Future of Immunotherapy in Ovarian Cancer to Include Combinations

Bradley J. Monk, MD

Prior studies of single-agent immunotherapy with checkpoint inhibitors have generally failed to show benefit in patients with ovarian cancer. This has not deterred investigators though, as there are currently 5 phase III clinical trials evaluating checkpoint blockade in combination regimens.

Although there are currently no FDA-approved immunotherapeutic agents in this space, combinations with immunotherapy and VEGF inhibitors, as well as with chemotherapy, may provide an avenue to approval, experts say.

OncLive: Where are we with immunotherapy in ovarian cancer?

In an interview with OncLive, Bradley J. Monk, MD, professor, director of the Division of Gynecologic Oncology at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, discussed these pivotal trials, as well as the potential for immunotherapy in ovarian cancer.Monk: We are all aware of the emerging immuno-oncology data across all solid tumors, and even Hodgkin lymphoma. There are currently no FDA-approved immunotherapy agents in gynecologic cancers, except microsatellite instability-high or mismatch-repair deficient endometrial cancers.

Have there been any recent trials that are of interest?

Ovarian cancer is a highly unmet medical need; most cases are diagnosed in advanced stages, and most cases recur. We need agents such as immuno-oncology agents to help patients live better and longer.We currently have 5 checkpoint inhibitors—PD-1/PD-L1 agents—and a CTLA-4 agent. All of these have been studied in ovarian cancer, but only in phase Ib expansion trials or very small phase II trials. Specifically, nivolumab (Opdivo), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi), and atezolizumab (Tecentriq). I am sorry to say that the single-agent activity of these PD-1/PD-L1 molecules is only between 10% to 15%. As such, we have been unable to gain accelerated approval as has been done in some other tumors.

Therefore, we are now studying combinations. The idea is to enhance the activity of these checkpoint inhibitors—converting what we call cold tumors to hot tumors, and there are 2 strategies. The first is to add immunogenic chemotherapy and an anthracycline, such as pegylated liposomal doxorubicin, or carboplatin/paclitaxel.

The other strategy is adding a PARP inhibitor. It may be that the homologous recombination repair deficiency, which is a predictive biomarker of PARP sensitivity, may also be a predictive biomarker for checkpoint sensitivity. This is because these cells that have damaged DNA-repair [enzymes] probably have more neoantigens, possibly more tumor-infiltrating lymphocytes, and might be more active. Single-agent checkpoint inhibitors are not very active, but maybe with chemotherapy they could be more active—sort of like what has been done in lung cancer. [It could be the same with] PARP inhibitors in combination with checkpoint inhibitors; those are our 2 most exciting strategies.

We currently have 5 randomized phase III trials adding checkpoint inhibitors to chemotherapy in ovarian cancer; 2 are with avelumab and 3 are with atezolizumab.

The avelumab program is further ahead. The first trial is called JAVELIN Ovarian 200 in patients with platinum-resistant, recurrent ovarian cancer. That study has already enrolled 550 patients, and that will be the first randomized trial to report; those results are eagerly awaited. The second trial is JAVELIN Ovarian 100, which is a frontline trial unlike JAVELIN Ovarian 200 that adds pegylated liposomal doxorubicin; this trial adds carboplatin and paclitaxel. This study is enrolling 950 patients and will also complete enrollment in the next few months. Both of these strategies test the hypothesis that adding avelumab, or a checkpoint inhibitor, to chemotherapy could induce immunogenic cell death.

Are there any safety issues with these combinations?

Could an oncolytic vaccine, similar to what we have available in melanoma, have potential in ovarian cancer?

What challenges still exist with immunotherapy in ovarian cancer?

The other 3 trials with atezolizumab involve adding chemotherapy and bevacizumab (Avastin) to atezolizumab. This regimen is chemotherapy, anti-VEGF therapy, plus a checkpoint inhibitor. We have 3 global indications in ovarian cancer for bevacizumab. The idea with bevacizumab is to add to those 3 opportunities: frontline, platinum-resistant, and platinum-sensitive settings. It is a very exciting time, and very ambitious.We have seen no safety contraindications; both PARP inhibitors and checkpoint inhibitors can generally be given at full dose. Again, these are in very early stages and need to be confirmed. Similarly, full-dose chemotherapy and checkpoint inhibitors can also be combined, but it is really the efficacy that we need to focus on.Another option would be to increase the mutational burden through the introduction of neoantigens. One strategy might be to use a vector—perhaps listeria—which could package neoantigens; that is certainly being tried by at least 2 pharmaceutical companies. There are a number of ways to deliver antigens to improve the efficacy of checkpoint inhibitors. The challenge in ovarian cancer with immuno-oncology has been that the number of tumor-infiltrating lymphocytes is relatively low, at 50%, and the number of cells that express PD-L1 are relatively low, as well. Importantly, the mutational burden or neoantigen levels are low. We haven't had the single-agent activity that we have seen in other tumors, where we have had accelerated approval from a single-arm trial with a high overall response rate, acceptable toxicity, and responses that are durable. We have had to do slow and expensive randomized phase III trials. It is exciting, but it will only be personally satisfying if we can bring these medicines to patients and prove that they are both efficacious and safe.

Although we don't have checkpoint inhibitors that are FDA approved yet, we certainly have 3 PARP inhibitors and, depending on what part of the world you live in, 2 or 3 bevacizumab indications. Therefore, we have immunotherapy, VEGF-targeted therapy, and PARP inhibition. The challenge is, do we combine all 3 together? Or just 2? If so, which 2 and in what sequence? That is going to fill our plate regarding research for the next 5 to 10 years.