Immunotherapy Combo Strategies Are Major Research Focus in Ovarian Cancer

Brian Orr, MD

Exploring checkpoint inhibitors in combination with PARP inhibitors, other immunotherapies, and chemotherapy are all novel tactics that could demonstrate improved activity versus single-agent immunotherapy, explained Brian Orr, MD.

For example, in the single-arm, open-label, phase I/II TOPACIO/KEYNOTE-162 trial, investigators evaluated the combination of niraparib (Zejula) and pembrolizumab (Keytruda) in patients with recurrent ovarian cancer or those with advanced or metastatic triple-negative breast cancer. Results of evaluable patients in the ovarian cancer cohort (n = 60) showed that the overall response rate (ORR) was 18% (90% CI, 11%-29%) and the disease control rate was 65% (90% CI, 54%-75%).

Beyond checkpoint inhibitors, he added, other immunotherapeutic approaches under investigation include tumor-infiltrating lymphocytes (TILs) therapy, CAR T-cell therapy, and dendritic cell vaccines.

“The next year is going to be exciting, and hopefully can inform some of these unanswered questions of how to use checkpoint inhibitor combinations; this is just the beginning of immunotherapy,” said Orr, an assistant professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at University of Pittsburgh Medical Center. “The TIL therapy, CAR T-cell therapy, and potential vaccines are all very exciting and promising, but we have yet to know if they are actually going to be active.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Orr discussed the challenges with immunotherapy in ovarian cancer treatment while pointing to early promising data with combination regimens.

OncLive: How would you define the current progress with immunotherapy in advanced ovarian cancer?

Orr: We do know that immunotherapy monotherapy has not had some of the success that we have seen it have in other tumor types. Therefore, how can we improve the immunotherapeutic response in ovarian cancer? We are looking at multiple types of combinations: PARP inhibitors plus immunotherapy, dual checkpoint blockade, and immunotherapy/chemotherapy combinations.

There is a lot of work to be done; I am excited about its potential. In the recurrent setting, [we had] results from TOPACIO/KEYNOTE-162, which showed that by combining PARP inhibitors and immunotherapy, we are seeing a much higher response rate than immunotherapy alone. It does beg the question of, “When do we use it?” The timing and in what combination [are also questions we have]. That is definitely something we need to sort out. Part of that is: where do PARP inhibitors lie in the landscape of ovarian cancer? Once we identify how PARP inhibitors are best utilized, then incorporating the PARP/immunotherapy [combination] component is next.

There is a lot of work; there are not just PARP inhibitor/immunotherapy combinations, but others include immunomodulators, CAR T cells, TILs, and dendritic cell vaccines. All of these are things that are in the much earlier stages but are exciting.

What other key trials have been conducted in this space?

It was important to test [immunotherapy] as a monotherapy and, earlier this year, the final publication data from KEYNOTE-100 came out. This showed that for monotherapy, it confirmed lower response rates as a single agent. TOPACIO/KEYNOTE-162 came out showing a much higher ORR of 18%. The majority of [these types of trials] are ongoing now, so the other combinations that we really would like to see the results of, that will inform us when and how to use combination therapy, won’t be out until next year.

Additional combinations are dual checkpoint blockade therapy, so [PD-1/PD-L1] and CTLA-4. With those combinations, we also see higher rates not just in ovarian cancer but in other tumors as well. It has to be balanced with toxicity, but it is also something that needs further testing.

There were some negative trials in this space as well. What are the key takeaways from those?

It is always important to report a negative trial. From the JAVELIN Ovarian 100 and JAVELIN Ovarian 200 studies, it’s important to know that immunotherapy may not have a role in those spaces. It is not clear where immunotherapy settles out in the frontline setting, and as a monotherapy it may not be appropriate there. If we are going to test it in the frontline setting, it probably should be in the combination form.

In the JAVELIN Ovarian 200 trial, where avelumab (Bavencio) was combined with liposomal doxorubicin, [those data] were also helpful. [Liposomal doxorubicin is part of] one of our go-to combinations in the platinum-recurrent setting; it is usually liposomal doxorubicin and something else—[it could be] bevacizumab (Avastin) or several other agents. However, to know that it didn’t offer as much benefit as we had hoped for is important.

Moving onto priming strategies, what is being explored to induce immune response?

There is a lot of depth to this “ocean” of unknown knowledge when it comes to immunotherapy. What is the role of not just checkpoint inhibition? There are a lot of factors that come into play. How do we identify the ones that are going to be most useful? Whether you are stimulating the immune system by using vaccine-based peptides, CAR T cells, TILs, or dendritic cell vaccines, there is a lot of ongoing research that is investigating this from a translational perspective in small studies, which will hopefully be ready for larger scale trials. Perhaps those are the steps that are necessary to improve immunotherapy in ovarian cancer.

Could you highlight the work being done with vaccines?

There are multiple different types [of vaccines]. If you have it based on a specific mutation, such as the NY-ESO-1 vaccine as well as any other common neoantigen that we can use to target the host immune system, it is definitely a theoretically exciting opportunity. It is not always translated as well in real life, but that continues to be an area of research that if we can improve, it could be very important.

What biomarker research is being conducted in this space?

Biomarkers are essential. Every clinical trial should [include] comprehensive testing from the tumor and blood work to identify the signals that [demonstrate whether] someone is going to respond or not. In some tumors, such as lung cancer, it is clear that PD-L1 is a good biomarker.

In the less immunogenic tumors, such as ovarian cancer, it is not clear whether [PD-L1 expression] is going to tell me who will respond or not. In prospective trials, it is absolutely imperative that we collect tissue and blood and find this out in post-study, translational research. I hope we are able to find a biomarker or a companion diagnostic that will tell us who will respond to immunotherapy.

Why are there challenges in identifying these biomarkers?

It is complicated with ovarian cancer with the tumor heterogeneity. Having a single biopsy to determine candidacy for immunotherapy is less fruitful than something that is more of a homogenous immunogenic tumor. Then, if you’re on a clinical trial and [the patient is] in the recurrent setting, obtaining tissue is not easy; it involves a biopsy. The ideal scenario is a pre-and posttreatment biopsy, and obtaining a posttreatment biopsy is very challenging.

Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5(8):1141-1149. doi: 10.1001/jamaoncol.2019.1048.