Combos Could Unlock Major Immunotherapy Benefits in Ovarian Cancer

John Hays, MD, PhD, an assistant professor in the Department of Internal Medicine, and member of the Translational Therapeutics Program at the Ohio State University Comprehensive Cancer Center-James

John Hays, MD, PhD

The role of immunotherapy continues to evolve in ovarian cancer, and to improve on the modest activity seen with single agents, researchers are exploring this class of drugs in combination with chemotherapy and targeted therapies, said John Hays, MD, PhD.

“I'm excited about where immunotherapy is going in ovarian cancer. We have tried several different trials examining single-agent immunotherapies and combinations,” said Hays. “While by themselves [these agents] may not be the most active, as we start to combine them with chemotherapy and other targeted therapies, we’re seeing more and more activity, both in the recurrent and up-front settings.”

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Ovarian Cancer, Hays, an assistant professor in the Department of Internal Medicine, and member of the Translational Therapeutics Program at the Ohio State University Comprehensive Cancer Center—James, discussed ongoing research with immunotherapy in ovarian cancer, challenges with determining predictive biomarkers of response, and promising emerging modalities.

OncLive: Could you provide a timeline of immunotherapy in ovarian cancer?

Hays: A few years ago, the PD-1, PD-L1, and CTLA-4 inhibitors were coming into the mainstream in many other cancers. As such, many companies were very interested in looking at [these agents] in ovarian cancer as well. We examined several of them as single agents, and the response rates across the board ranged from 10% to 15%—which is not bad, but nowhere near as good as we would like them to be. If we hold the bar up to the response rates that we see in a disease like melanoma, they were not as high as we [had hoped].

Looking back, while [these were] good drugs in the armamentarium to have, [we felt] it would be nice if we could increase those response rates. As such, the next step was: How do we make them better? [It was felt that you] do that by either trying to identify the patients who respond really well, or by adding [drugs to these agents] to increase [activity]. Sometimes, the easiest thing to do is to add other drugs to these immunotherapies to make them work a little bit better, whether that's chemotherapy or a targeted therapy.

When we add chemotherapy to immunotherapies, we seem to get a little better of a response in some cases—in other cases, not so much. In the up-front setting, the current trend is to look at what we can do—not only to add to current up front chemotherapy, but also to chemotherapy or targeted therapy in the maintenance setting—in an attempt to increase response rates and the number of patients who don't have disease recurrence.

One of the combinations under exploration has been immunotherapy with PARP inhibitors. Could you discuss the phase I/II TOPACIO/KEYNOTE-162 trial with pembrolizumab (Keytruda) and niraparib (Zejula)?

The TOPACIO trial is interesting because it examined patients with BRCA mutations and BRCA wild-type ovarian cancer, and the addition of a PARP inhibitor—which is to some extent a targeted therapy, but also can cause DNA damage—to immunotherapy. We saw that in the BRCA mutation carriers; the response rate was likely pretty similar to what you would see with a PARP inhibitor by itself. However, in patients without BRCA mutations, or those don't have homologous recombination deficiencies as they were defined in the trial, the response rates were significantly higher than you would see with either agent alone. In that population, you may see a benefit for adding a PARP inhibitor to immunotherapy. 

Also, the MEDIOLA trial examined olaparib (Lynparza) in combination with immunotherapy in patients who had germline BRCA mutations and platinum-sensitive disease, and they stratified their patients by the number of lines of therapy they received prior to going on the trial. [With this approach], the response rate was fairly high; it was 75% or so in this patient population. For patients with recurrent ovarian cancer, very few trials have shown that kind of response rate, even in the platinum-sensitive setting. I believe we are all very excited about being able to identify a certain population that may respond well to these therapies.

Are there studies examining PARP inhibitors plus immunotherapy and chemotherapy?

There is a great desire [to do that], and we, as medical oncologists and gynecologic oncologists, have a strong history of saying, "If 1 thing works, let's do 2. If 2 things work, let's do 3." I believe that we may see some exciting results by going in that direction.

However, we also have to watch out for potential unexpected adverse events as we start to add more drugs together. Right now, the combinations have been fairly well tolerated, so we are fairly cautiously optimistic that they will continue to be well tolerated as we move forward. In the frontline setting, [we are] combining [strategies] like immunotherapy and PARP inhibitors, or immunotherapy and VEGF-targeting agents with chemotherapy, to see if we could increase the overall response rate in patients.

Are there any predictive biomarkers to indicate response to immunotherapy?

That is the holy grail for almost all of these therapies at this point in time. Whether it's with immunotherapy or targeted therapies, we are starting to have more drugs in our armamentarium. The biggest question is, "What is the right drug, for the right person, at the right time?" We have some markers that may help limit those populations, but I don't believe that we have found the perfect biomarker to say whether this is the right drug to give at the right time for this patient. We're all still looking for that.

What other classes of immunotherapy are under investigation in ovarian cancer?

One of the exciting [areas of research] is determining what are other ways we could use immunotherapy beyond checkpoint inhibitors. Probably the most intriguing [modalities] that are being looked at in hematologic cancers right now are tumor-infiltrating lymphocytes (TILs) and CAR T-cell therapies. We are very much in the infancy of that [work] in most solid tumors, but we are starting to gain a little bit of steam. We have trials open with TILs in cervical cancer and CAR T cells in ovarian cancer. However, we still have very limited data for how efficacious those [approaches] might be.

Could you expand on the research being done with CAR T-cell therapies?

Are the T cells being directed to CD19, or is there another expression to target? It's a different expression for most solid tumors. Most hematologic malignancies, especially B-cell malignancies, have been CD19-directed. As we get into solid tumors, we have to find what the marker is, and each one may be specific [to an individual tumor]. There may be some solid markers, or markers that are expressed in more than 1 cancer; there may be some that are expressed solely in ovarian cancer or solely in cervical cancer.

Finding the right marker for those T cells has been the [most challenging] part [of that research] to date. The most work has been done in cervical cancer, [where investigators are] finding HPV-derived antigens as a target for CAR T cells and derivatives. In ovarian cancer, some other germ cell—type markers have been looked at as well.

How would you define the future role of immunotherapy in ovarian cancer?

It’s evolving. Early trials held a lot of excitement with single agents, but as the results started coming in, they were a bit more disappointing than we would have liked them to have been—although they weren’t negative. Many trials are ongoing. We are waiting for the data to come out on immunotherapies in combination with either targeted therapies or chemotherapies, with the hope that those results will get better as we go along. For now, we are cautiously optimistic and keeping our fingers crossed.