New Treatment Approach for Newly Diagnosed Glioblastoma Shows Early Signs of Safety, Efficacy

David Reardon, MD

The first glioblastoma study to combine a DNA plasmid with PD-1 blockade (NCT03491683) showed no new or synergistic toxicities in patients with both methylated and unmethylated tumors. Seeing high tolerability of the combination of INO-5401 and INO-9012 with cemiplimab (Libtayo), David Reardon, MD stated that the vaccine plus cemiplimab shows promise for patients with newly diagnosed glioblastoma.

“The interim results demonstrated for us that we had a very reassuring rate of adverse events and toxicity. These agents were well tolerated. The vaccine had no significant adverse events (AEs) associated with it and the PD-1 inhibitory agent had the usual spectrum of adverse events that we know are associated with PD-1 inhibitor therapy. Nothing was unexpected or new,” Reardon said.

The phase 1/2 open-label study also demonstrated a preliminary survival advantage for patients with newly diagnosed glioblastoma, according to interim analysis results presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Out of 52 patients, 32 of whom had unmethylated tumors and 20 of whom had methylated tumors, the most common grade 3 or higher AEs were decreased platelet count (11.5%), tumor inflammation (7.7%), seizure (7.7%), increased alanine transferase increased (7.7%), and decreased lymphocyte count (7.7.%). There were 69 serious AEs reported, but only 1 of them was found to be related to the combination. Serious AEs included increased alanine transferase increased (9.6%), increased aspartate transaminase (7.7%), diarrhea (7.7%), pyrexia (7.7%), and tumor inflammation (7.7%). The majority of the AEs observed in the trail (71%) occurred within the first 12 weeks of therapy.

In terms of preliminary efficacy, the overall survival (OS) rate at 12 months was 84.4% (95% CI, 67.2% -94.7%). T cell responses were also observed in patients from the methylated tumor cohort who received INO-5401. In addition, flow cytometry showed evidence that the combination led to the activation of INO-5401-specific CD8-positive T cells with lytic potential.

In an interview with Targeted Oncology, Reardon, clinical director, Center for Neuro-Oncology, institute physician, and professor of Medicine, at the Dana-Farber Cancer Institute, discussed the background and findings for the phase 1/2 clinical trial of INO-5401 and INO-9012 plus cemiplimab in patients with newly diagnosed glioblastoma.

TARGETED ONCOLOGY: Can you begin by explaining what these two agents are and what data supports their use in glioblastoma?

Reardon: INO-5401 and INO-9012 are being evaluated an ongoing clinical trial for patients with newly diagnosed glioblastoma, and preliminary results of this trial were recently presented at the 2020 ASCO meeting. The 2 compounds are novel DNA plasmid constructs that include 3 tumor-associated antigens in the INO-5401 that are highly regulated and expressed by glioblastoma tumor cells. These include human telomerase, Wilm’s tumor 1 protein, and the

prostate specific membrane antigen (PSMA). The idea is that the 5401 plasmid will induce immune responses against these 3 immune tumor-associated antigens.

The second plasmid, INO-9012 is engineered to express interleukin 12, which is the very molecule involved in attracting and activating dendritic cells, so that when the antigens are delivered and administered through INO-5401, INO-9012 will help to bring in additional immune effector cells that could help the immune system sensitize against these specific

targets associated with glioblastoma.

The 2 plasmids are delivered via intramuscular injection, accompanied by electroporation for

patients, which is designed to enhance the expression and activation of these antigens for the immune system of each patient.

These are plasmid vaccines that are incorporated into the clinical trial and co-administered with standard radiation, and temozolomide chemotherapy in patients with newly diagnosed glioblastoma. The other novel aspect of this trial is that we also included the PD-1 inhibitor cemiplimab, which is a highly specific PD-1binding agents andprevents PD-1 activation or signaling. The thought behind that is that when anti-tumor immune responses are activated, we know that inhibitory immune checkpoint molecules, like PD-1, are regulated. If we are trying to drive an anti-tumor immune response into the tumor with the vaccine complex, and the IL-12,

PD-1 upregulation would give those defector cells, immune T cells that are migrating into the tumor, a better chance of having an anti-tumor response.

