Expert Discusses Promise of Checkpoint Inhibitors in Ovarian Cancer

Jonathan Ledermann MD, FRCP

Checkpoint inhibitors are charging ahead in the race toward immunotherapy in the treatment of patients with ovarian cancer. Although studies are still in their early days, there seems to be emerging promise, said Jonathan Ledermann, MD.

One such study is JAVELIN Ovarian 200, a study of avelumab (Bavencio) alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer. This phase III global study is currently ongoing (NCT02580058).

Additionally, checkpoint inhibitors in combination with PARP inhibitors are garnering interest, with the impact of PARP inhibitors already well established in this tumor type.

OncLive: What is the status of immunotherapy in the treatment of patients with ovarian cancer?

In an interview with OncLive during the 2017 ESGO Congress, Ledermann, professor of medical oncology, UCL Cancer Institute, London, United Kingdom, discussed the promise of immunotherapy in ovarian cancer and emphasized the importance of participation in clinical trials.Ledermann: To summarize, there are now single-agent studies with 4 of the checkpoint inhibitors that have been tested in ovarian cancer. At the moment, we are still at a very early stage in understanding the data. Only 1 of those [trials] has been published; the others have been presented.

One of the reasons that the results are slow coming forward is because we do need to follow these patients for a period of time. No longer can you use surrogate markers such as tumor response to give us an indication that these drugs are active—actually, the response rates are not that high. Therefore, we have to look at the length of disease control, progression free-survival, and perhaps even overall survival to get a feeling of whether these agents will be helpful for these patients. That is why we don't have those data yet.

Having said that, the next wave of trials is well underway and some have already completed. One is combining chemotherapy and/or bevacizumab (Avastin) with checkpoint inhibitors. Now, there are some scientific theoretical and circumstantial evidence to suggest that either chemotherapy, bevacizumab, or both, benefit the activation of the immune system. After all, this is what these drugs are doing—activating the host’s immune system. If you can improve the immune environment in the tumor, you may help the activation of the immune system. That is what the rationale is of adding cytotoxic drugs or bevacizumab to the milieu. However, of course, it is a big undertaking, and an expensive undertaking. Yet, there are a number of trials combining those agents with checkpoint inhibitors.

Is it too early to tell if either PARP inhibitors or chemotherapy will be more effective combined with immunotherapy?

There is also some early work going on with combining checkpoint inhibitors with other molecularly targeted therapies, particularly PARP inhibitors. There are some data to suggest that the combination of PARP inhibitors and checkpoint inhibitors will enhance the antigen expression and the immune activation. Therefore, those phase I/II trials are ongoing. People are now talking about launching larger randomized trials, which is interesting considering we haven't seen some of the early data yet. That just shows the interest and the head of steam that checkpoint inhibitors have in ovarian cancer. It is too early to tell. However, the first combination with chemotherapy, the JAVELIN Ovarian 200 study, has finished recruitment. We are very eager to hear those data, but that will be probably another 9 to 12 months. That will be the first point in this combination with chemotherapy.

What would your advice be on approaching immunotherapy in ovarian cancer with such little data?

Combinations with other drugs, such as bevacizumab or PARP inhibitors, are way behind. Although some randomized trials have started, it is going to be a long time before we know the activity of those drugs. My advice would unequivocally be to enroll patients in clinical trials. We should not be dabbling around and giving immunotherapy to everyone when we really don't understand which drugs are active in which patients. For example, we know very little about the predictive factors for response. It is important that, as clinical academics, we encourage the industry to study what is happening in the tumors within the immune environment. How is it changing with these drugs, especially with chemotherapy? What is changing when you add bevacizumab?

We must understand what it is that make some patients benefit quite well and others not at all. This could be simple things, such as measuring PD-1 and PD-L1. Is it an oversimplification? It certainly could be in the field of ovarian cancer, but possibly other cancers, as well.

What I would say to oncologists in the community would be to try to get your patients into a clinical trial so that they can be studied in an environment where they can gain information as they gain benefit from the treatment.