Work Remains With Immunotherapy in Ovarian Cancer

Daphne B. Stewart, MD

Although the utility of immunotherapy is limited to a small percentage of patients with advanced epithelial ovarian cancer, research continues to define these responders in the hopes of providing them with durable responses and potential remissions, explained Daphne B. Stewart, MD.

“The CTLA-4 inhibitors do not have a whole lot of clinical trial evidence to support their use at this point, perhaps in combination,” said Stewart. “The more important inhibitors are the PD-1 and PD-L1 inhibitors, for which there are many clinical trials that are currently enrolling.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Stewart, an associate clinical professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discussed the progress that has been made with immunotherapy in ovarian cancer, provided insight into the focus on combination therapy with checkpoint inhibitors, and explained the impact of negative trials on the field.

OncLive: Could you discuss the progress that has been made with immunotherapy in ovarian cancer?

Stewart: [In my presentation, I] spoke about the impact of immunotherapy in the treatment of patients with advanced epithelial ovarian cancer, specifically discussing the tumor microenvironment and the reasons why immunotherapy ought to be a paradigm shift change in the management of ovarian cancer. I introduced the number of trials that have shown responses, some of which have been impressive and durable. I concluded by speaking about future directions and remaining questions.

Could you speak to the potential of dendritic cell-based immunotherapy?

Tumor vaccines, which have to do with dendritic cell-based therapies, have been very interesting and certainly show a lot of promise. However, at this point, instead of going the vaccine route, we have been predominantly using checkpoint inhibitors, which simply turn a silencing signal sent by the tumor microenvironment off so that the immune cells can wake up again. As long as the immune cells have access to tumors, the switch that goes off that is mediated by T cells can lead to tumor cell [death].

Given the low response rates that have been observed with checkpoint inhibitors, why is research so heavily vested in them?

Although the responses are very low, they are very durable. The patients who are lucky enough to have a response tend to respond for a long time and their survival seems to be improved. We can try to extrapolate from other tumor models, but it's a little difficult because the types of tumors and the responses to therapy are different for a variety of reasons. Secondly, they are very well tolerated. Therefore, although there are adverse events (AEs), the AEs are quite distinct from standard chemotherapy. That makes us interested as another venue. Certainly, the question of combining therapies is very attractive, as we want to see whether we can achieve a greater response rate as well as more durable responses [with that approach]. That’s the future.

Among those responders, is there a unique signature that may be helpful in predicting response?

There is no unique signature that has been [determined to be] reliable. There are many interesting markers, but they do not seem to pan out. [A patient's age or performance status] does not predict response either, unfortunately. We were expecting that certain tumor histologies would be nonresponders, and, in fact, that's not true either.

For example, in ovarian clear-cell carcinoma, there are some miracle responses that seem very inspiring, and certainly indicate that patients should at least have the opportunity to be exposed to these therapies.

Are there any ongoing clinical trials that are of particular interest to you?

The trials that are combining PARP inhibitors alongside checkpoint inhibitors seem to have a response rate in the range of 25% to 30% in patients who you would not expect to respond. Again, this is opening a window for patients who do not have deliberate markers to indicate response to one or the other, showing that they may do very well with combination [immunotherapy].

Is immunotherapy being tested across all lines of therapy?

[This approach is] being looked at as maintenance therapy in patients who have had frontline chemotherapy [in an attempt to] maintain their degree of remission. It is also being looked at in more advanced disease.

Could you discuss some of the negative trials that have read out? What are the main takeaways from this research?

Unfortunately, there are several trials that have discontinued enrollment very recently as a result of no real signal of efficacy. It’s disappointing, but it just means we have to work harder. We need to better identify patients and make more thoughtful combinations and sequencing.

The main takeaway is that this is truly investigational. Exposing patients to single-agent checkpoint inhibitor therapy is associated with a very low likelihood of response. We have a lot of work to do before we will be able to offer patients really promising opportunities.

Are patients asking about the potential of immunotherapy?

I would say 95% of patients who come into clinic are asking about immunotherapy. I am not opposed to it; I just wish I could understand when the ideal time to use it is, based on studies. Furthermore, in old trials, investigators were looking at whether there were patients who were very late responders. This meant that patients were left on therapy for a long time before a response was ruled out.

With more experience, we are understanding that that's probably not the case. Several cycles or 2 to 3 months of therapy with disease progression is an ample amount of time. In other tumor subtypes, it's interesting that nonresponders have survival benefits. We have seen this in the breast cancer population. Who knows what will happen with patients with longer follow-up and as more patients are enrolled in pivotal trials.