Dmitriy Zamarin, MD, PhD
In advanced ovarian cancer, initial interest with immunotherapy focused on single-agent PD-1/PD-L1 blockade. Due to disappointing activity, however, investigators have turned to the use of combination strategies with chemotherapy, angiogenesis agents, and PARP inhibition with some success, explained Dmitriy Zamarin, MD, PhD.
“There has been an explosion of trials using immune checkpoint inhibitors, namely PD-1/PD-L1 inhibitors, in the upfront and recurrent settings in combination with chemotherapy, bevacizumab (Avastin), and PARP inhibitors,” said Zamarin. “It is likely that a combination of several drugs will be needed to achieve efficacy with immunotherapy in ovarian cancer.”
In 2018, the JAVELIN Ovarian 100 and JAVELIN Ovarian 200 trials reported negative findings with the combination of the PD-L1 inhibitor avelumab (Bavencio) and chemotherapy in patients with treatment-naïve and platinum-resistant/refractory ovarian cancer, respectively.1,2
In terms of PD-1 blockade, the combination of pembrolizumab (Keytruda), bevacizumab, and metronomic cyclophosphamide resulted in a 95% disease control rate and 40% overall response rate in women with recurrent ovarian cancer, according to phase II study results presented at the 2019 SGO Annual Meeting.3
Although these response rates may pale in comparison to those observed in other solid tumors, Zamarin explained that inter- and intratumor heterogeneity poses a unique challenge to the modality’s integration in ovarian cancer. As such, other strategies exploring vaccines and CTLA-4 inhibition are also underway.
In an interview during the 2019 OncLive®
State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Zamarin, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed ongoing research regarding immunotherapy and synergistic strategies also under investigation in advanced ovarian cancer.
OncLive®: What is the outlook for immunotherapy in advanced ovarian cancer?
: There have been several studies utilizing various immunotherapies, namely immune checkpoint inhibitors in newly diagnosed and advanced ovarian cancer. Most of the studies have been done primarily in patients with advanced platinum-resistant disease. The response rates we have seen so far have been rather disappointing. Initially, there was enthusiasm for these drugs, but to date the single agent PD-1/ PD-L1 inhibitors have shown response rates of approximately 9% to 10%. We still don't have a good biomarker of response.
Even if we do get the best possible biomarker, there will still be another 90% of patients who need better therapies. The most natural and readily available combination would be with chemotherapy. We already have very good data from trials in lung cancer demonstrating that the frontline combination of immunotherapy—specifically pembrolizumab with chemotherapy—can improve survival. Several studies are exploring this concept in ovarian cancer, both in the newly diagnosed and recurrent settings.
There have been some negative trials reported to date, such as the JAVELIN Ovarian 200 trial with the PD-L1 inhibitor avelumab and liposomal doxorubicin. Similarly, a combination of avelumab and carboplatin/paclitaxel in the frontline setting [in the JAVELIN Ovarian 100 trial] did not meet its primary endpoint. However, we're still awaiting the exact details from the trial.
This does not mean that immunotherapy does not work with chemotherapy. It may mean that we need other types of combinations with other types of chemotherapy.
What was the biggest takeaway from the negative trials that have been reported to date?
Unfortunately, these data are still too early [to say]. Most of the negative trials that have been reported to date have not been presented or published. We’re still awaiting these data. We’re hoping that even with the negative data, we'll be able to derive some biomarkers from these trials.
For example, does homologous recombination deficiency or BRCA
status predict better or worse response to immunotherapy? Or, is there an overall survival (OS) benefit despite there not being a benefit in PFS as we often see in these trials. That will be important to understand once we see what the data are.
Are antibody-drug conjugates (ADCs) a potential path forward?
This is an antibody that targets a specific receptor on the surface of a cell [that can deliver] the drug [to the malignant cell]. There have been some successful trials with ADCs, namely ADCs targeting the folate receptor. However, some of the later data that have been reported have not necessarily been very positive across the unselected patient population. However, patients with folate receptor expression were more likely to respond. These are the type of data we need in immunotherapy trials.