Oliver Dorigo, MD, PhD
There are more than 1000 investigational immunotherapy combinations being explored in the ovarian cancer space; of these agents, ones with PARP inhibitors have shown notable activity, explained Oliver Dorigo, MD, PhD.
In the phase I/II TOPACIO/KEYNOTE-162 study, patients with recurrent ovarian cancer were treated with the combination of niraparib (Zejula) and pembrolizumab (Keytruda). The overall response rate (ORR) was 25% among 60 patients who were eligible for evaluation. Of those who harbored BRCA
mutations (n = 12), the ORR was 42%.
Niraparib is currently approved by the FDA as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
“The therapies we have now are well designed. Our knowledge of the biology and immunology of ovarian cancer has greatly increased,” said Dorigo. “Therefore, I believe that given the activity we have seen in clinical trials and given what we can do in the laboratory to test the tumor for immune infiltrating cells, we will finally come up with a predictive [assay] that is meaningful for patients. It is only a matter of time until we have an answer.”
In an interview during the 2018 OncLive®
State of the Science Summit™ on Ovarian Cancer, Dorigo, an associate professor of Obstetrics and Gynecology at Stanford University Medical Center, Stanford Medicine, discussed the promise of immunotherapy in ovarian cancer.
OncLive: Where does immunotherapy stand in ovarian cancer?
: Immunotherapy is being investigated in many clinical trials and has already shown some very promising efficacy in certain patients. Immunotherapy in ovarian cancer is not a new concept. We have been pursuing this for many decades now. Early trials have shown that tumor-infiltrating lymphocytes or white blood cells that are extracted from a patient's tumor, expanded in cell culture in the laboratory, and then reinfused into the patient, can have some very significant antitumor activities.
This type of cell therapy is now being modified genetically, so that we can make T cells that are better able to recognize the cancer cells and remain active in an otherwise immunosuppressive microenvironment. By using checkpoint inhibitors as single agents, we’ve observed response rates between 10% and 15%. Up to 35% of patients have benefited from these types of approaches with stable disease and have done very well, overall.
We need to further increase the efficacy of these types of therapies by modifying our approaches. For example, we can potentially combine checkpoint inhibitors with other drugs. Promising early efficacy has been generated by combining checkpoint inhibitors with PARP inhibitors. We have seen that patients without BRCA
mutations can have very significant antitumor responses. We have to learn much more about what patients are good candidates for immunotherapy. We have certain ideas on what we could potentially use as a predictor for immune therapy in the tumor and in the blood, but these studies need to be extended to more patients.
What immunotherapy and PARP combinations are being investigated?
The combination of PARP inhibitors and immunotherapy has shown very promising clinical efficacy. In the phase I/II TOPACIO trial, for example, niraparib was combined with pembrolizumab. Results showed that platinum-resistant patients have about a 25% response rate. What is more interesting is the fact that the response does not seem to depend on a molecular signature as one might assume when using PARP inhibitors. PARP inhibitors usually work best as single agents in patients who have germline or somatic BRCA
mutations. In the first phase of the trial, patients responded regardless of whether they had these mutations or not.
In terms of synergistic effects, does a certain combination stand out?
There are about 1000-plus combination trials with immune checkpoint inhibition. Those treatment modalities vary from additional immunotherapies, to chemotherapy, to radiation, to antiangiogenic therapies. It is too early to tell which one of these combinations will have the best efficacy and in what kind of patients. Given the number of various trials going on, we will probably have a much better understanding of what therapy will work the best in the very near future.
Are there clinical trials enrolling specific subsets of patients with ovarian cancer?
At this point, we're enrolling a wide range of patients with ovarian cancer. We’re not necessarily targeting a certain subpopulation. We do know that those patients who have germline BRCA
mutations have a tumor microenvironment that might be more conducive to generate more antitumor effects. We also know that tumors that are heavily infiltrated with lymphocytes are likely more responsive to immunotherapy. Third, we have seen that tumors with a high level of neoantigen expression seem to respond better to immunotherapy. In the future, we're going to have to carefully think about how to combine these types of scores and potentially find other predictors.
What is your outlook on the use of immunotherapy in the ovarian cancer space?
There is a lot of promise in immunotherapy, but we still need to overcome a lot of obstacles. We need to understand which patients are best suited for immunotherapy. We also need to find the best approaches for immunotherapy. It's exciting to see how many different approaches are now being investigated. On the other hand, it's exciting to see how many of those patients with ovarian cancer are willing to participate in clinical trials. Knowledge is not only generated in the laboratory. We need to enroll patients in clinical trials and those volunteers are really who we have to be very thankful for.
Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/KEYNOTE-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort. J Clin Oncol. 2018;36(suppl; abstr 106). doi: 10.1200/JCO.2018.36.15_suppl.106.