-5401 contains plasmids that encode the tumor-associated antigens human telomerase, Wilms tumor 1, and prostate-specific membrane antigen. INO-9012 is a synthetic DNA plasmid, which encodes interleukin 12 and works to stimulate the T cells locally.

The primary objective of the study presented at ASCO was to demonstrate safety and tolerability, with secondary end points of preliminary efficacy and immunogenicity, and OS at 18 months. There were several exploratory objectives, including an examination of links with biomarkers.

So far, Reardon said, the regimen seems to be well tolerated and merits further study. Adverse events were consistent with those seen in other studies of checkpoint inhibitors. “Most of these were grade 1 or grade 2 and manageable in terms of the efficacy of the study,” he said. “The median overall survival for all patients was 19.5 months.”

The study broke the patients down by their MGMT status, methylated or unmethylated, as this marker is known to dictate the effectiveness of therapies in glioblastoma. As expected, the patients with methylated MGMT status fared better. Median OS for patients with unmethylated MGMT status was 17.9 months, which Reardon compared with historical averages of 14.6 to 16 months. For those with methylated status, the median OS was 32.5 months, compared with historical averages of 23.2 to 25 months; 3 patients were still alive and on the study at the time of data cutoff in April 2022.

Study method. Following tumor resection and enrollment in the study, all patients received the dual DNA regimen with cemiplimab 2 weeks prior to treatment with radiation, to trigger a T-cell response. Radiation was given with temozolomide for 3 weeks in all patients.

There were 2 cohorts of patients: cohort A had unmethylated MGMT (32 patients) and cohort B had methylated MGMT (20 patients). In addition, temozolomide was given to cohort B for 6 adjuvant cycles. All the while, cemiplimab was given every 3 weeks until disease progression.

The median time on study for cohort A was 17.9 (3.7-42.3) months, with a median of 10 (1-60) doses of cemiplimab. For cohort B, the median time on study was 30.7 (1.3-41.9) months, with a median of 17 (1-53) doses of cemiplimab. Most patients discontinued the study due to disease progression.

“We saw a good safety profile and some encouraging survival benefit, but this clearly needs to be definitively evaluated in a randomized clinical trial,” Reardon said.

Reference
Reardon DA, Brem S, Desai AS, et al. Intramuscular (IM) INO-5401 + INO-9012 with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma. J Clin Oncol. 2022;40(suppl 16):2004. doi:10.1200/JCO.2022.40.16_suppl.2004