Combinations May Be Crucial for Immunotherapy in Ovarian Cancer

Dmitriy Zamarin, M.D., Ph.D.

The future for immunotherapy treatment for gynecologic cancers may be found in drug combinations, according to Dmitriy Zamarin, M.D., Ph.D., who admits that these agents have been slower to demonstrate progress in this group of patients.

“We have not increased the number of patients that we have cured of ovarian cancer in the past 20 or 30 years,” states Dmitriy Zamarin, M.D., Ph.D.

Success with these agents may rely on combination approaches, which has shown improvement in responses with other cancer types, such as melanoma. There is an ongoing phase 2 study investigating the CTLA-4 inhibitor Yervoy (ipilimumab) and the PD-1 inhibitor Opdivo (nivolumab) for patients with recurrent ovarian cancer, primary peritoneal, or fallopian tube cancer, with results expected to readout in the coming months (NCT02498600).

Can you provide an overview of your recent presentation on immunotherapy in ovarian cancer?

What have we seen so far regarding vaccines?

In an interview with CURE, Zamarin, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses immunotherapy for patients with ovarian cancer.I discussed the different types of treatments that are used, such as vaccines. I mainly focused on immune checkpoint inhibitors, which is the class of agents that has been in the most advanced clinical development—not just in ovarian cancer, but other cancer types, as well.Cancer vaccines are probably one of the older types of immunotherapy. The interest stems from the success of vaccines in the infectious disease setting. The idea was: can we use this in a therapeutic setting in advanced cancers, or even in some of the precancerous conditions?

Unfortunately, in the advanced cancer setting, we have not seen much success from the traditional types of vaccines. By this, I mean peptide vaccines that are representing some of the commonly shared tumor antigens. For example, there are cancer germline antigens, such as NY-ESO-1. Those vaccines have shown some signals of activity, but we have not seen major activity that would cause tumor regressions or, even when used in maintenance, would result in a prolongation of progression-free survival or cures.

Vaccine is a very broad word. It encompasses many different types of treatment strategies. There is one vaccine that is currently approved for metastatic melanoma that works very well called Imlygic (T-VEC; talimogene laherparepven). This is a vaccine that is an oncolytic herpes virus expressing GM-CSF that is given intralesionally. We don't know if similar strategies will be effective for cancers of gynecologic origin, but they are certainly worthy of investigation.

What are the latest data that we have with checkpoint inhibitors in this landscape?

This is an in situ vaccine, meaning it targets a patient's own tumor—allowing them to generate immune response against their own cancer. In ovarian cancer, we haven't seen much promise in the advanced confirmatory phase 2 studies that would suggest that vaccines are effective.Some checkpoint inhibitors have seen approval in many cancer types, with melanoma being the first one. The main checkpoint inhibitors that we see in clinic are the antibodies that are targeting CTLA-4, PD-1 or PD-L1. All have been tested in ovarian cancer. In the initial studies with antibodies targeting PD-1/PD-L1, the response rates are not as high as what we see in some of these other cancer types.

In ovarian cancer, the response rates seem to be around 12 percent to 15 percent. There is a significant number of patients who do have some disease stabilization with these therapies. This is not to say that the response rate is very low and the drugs are not worth investigation, but durable stable disease is certainly something that we can strive for.

More importantly, what those studies also suggest is that patients with ovarian cancer are obviously different. The biology of the tumor is different than these other cancer types. Perhaps the biomarkers that we have in the other cancers are not the same as what we are going to have for ovarian cancer.

Are there any combinations going on right now with immunotherapy that you think are interesting?

Most importantly, these drugs are not going to work alone. We need to use them in combination with some of these other drugs—either standard or investigational. There are quite a few ongoing combinations in ovarian cancer and in many other cancer types. The only real combination that has been approved so far, at least in metastatic melanoma, is the combination of targeting CTLA-4 and PD-1 with the drugs Yervoy and Opdivo. There are currently studies that are evaluating the same combination in ovarian cancer. We should probably have the results from these studies coming up within the next few months.

There are combinations of these drugs with standard chemotherapy, too. We do have safety and efficacy data from lung cancer studies, demonstrating that even using standard combination chemotherapy with a platinum doublet and another chemotherapy can be safe and effective when combined with PD-1 inhibitors.

There are quite a few studies that have now been opened to evaluate this in ovarian cancer. This is going to be done in the upfront setting, meaning that the patients who undergo an initial debulking surgery will be able to receive it in the adjuvant and maintenance settings. It will also be done in the recurrent setting, both in the platinum-sensitive disease recurrence where patients can receive these drugs in combination with their first platinum doublet at the platinum-sensitive recurrence, and in combination with chemotherapy—usually a single-agent chemotherapy in a platinum-resistant setting.

What do you envision for the future of checkpoint inhibitors over the next five or 10 years in this landscape?

These studies are also incorporating the use of Avastin (bevacizumab). Some of these patients will receive four drugs including carboplatin, paclitaxel, bevacizumab and the immune checkpoint inhibitor, which in this case would be Tecentriq (atezolizumab). It is exciting because they are being used in the upfront setting. This is where the value of these drugs may come out to be the most beneficial since we have not increased the number of patients who we have cured of ovarian cancer in the past 20 or 30 years. Perhaps the value of using these drugs early can increase the number of patients who will never see their cancer come back.Based on the preliminary data that have already been published, it is likely that we will see an approval with at least two or three different agents as monotherapy in an advanced disease setting. Many of these drugs will start moving into the frontline setting in combination with the standard treatments, such as chemotherapy. Additionally, with the development of immunologic and genomic profiling techniques, we will hopefully be able to better understand the mechanisms that guide response or resistance to such agents. We will be able to know what is the best drug to combine a checkpoint inhibitor with for each patient.

In ovarian cancer, we know there are multiple mechanisms that drive resistance just within the tumor microenvironment, whether they are tumor-associated macrophages or regulatory T cells. Unfortunately, we don't have very good drugs to target these specific components of the tumor microenvironment or other inhibitor molecules.

Hopefully, we will within the next few years. That is going to create a lot of excitement for personalized clinical trials for patients. We’ll be able to target the specific components of the tumor microenvironment depending on what we see within the tumor.