Immunotherapy Combinations Slated to Pave the Way in Ovarian Cancer Treatment

Kathleen N. Moore, MD

Ongoing clinical trials are in the midst of exploring the greater role of immunotherapy agents in patients with ovarian cancer who do not have microsatellite-instability high (MSI-H) tumors, according to Kathleen Moore, MD, who adds that such research could eventually determine the role of this class of drugs in the paradigm.

To date, immunotherapy has not had a defined role in ovarian cancer, outside of the 2% of patients with MSI-H disease. However, immunotherapy is currently being studied in combinations with VEGF inhibitors, PARP inhibitors, and other immunotherapy agents.

For example, preliminary findings of the phase I TOPACIO/KEYNOTE-162 trial demonstrated that the combination of niraparib (Zejula) and pembrolizumab (Keytruda) has early signs of efficacy in patients with platinum-resistant recurrent ovarian cancer or metastatic triple-negative breast cancer (TNBC). Out of 8 evaluable patients with ovarian cancer, 4 patients responded and the remainder had stable disease.

“Patients with BRCA mutations who respond to PARP inhibitors experience an increase in the neoantigen load, which makes bringing in an immune checkpoint inhibitor an efficacious option for these patients,” explains Moore.

OncLive: What is the current role of immunotherapy in ovarian cancer?

Are there trials in development for immunotherapy in patients without MSI-H tumors?

In an interview with OncLive at the 2018 Society of Gynecologic Oncology Annual Winter Meeting, Moore, assistant professor in the section of gynecologic oncology and director of the Oklahoma TSET Phase I Clinical Trials Program at Stephenson Cancer Center of the University of Oklahoma, discussed combination strategies with immunotherapy for patients with ovarian cancer.Moore: Immunotherapy is very exciting. There are not yet any indications in gynecologic cancers except for those who have MSI-H tumors, which we have seen in 2% of ovarian cancers but is more applicable to endometrial cancers. Currently, there is not an ovarian cancer indication for immunotherapy but there is ongoing clinical research.For both endometrial and ovarian cancers, most patients do not have MSI-H tumors. The question is whether there is a role for immunotherapy in their care. I hope the answer is “yes.” There have been a few small trials of single-agent immunotherapy, mainly monoclonal antibodies targeting either PD-1 or PD-L1, but there are other checkpoint inhibitors that are under development. Currently, those studies have been done with PD-1/PD-L1 inhibitors across a number of agents.

The response rates have been from 11% to 25% across the studies, with some variants in eligibility. They are all within the same range. Those patients who responded in those studies tend to have durable responses, which is the ideal scenario. We want a patient's tumor to shrink but also gain that benefit for many months—not just 2 months.

We all agree that the signals are modest. Those patients were mostly unselected. One of the studies tried to select for PD-L1 expression on the tumor, but it did not seem to identify a group of patients who did better than unselected patients.

What is the rationale behind combinations of immunotherapy and VEGF inhibitors?

There is a signal. It is most likely that the efficacy for this class of agents in ovarian cancer without MSI-H tumors will be in combinations. There is a lot of basic science and translational science that supports these combinations. It is good that we are following the science in developing these combinations, rather than just adding things together and hoping they work.

There are several combinations that are of interest across all solid tumors, including ovarian cancer. Those include combinations of immune agents with antiangiogenic agents, combinations of immune agents with PARP inhibition or other DNA-damaged response inhibitors, combinations with cytotoxic chemotherapy, and combinations with other immune agents. Trying to capitalize on different aspects of our immune system is the rationale behind immunotherapy combinations.

Can you discuss the efficacy of combining immunotherapy with PARP inhibitors?

We know that VEGF is a proangiogenic molecule, but it is a very immuno-suppressive molecule in a number of ways. It directly and indirectly inhibits the immune response to cancer. Combining something that targets VEGF helps from an antiangiogenic standpoint, which is important for ovarian cancer with drugs such as bevacizumab (Avastin) and cediranib. It also shifts the immune milieu in the tumor microenvironment to be more favorable. It makes sense to come in with a drug, such as an anti—PD-1/PD-L1 agent, which hopefully prevents the tumor from evading the immune response, but there are other combinations that would make sense as well.We have evidence for combining PARP inhibition with immune agents in patients with BRCA mutations. In ovarian cancer, we have a lot of inherent DNA-damaged response abnormalities that result in many mutations that could be neoantigens.

Are there any other immunotherapy combination strategies showing promise?

We already have evidence of that in the clinic. There are many ongoing trials, but an example would be the TOPACIO/KEYNOTE-162 trial, which was with niraparib plus pembrolizumab in TNBC and ovarian cancer in BRCA wild-type and BRCA-mutated patients. That has been presented in abstract form thus far, but has shown efficacy. We already see planned studies in frontline ovarian cancer looking at combinations of PARP inhibitors and immunotherapy. Those studies are being planned and about to launch. Chemotherapy is similar to PARP inhibition. When you give chemotherapy, you cause a release of neoantigens. There is preclinical evidence that when you give taxanes and carboplatin, you increase the CD8-positive cells, which are the important ones for the immune response. We have evidence of that already in models. It makes sense to use immunotherapies with chemotherapy.

A great example of that in frontline ovarian cancer is the JAVELIN Ovarian 100 study, which combined standard chemotherapy with avelumab (Bavencio) or alone and then added maintenance therapy. That study has completed accrual and should be reporting out in the next year or so for the progression-free survival endpoint. Those 3 combinations, which have a lot of preclinical and recurrent clinical data, have quickly jumped into frontline ovarian cancer, which some may question.

Additionally, there is a study of ipilimumab (Yervoy) and nivolumab (Opdivo). That study is completed but we have not seen the results yet. We have one [phase II] study that has been completed with combination immunotherapies. There is another trial that was completed investigating a PD-1 inhibitor with a BTK inhibitor, which is a different way to target the immune system. That study is completed, and we are waiting for results on that as well.

What are some of the most prominent challenges with regard to immunotherapy in ovarian cancer?

It is an exciting time to see which of these combinations will benefit our patients and move our survival curve forward. In general, immunotherapy is well tolerated. However, there are significant toxicities that occur that providers need to be mindful of because the responses to them are different than other agents. There are ongoing studies with immune checkpoint inhibitors, so the education is out there and we are meeting that safety bar now. That is the same with any new agent. It is important to manage the safety for our patients, which is true across all solid tumors.

The biggest challenge is identifying whether this a class of drugs that belongs in our treatment paradigm. I hope the answer is “yes,” since there are many options for targeting the immune system. We are using PD-1/PD-L1 and CTLA-4 inhibitors, but there is a pipeline of agents that are different checkpoint modulators. Even different ways to target different parts of the immune system are important. It may be that checkpoint inhibitors aren't the way that we should be targeting ovarian cancer for immune response, but there could be other effective ways to do it.

Can we target the immune system to improve survival in ovarian cancer? What are the best combinations and when should we use them? When do you get the best benefit for patients? We just don't know yet, but there are many studies that are open and the accrual to them has been tremendous. Our patients want these therapies; they are interested in immune therapy. They have seen the efficacy in other tumors. There is a tidal wave of enthusiasm, so we are going to have good data in the next few years. We will define the role and the line of immunotherapy.

Konstantinopoulos PA, Sachdev JC, Schwartzberg L, et al. Dose-finding combination study of niraparib and pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC) (TOPACIO/KEYNOTE-162). Ann Oncol. 2017;28(suppl 5). doi: 10.1093/annonc/mdx376.009.

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