Refined Approach Required for Immunotherapy Success in Gynecologic Cancers

Dmitriy Zamarin, MD, PhD

Dmitriy Zamarin, MD, PhD

Immunotherapy with PD-1/PD-L1 inhibitors has been slower to develop in gynecologic cancers than in several other solid tumors.

Success with these agents in gynecologic cancers will require combination approaches, biomarker development, and identifying subpopulations who more likely to benefit, such as patients with microsatellite instability-high tumors, explains Dmitriy Zamarin, MD, PhD.

Onclive: What have been the findings so far with immunotherapy in gynecologic cancer?

In an interview with OncLive, Zamarin, a medical oncologist at Memorial Sloan Kettering Cancer Center who specializes in the care of women with gynecologic cancers, discusses previous findings and the next steps necessary to advance immunotherapy in the field.Zamarin: The immune checkpoint inhibitors, which have been the most promising in other cancers, have unfortunately not worked out as well in gynecologic malignancies. In the general population now of cervical cancer, ovarian cancer, or endometrial cancer, the preliminary reports that have been presented at meetings show the response rates seem to range from 10% to 15%.

It may also be another 10% to 15% of patients having disease stabilization, which is much lower than what has been seen in some other cancers like bladder cancer, lung cancer, and myeloma. These drugs are certainly very promising for the patients with gynecologic cancers, but I think we still need to identify the right kind of patients that could benefit from these drugs, and unfortunately, we don't have the right biomarkers yet.

The one exception to this is the use of the PD-1 inhibitors in patients with mismatch repair deficiency, such as endometrial cancer that is associated with Lynch syndrome. Even though there are only a few patients that have been reported who were treated with these drugs, their response rates are high, so far.

In a paper that was published in The New England Journal of Medicine last year, it was discussed that many of the patients that had high microsatellite instability-high cancers, including colorectal and endometrial cancers, seemed to have responded very well. I think that these drugs are certainly providing a lot of promise within this minor population.

Can you discuss the current state of biomarker development in gynecologic cancers?

For the rest of the patients, I think these drugs still hold promise and the response rate does mirror something that we see with single-agent chemotherapies in the later line settings, but it's not going to be the immunotherapeutic solution to gynecologic cancers. This is a problem that plagues not just gynecologic cancers but any cancer. Unlike the biomarkers for some of the targeted therapies, where presence of a specific mutation or overexpression of a certain protein can predict whether a patient would respond to certain drugs or not, I think we are understanding that the biomarkers for immunotherapies are likely going to be much more complex.

What are some, if any, notable combinations that have shown success?

How has the safety profile been with immunotherapy in gynecologic malignancies?

What should be the main focus now of immunotherapy research in gynecologic cancers?

It is not going to be a single “yes or no” entity that will define whether a patient will respond or not. There is some evidence of pre-existing immune response, meaning that the tumors are infiltrated by lymphocytes, and if the tumor expresses PD-L1, those patients may be more likely to respond to these drugs. However, the markers are not absolute. There may be some trends that can help better select for that patient population. But, we also know that patients that lack those specific markers can still have a clinical benefit from these drugs. We are not close yet.There is nothing that has been reported yet. However, as I've mentioned, we do have the data on the single-agent PD-1 and PD-L1 inhibitors, which provide some modest efficacies. There are several ongoing trials that are trying to enhance the efficacy by combining them with other drugs that we know could be effective in the gynecologic malignancies. We are also looking at combinations of drugs that might not have some efficacy by themselves but may work better when combined with PD-1 inhibitors. Regarding the immune checkpoint inhibitors, at least from what has been reported, it seems like the side-effect profile in gynecologic patients appears to be similar to what has been seen in other cancer types. We have not seen the reports yet of the combination studies using not just PD-1 and PD-L1 inhibitors, but combinations of CTLA-4 inhibitors and PD-1 inhibitors. It would be interesting to see what the side-effect profile of these combinations is like in the gynecologic patients, just because we know that CTLA-4 blockade in myeloma seems to be better tolerated than some of the other cancers, such as prostate cancer, where the tolerability was much lower. My personal interest with the gynecologic cancers is to come up with the right combinations. Right now, those are the combinations that are using a PD-1 or PD-L1 blockade as a backbone. The goal is to come up with the right combination to extend the benefit of the PD-1 and PD-L1 inhibitors to more patients, not just the 10% to 15% that we have seen so far. The question is what the combination is going to be.

Is there anything else you would like to add?

For me personally, I am still a strong believer in the vaccines but not the classical vaccine types that are targeted to a specific antigen. I am much more in favor of in situ vaccines, meaning using the patient’s own tumor to generate the antitumor immune response. An example of such a strategy would be something that is delivered directly to the tumor to generate tumor lysis and inflammatory response and combining that with systemic immune checkpoint blockades to make that antitumor immune response be active.Another important development is the CAR T-cell therapies. So far, those have been primarily explored by the hematologic malignancies and not as much for the solid tumors, but based on the preclinical models, there is no reason why these types of strategies would not work for the solid tumors. We do have an ongoing trial using a CAR T-cell therapy that is using CAR T cells in ovarian cancer patients that have been administered both intravenously and intraperitoneally. There is preclinical data that the delivery of the T cells directly to the tumor site can also lead to better antitumor immunity.