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.
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.
OncLive: Where are we with immunotherapy in ovarian cancer?
: 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.
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.
Have there been any recent trials that are of interest?
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.