Two Immunotherapy Combinations Show Promise in Glioblastoma

Sumanta Kumar Pal, MD

David Reardon, MD

The combinations of nivolumab (Opdivo) plus ipilimumab (Yervoy) and pembrolizumab (Keytruda) plus bevacizumab (Avastin ), both show promising efficacy in recent trials, possibly paving the way toward a new era of treatment for patients with glioblastoma.

In an interview with Targeted Oncology, David Reardon, MD, Clinical Director, Center for Neuro-Oncology, Physician, Dana-Farber Cancer Institute, discusses the safety profiles and efficacy of the two immunotherapy combinations, as well as future research into immune correlative biomarker assays, which may become increasingly important, he says.

TARGETED ONCOLOGY:Can you tell us about the recent data reported from the two studies looking at immune checkpoint inhibitors in glioblastoma?  

Reardon:

For the first time, we have some of the maturing data from the initial studies looking at immune checkpoint inhibitors for brain cancer patients, specifically, those with glioblastoma, the deadliest and most difficult type to treat. There are two major studies that have preliminary results presented recently. The first is a study of recurrent glioblastoma patients treated with nivolumab, or the combination of nivolumab and ipilumimab.

In this study, patients at first recurrence were first randomized to receive either the single agent or the combination. The initial dosing schedule involved what had been initially recommended for the ipilumimab dosing, which was 3 mg/kg along with a standard dosing of nivolumab, which was 1 mg/kg. Similar to other types of cancers, the experience in glioblastoma was that patients on that combination with the initial dosing schedule had a fair amount of significant grade 3 and grade 4 toxicities.

With that experience, the study was amended, and what we've updated and presented recently is the experience of an additional 20 patients treated with an adjusted dosing schedule where nivolumab was increased to 3 mg/kg and the ipilimumab was decreased to 1 mg/kg. That same modified dosing schedule has been used in many other cancer indications since that time.

What we show in the mature data of these 20 patients is that the safety profile of the adjusted dosing schedule was much improved. In fact, it's quite comparable to that of nivolumab when used as a single agent. We did see, although it was not the primary endpoint, some encouraging results of these initial patients. Specifically, there was one patient with a sustained partial response, and about half of the patients achieved stable disease. There is an intriguing tail of the curve, but this is still very preliminary and not mature enough to suggest that these responses and achievements are durable.

This study was very important to help give us guidance going forward with how to optimally use these drugs, and to use them safely for this particular indication.

The second study looked at an additional, or alternative PD-1 inhibitor called pembrolizumab. In this study, which we reported at ASCO, used pembrolizumab in combination with bevacizumab. There was a strong rationale for combining the two agents, because anti-antigenic agents like bevacizumab can enhance the activity of immunotherapies against a tumor. What we're reporting is the first data, showing that the combination is well-tolerated and there were no unexpected side effects associated with the full doses of these agents.

This particular study included the safety lead in to look at the important consideration of how well these two drugs would be tolerated together, and fortunately they are and can be used safely. The study also includes a larger, randomized component, which has completed accrual where patients receive either pembrolizumab monotherapy or pembrolizumab plus bevacizumab. All of these patients have recurrent glioblastoma.

Hopefully within the next 6 to 12 months, we'll actually have the efficacy readout of this part of the study in addition to the safety readout that we've reported.

TARGETED ONCOLOGY:What do you think has been the most challenging part with moving these agents in brain cancer?  

Reardon:

Reardon: Glioblastoma in general is not a particularly inflamed cancer microenvironment. We know from other cancer types where there's not a lot of pre-existing inflammation, these immune checkpoint inhibitors may need a little help to actually enhance the immune response against the tumor.

We are anticipating a modest single-agent benefit, but where I think we'll get a bigger benefit for patients is with combinations, particularly something that can enhance an immune response into the tumor and then combine the checkpoint blockade to limit the suppressive capability that the tumor it is trying to protect itself with.

Another important consideration and unique aspect for brain cancer patients is that these agents can cause inflammation. They can do that for any type of cancer when the immune system is activated against the tumor. It's a little different when that happens in the brain, because there's only so much room for swelling. There are critical structures in the brain that can get compressed and translate into symptoms and issues for patients. So this has been a unique, particular challenge for brain cancer.

TARGETED ONCOLOGY:With the aforementioned studies, are there any kind of immediate steps?  

Reardon:

Reardon: All of the patients have accrued to the subsequent studies that are tied in with both of these safety analyses. We're continuing to treat and monitor the patients closely, and of course reviewing all the data as it's coming in and analyzing it for evidence of efficacy and any other evidence of unexpected side effects.

We also built into the studies a number of immunocorrelative studies and assays that are being done to try and tease out what these drugs are causing that may or may not be associated with response, or even what may be associated, they may be associated with a subset of patients who don't respond. I think the immunocorrelative biomarker assays that are ongoing may be important and critical as well, so stay tuned.