Immunotherapy Agents Emerging as Key Players in Sarcoma

Breelyn Wilky, MD

Excitement continues to surround the potential role of immunotherapy agents in the treatment of patients with sarcoma, according to Breelyn Wilky, MD.

In November, The European Commission granted an accelerated approval to olaratumab (Lartruvo) in combination with doxorubicin as a frontline therapy for patients with advanced soft tissue sarcoma, based on findings from the phase II JGDG study, which showed an 11.8-month improvement in overall survival (OS) with the PDGFRα antagonist versus doxorubicin alone.

OncLive: You recently presented the phase II clinical trial looking at concurrent axitinib and pembrolizumab in advanced alveolar soft part sarcoma, and other soft tissue sarcomas. Can you provide an overview of the study?

In an interview with OncLive, Wilky, an associate professor of Medicine, Sylvester Comprehensive Cancer Care, University of Miami Health System, discusses recent findings of a trial investigating axitinib (Inlyta) and pembrolizumab (Keytruda) in soft tissue sarcomas, as well as the role she envisions for immunotherapy in this treatment paradigm.Wilky: This study is designed to sort of carry immunotherapy one step further. Immunotherapy has had some dramatic responses in sarcoma, but it doesn’t work for everyone.

One of the reasons people think immunotherapy may not be effective is that potentially there are problems getting the immune cells into the tumor. You have to have the immune cells in the right location for them to get turned on by the checkpoint inhibitors.

A lot of people, including Dmitry Gabrilovich, MD, PhD, have done a beautiful body of research showing that a protein called vascular endothelial growth factor (VEGF)—which most people think of as being responsible for forming new blood vessels to feed tumors—also has direct effects on shutting down the immune system in tumors.

What were the most significant findings from that trial?

The concept of the trial is basically to use a VEGF blocker to sort of prime the tumor environment and hopefully get immune cells into the tumor, and then use the checkpoint inhibitor to turn them on.The trial is currently in progress, so we don’t have any official findings as of yet. We have currently put on 13 of the 30 planned patients. There are several patients with alveolar soft part sarcoma, but also other histologies in soft tissue sarcoma.

At this point, what I can say is that we have not seen any prohibitive, severe toxicities from the regimen, people have been able to do the regimen. As far as the results, we still have patients being treated on the study, so I can’t comment on any findings as of yet.

There were recently updated results presented from the SERCA2a study looking at pembrolizumab. Can you discuss those findings?

Can you talk a little bit about what role you think immunotherapy will play, or what role you would like it to play in the future treatment landscape of this disease?

Our hope is that we will finish accruing the study probably within the next 6 months, so my goal is to have at least some preliminary data for next year’s ASCO Annual Meeting.I think we’re all really excited to see the correlative studies, which will hopefully offer some clues as to how to pick the patients this treatment is most likely to help—that we didn’t see. However, what was nice to see is the data showing that these responses, when they do occur, tend to last a longer period of time. To me, the results from SERCA2a just continue to tell us there is a signal for a select group of patients, and it just makes me more inspired to try and figure out who those patients are and how to make it work better for more patients.Absolutely. Dr. Tap said it beautifully when he showed the 5 pillars of cancer care, and I think many people are convinced that immunotherapy is here to stay. I do believe that we’re just beginning to look at this in sarcoma and to understand how to use it properly.

Can you talk about the strategies involved with deciding which agents suit which patients best?

I think the perfect scenario in the future would be when a new sarcoma patient comes to you, you have the ability to do a biopsy and profile that tumor, including for how active the immune system is in these various features within the tumor. That way, you can make your selections from your different treatment modalities, whether it’s chemotherapy, whether it’s immunotherapy, or targeted therapy, and really customize treatment for sarcoma much more detailed than we currently can.When I think about how I’m going to treat a patient with sarcoma, the pathology and the biopsy are really key. You want to know exactly what type of sarcoma this is because there are over 100 different types, and then you look at the patient. Know the tumor and know the patient.

What would you like the community oncologists to ultimately take away from the study findings you presented?

There are some patients that may be great chemotherapy patients—they’re super young and super healthy. And then there are others that might not be able to tolerate that significant of treatment, so we customize all along the way. But certainly this particular histology, and I think hopefully in the future more genetic information and hopefully more immuno-profiling information will help us customize even further.I think our consensus is that yes, immunotherapy, specifically checkpoint inhibitor therapy, is likely to play a role for some patients with sarcomas, however, all sarcomas are not created equal and we’re just beginning to understand which patients this is likely to help.

What would you like to see in this treatment landscape in the next 5 to 10 years?

Certainly, I think everyone agreed that off-label use or using checkpoint inhibitors as a last-ditch effort without knowing more about it is probably not the way to go, not only for the potential side effects to the patient, but for relatively lower chance of benefit. These patients really need to be treated on a trial so that we can learn how to use drugs better.Immunotherapy, immunotherapy, immunotherapy. I am so incredibly excited because there are tons and tons of new drugs and new targets within the immune landscape that other cancer types are furiously going through research to identify and learn how to use.

What I would like to see is that in 5 to 10 years, let’s say we decide that a patient is a good candidate for immunotherapy. I don’t just reach for a checkpoint inhibitor, I reach for a sort of cocktail therapy, kind of like what we do for HIV infection nowadays where you don’t just hit it with 1 method, you hit it with multiple methods all at the same time. So maybe for sarcoma that means the patient gets a vaccine, or the patient gets T-cell directed therapy first, followed by a checkpoint inhibitor and maybe treatment to also inhibit either T-regulatory cells or suppressive macrophages, and ideally all of that information would be guided by what is actually currently existing in the patient’s own tumor.