TARGETED ONCOLOGY: Can you explain the trial design? What were the key characteristics of the patients enrolled?

Reardon: The trial was designed as a straightforward 2-arm trial of patients with newly diagnosed glioblastoma. A safety lead-in component of the study was performed because the vaccine complex of INO-5401 and INO-9012 had not been previously administered to patients with glioblastoma in the context of standard radiation therapy, nor had it been administered with PD-1 blockade.

The safety lead-in confirmed that these agents were well tolerated and did not cause any AEs. Then, we moved right into the phase 2portion of the study during which the

newly diagnosed patients were divided into groups. [One group included] those who had an MGMT unmethylated promoter, which is seen in about two-thirds of patients with newly diagnosed glioblastoma who are predicted to have a lower benefit rate from our standard of care therapy with temozolomide (Temodar). The other arm of the study included patients with a methylated MGMT promoter of their tumor and those patients who are predicted to have a higher likelihood of benefit from temozolomide chemotherapy.

All patients in the trial received radiation with daily temozolomide because daily temozolomide has the potential to act as a radiosensitizer and enhance of the benefit of radiation therapy, which is what we want to do in the context of immunotherapy trial.

After radiation was completed, the patients in cohort A, who had the unmethylated tumors and were not expected to get benefit from temozolomide, did not received any further temozolomide.

Cohort B received temozolomide during radiation as well as in the standard regimen setting, then the immunotherapy regimen of the vaccine plus the regular dosing of cemiplimab was administered.

The vaccine was started prior to initiation of radiation therapy for all patients, as was the cemiplimab and the PD-1 blocking agent. Then both agents were continued after radiation therapy was completed.

TARGETED ONCOLOGY: What were the findings of the interim analysis?

Reardon: The interim results demonstrated for us that we had a very reassuring rate of AEs and toxicity. These agents were well tolerated. The vaccine had no significant AEs associated with it and the PD-1 inhibitory agent had the usual spectrum of AEs that we know are associated with PD-1 inhibitor therapy. Nothing was unexpected or new.

Now we have 52 patients treated, and we feel very comfortable because all of those patients had a very reassuring safety profile associated with the study therapy.

It’s really too early to assess efficacy, however, we did see reassuring rates of progression-free survival at 6 months, as well as OS at 12 months. Those were in the higher range of what would be expected at this time point for newly diagnosed patients.

Again, it is too soon to draw any conclusions, but it’s reassuring that they were in the ballpark of where we expected to be for both cohorts. The progression-free survival rate was between 75% and 80%, and the OS was 84% to 85%. Those are encouraging numbers, but ongoing treatment and follow up of the patients is clearly important.

Another exciting point about the study is that we did detect evidence of immune responses against the vaccinated targets.

TARGETED ONCOLOGY: What are the clinical implications of this research?

Reardon: The take-home message for me is that we need some out of the box thinking and approaches if we're going to have an impact against this very challenging disease. Thinking about rationally designed combinatorial regimens is certainly 1 promising approach where headway may be able to be made.

In this trial, we combined 2 agents that hadn't been previously combined, and traditionally we would put them into a trial with each agent separately before moving them together.

I think we need more innovative thinking for very challenging cancers like glioblastoma. I think the other take home message here is we know that, unfortunately, the glioblastoma therapies have not been able to make much of a difference. Three studies have been reported. We need to better understand why those studies are negative, what is different about glioblastoma tumors, in particular, compared with other tumors? We have to figure out how we might be able to design therapeutic strategies that will allow efficacy.

_Reference:

_{Reardon DA, Brem S, Desai AS, et al. INO-5401 and INO-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma (GBM): Interim results. J Clin Oncol. 2020: 38 (suppl; abstr 2514). doi: 10.1200/JCO.2020.38.15_suppl.2514}