Capitalizing on Integrative Immunotherapy in Ovarian Cancer

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.

OncLive^®: What is the outlook for immunotherapy in advanced ovarian cancer?

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.Zamarin: 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.

What was the biggest takeaway from the negative trials that have been reported to date?

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.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.

Are antibody-drug conjugates (ADCs) a potential path forward?

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.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.

Are priming strategies also being explored?

When I discussed immunotherapy, I primarily focused on PD-1/PD-L1 inhibitors, but there are other drugs as well. The first immunotherapy drug that was approved by the FDA for melanoma was a CTLA-4 inhibitor. There was one positive trial that was reported in ovarian cancer combining CTLA-4 blockade and PD-1 blockade with ipilimumab (Yervoy) and nivolumab (Opdivo). This was the NRG-GY003 trial, which was a randomized study of nivolumab alone versus the combination. The response rates were significantly higher and therein met the primary endpoint of the trial. There was an over 30% response rate with the combination as opposed to 12% with nivolumab alone. There was a statistically significant PFS benefit, as well. It is certainly an active combination. There is definitely rationale to explore this combination further, either alone or in combination with other agents.With priming, we’re looking at what we can do to induce an immune response. Traditionally, we thought of priming with vaccines. For example, administering an antigen and hoping the patient would develop an immune response that would cross-react with their tumor. There are a variety of strategies that have been explored in gynecologic cancers, starting with peptide vaccines or whole proteins vaccines, primarily targeting antigens that are known to be overexpressed in ovarian cancer such as NY-ESO-1. As single agents, these have not been effective. The question always comes up of whether combining these vaccines with immune checkpoint inhibitors would be effective, as has been shown in many preclinical studies.

How far away are we from an immunotherapy approval in ovarian cancer?

Is there ongoing work with biomarkers?

What class of immunotherapy holds the most promise?

What is the biggest takeaway with regard to immunotherapy?

There are several ongoing studies that have been initiated to try to address this question in the advanced setting, and occasionally in patients with minimal or no residual disease after completing upfront chemotherapy, or chemotherapy in the recurrent setting. It is certainly a very valuable strategy. In terms of what the best vaccine is, we still don’t know. Hopefully, with the emergence of some of the newer vaccination strategies such as neoantigen-based vaccines, we'll be able to see some efficacy.I'm not aware of any companies that have submitted information to the FDA for approval. The largest study that has been reported to date has been the KEYNOTE-100 study with pembrolizumab. The study enrolled over 300 patients. In the unselected patient population, the response rate was approximately 9% to 10%. We'll probably need combination studies to be done to show greater success than what we’ve seen with single-agent studies.We still don't have biomarkers that could predict which patients would respond to [an immunotherapy] approach and which patients would not. We also know that ovarian cancer might not be like other cancers, namely because ovarian cancers have a very significant inter- and intra- tumor microenvironment and molecular heterogeneity. If we know that a “hot” microenvironment is more likely to respond, but we have a patient with 3 or 4 different types of coexisting microenvironments, it is very hard to develop a treatment strategy for these patients. Addressing the issue of this tumor microenvironment heterogeneity will become important and may be addressed with appropriate combination strategies.Right now, we have sufficient evidence that PD-1 blockade can work in ovarian cancer and that PD-1 with CTLA-4 blockade can work even better. We need to learn how to deliver this combination therapy effectively, but it's not the answer to every patient. I would probably explore a combination of PD-1 and CTLA-4 blockade with something else.Immunotherapy still has a long way to go in ovarian cancer. The drugs do work for some patients. Even without improving PFS, the response rates across trials appear to improve OS. We're still trying to understand that. I always encourage my colleagues to encourage their patients to participate in these trials. Even without the obvious benefit, there may be a benefit for these patients in the future from mechanisms of tumor biology that we might not fully understand yet.

References

1. Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on JAVELIN Ovarian 100 Trial of Avelumab in Previously Untreated Advanced Ovarian Cancer. Merck KGaA and Pfizer. Published December 21, 2018. https://bit.ly/2ROhEcZ. Accessed December 21, 2018.
2. Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on Avelumab in Platinum-Resistant/Refractory Ovarian Cancer. Merck KGaA and Pfizer. Published November 19, 2018. https://bit.ly/2PGGzPB. Accessed November 19, 2018.
3. Zsiros E, Frederick PJ, Akers SN, et al. A phase II trial of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Presented at: 2019 SGO Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract LBA4.