Novel Immunotherapeutic Agent Shows Benefit in Ovarian Cancer

Premal H. Thaker, MD

The immunotherapeutic agent EGEN-001 in combination with pegylated liposomal doxorubicin (PLD) showed clinical benefit in recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer patients, according to a recent NRG/GOG study.

EGEN-001 consists of a human IL-12 plasmid that encodes for functional IL-12 and a synthetic DNA delivery system polyethyleneglycol-polyethyleneimine-cholesterol that facilitates plasmid delivery into cells.

Intraperitoneal injection of EGEN-001 is associated with increases in IL-12 levels and its downstream cytokines in the tumor environment without a significant increase in systemic circulation.

The study used a dose escalation model, with 16 evaluable patients receiving PLD every 28 days and EGEN-001 on days 1, 8, 15, and 22 of a 28-day cycle. Cycles were repeated every 28 days until disease progression. Three dose levels were evaluated.

A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease, with the highest number of partial responses found at dose level three (28.6%). The maximum tolerated dose was not reached.

Side effects included anemia, abdominal pain, and neutropenia.

Although the study examined a small population, the results are promising for the potential of immunotherapy agents in ovarian and other similar cancers, said lead study author Premal H. Thaker, MD, associate professor, Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine/Siteman Cancer Center. In an interview with OncLive, Thaker explains the impact these findings may have on the difficult-to-treat patient population.

OncLive: What were the most significant findings from this study?

Dr Thaker: It was an NRG/GOG study looking at platinum-resistant ovarian cancer using a combination of doxorubicin and an EGEN-001 compound, which is a human IL-12 along with a DNA platform in order to introduce it intraperitoneally. We used this combination in a dose escalation model. We had three dose models and 16 patients. We found that we had an almost 86% clinical benefit in our highest dose level, which was level three. This was very exciting because, in this patient population, we do not have many treatments available. It was also encouraging because we did not even have to reach our maximum tolerated dose. We are excited to use this therapy in future studies.

How did the other two dose levels compare to dose level three?

The other two dose levels were effective, as well. However, what was encouraging about dose level three is that we saw the highest level of stabilization of disease. Two patients in the high-level group also had partial responses. We found that to be very encouraging because the patient population had been heavily pretreated and do not have many options. The idea of putting together standard chemotherapy and immunotherapy and giving it intraperitoneally, which is a novel administration method for ovarian cancer, is very exciting.

What are the current treatment options for this patient population and what role could this new agent have?

Right now, the standard is to just use stand-alone chemotherapy with perhaps other tyrosine-kinase inhibitors. However, when patients become platinum-resistant, which is our best chemotherapy, they have about a 20% response rate to standard chemotherapy. In this case, we might get a PFS benefit of 3 to 4 months. We are hoping to push that and make it even better.

This is one of the few immunotherapy options. With these types of novel therapies, we may be able to improve women’s lives.

Are there any concerning toxicities with this combination?

We really only saw neutropenia, which can be easily overcome with the use of agents to help stimulate patients’ bone marrow. That was really a minor toxicity. It was very encouraging and gives us incentive to try and push the doses further to determine if we can achieve even better responses.

What are the next steps in this research?

The next step is to see if we can reach our maximum tolerated dose. We have also considered combining it with bevacizumab (Avastin). We have seen a lot synergy with the intraperitoneal combination of IL-12 along with bevacizumab, so we are encouraged to maybe use that with chemotherapy. Perhaps if we use three agents, we may get even better results. We already know that bevacizumab has a good safety profile in this patient population when paired with chemotherapy, so adding an immunotherapy agent may target a different aspect of the cancer and and give us a better result.

How do you see immunotherapy evolving in ovarian cancer?

I think immunotherapy will be part of the future treatment paradigm for this disease. Immunotherapy has been studied in this space for 20 years, but there were always so many side effects.

However, with this new agent, we were able to synthesize it differently. Now, we are not seeing those side effects. We are seeing benefit without those harsh side effects. Because of that, we are actually able to combine it with chemotherapy and other agents. The immune system has always been the way we thought cancer arises, as the cancer could be suppressed in the immune system. Now that we have a way to target the immune system, it is very exciting and I feel I can truly encourage my patients. It is an encouraging time in oncology to try and target and harness another therapy.

Thaker P, Brady W, Bradley W, et al. Phase I study of intraperitoneal IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer administered in combination with pegylated liposomal doxorubicin in recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients: an NRG/GOG study. J Clin Oncol. 2015;33 (suppl; abstr 5541).