Immunotherapy in Soft Tissue – 5 min Sarcoma Talk #6 with Sandra D’Angelo

Shushan Hovsepyan: Hello, everyone. Welcome back to another episode of ‘5 Minute Sarcoma Talk’ here on OncoDaily. I’m your host, Shushan Hovsepian, and today we have a fascinating topic to discuss, immunotherapies in soft tissue sarcomas.

And for that, I’m honored to introduce our guest speaker, Dr. Sandra D’Angelo, who is a distinguished medical oncologist working at Memorial Sloan Kettering Cancer Center, specializing in the care of soft tissue sarcomas, bone sarcomas. So, welcome, Dr. D’Angelo, and thank you for accepting our invitation.

Let’s find out that now. And my first question would be, could you provide an overview of current immunotherapy approaches being utilized for soft tissue sarcomas? What have been the most significant findings regarding the efficacy and clinical outcomes of immunotherapy treatments in STS?

In fact, it’s a disease that’s characterized by 70 to 80 different histological subtypes, and how we approach care and how we conduct clinical trials has really impacted where the field stands. And in general, there’s been a trend towards histology-specific clinical trials and approaches, and I think that has led to some of the more interesting and promising findings in the field. So, I’ll break immunotherapy broadly down into two categories.

First is checkpoint blockade and specifically monotherapy checkpoint blockade. The FDA approval that we have in the United States is just in alveolar soft part sarcoma. In ASPS, we see a promising response rate with a tesolizumab of about 30 to 40 percent, and that drug was actually recently approved in the United States.

And it is, in fact, the only FDA approval for checkpoint blockade in sarcoma. That being said, we’ve seen hints of activity which have allowed us as a field to offer these therapies through NCCN listings. To that end, we’ve seen promising responses in undifferentiated pleomorphic sarcomas, where pembrolizumab has shown a response rate of about 20 percent, and de-differentiated liposarcoma.

Similarly, pembrolizumab has shown a response rate of about 10 percent as well. And to that end, you know, we feel that those are promising options because chemotherapy and those respective diseases have quite similar response rate. Then, sort of shifting gears a little bit, the other efforts have been centered around adoptive cell therapy, specifically T-cell therapy.

And much of the work with that has really been centered around synovial sarcoma and myxoid round cell liposarcoma. And specifically, T-cell therapy that targets cancer testes antigens, such as MAGE-A4, with a drug called afamisel, has shown a promising response rate of 40 percent, which is durable well beyond the year, and really one of the most promising immunotherapies in our field at this time.

And afamisel is actually currently being reviewed at the FDA for potential approval, which would offer a promising option for our patients with synovial sarcoma.

In addition, there’s been efforts with other cancer testes antigens, namely NY-ESO. And recently at ASCO, we presented data with leticell. And leticell actually similarly demonstrated a 40 percent response rate in synovial sarcoma and myxoid round cell liposarcoma.

So, T-cell therapy is limited to these two histological subtypes. Importantly, T-cell therapy is limited to specific HLA blood types. So, this is not something that’s broadly applicable, but that to me highlights where the field needs to improve on and do better and offer alternative options for our patients.

The other important effort with immunotherapy has been in the neoadjuvant setting. Dr. Kirsch recently presented data demonstrating that pembrolizumab in the neoadjuvant setting prior to resection in undifferentiated pleomorphic sarcoma and undifferentiated liposarcoma actually improved disease-free survival. An important and interesting study for those patients because adjuvant therapy in sarcoma is complex and the standard of care or the presumed standard of care, I should say, is typically with doxorubicin and ifosfamide.

At times, older patients are not candidates for this intensive chemotherapy regimen. And so, pembrolizumab offers an alternative. I think the study was a promising one and an interesting one, and it also now adds an additional approach for patients who have extremity UPS or D-dif-lipo and one that certainly will be included as an alternative way to treat patients.

And then the last disease I’ll highlight is angiosarcoma, which also specifically cutaneous angiosarcomas. There’s been a number of studies that have been published that also have shown promise demonstrating efficacy mostly with monotherapy and cutaneous angiosarcomas. And so, all of what I’ve discussed has really just been in the context of monotherapy checkpoint blockade.

Just to highlight some of the studies, I conducted a study of nivolumab with ipilimumab through the alliance cooperative group, and we did show that the combination had an overall higher numerical response rate. The trials were not designed to statistically derive a difference, but broadly speaking, with nivolumab and ipilimumab, the response rate was about 15 to 16%, and with monotherapy nivolumab, it was about 5 to 10%. We then conducted expansion cohorts, specifically in UPS and de-differentiated liposarcoma, and we were able to recapitulate those data.

Obviously, the important thing is that you want to balance that with the added adverse events and understanding whether it’s worth those additional toxicities based on the sort of marginal improvement in efficacy. There were similar studies with dervalumab and tremolumab, and so adding that second immunotherapy compound may or may not be worth it for most histological subtypes. A disease that I’d like to pull out, though, is again angiosarcoma.

There was a clinical trial of nivolumab with cabozatinib that was conducted by the alliance group and led by Dr. Juniko Olsen, who’s a sarcoma investigator at Duke, and in that study, she demonstrated that the addition of nivolumab to cabozatinib led to a very promising response rate of almost 60%. So, this is probably one of the highest response rates, and what was remarkable about that particular study is that the efficacy was not limited just to cutaneous angiosarcoma. In fact, the efficacy was shown in a number of different angiosarcoma subtypes, and so I look forward to future efforts in that particular disease with that combination.

I imagine there’ll be more confirmatory studies in the future. When we look at, though, a combination of chemotherapy, interestingly, in the context of that alliance angiosarcoma trial, there was also a cohort that investigated the addition of paclitaxel to nivolumab, and so the design of that study was paclitaxel with or without nivolumab, and interestingly, we did not see an improvement with the addition of nivolumab. Actually, the efficacy and the PFS, the response rate were quite similar.

So, that’s an interesting finding. On the contrary, my colleague at MSK, Dr. Rosenbaum, conducted a trial of gemcitabine docetaxel with retifanimab, which is another checkpoint inhibitor, and in the context of that study, he reported high response rates, and a cohort of angiosarcoma patients was about 10 patients. The response rate was close to 80%, and so to me, these data highlight how much we don’t know, why paclitaxel was not effective, why gemcitabine docetaxel seemed to have some hints of activity that seemed to be higher than the chemotherapy alone.

It leaves a lot of unanswered questions. It also highlights the need to better understand the diseases, and the correlative work will obviously enhance these clinical data. I think that’s an important piece of the efforts, not just conducting through trial, but actually trying to understand which patients benefit and which patients do not.

There’s also an upcoming study of doxorubicin with pembrolizumab conducted through our ECOG cooperative group. This is going to be led by Dr. Seth Pollack. Again, this is based on some data that the combination seemed to yield higher response rate.

I think that’ll be an interesting trial, because it is randomized, and so we’ll be able to really tease out the additional benefit of the checkpoint blockade on top of chemotherapy.

We’re limited to selecting and conducting these trials in histology-specific cohorts and building on the efforts. If you see a signal of efficacy, then you can build out to other histologies. I think the challenge is more the disease and how complex and how many subtypes there are.

I think what’s wonderful is that our sarcoma community is actually quite knit, and there are avenues and mechanisms for us to run clinical trials through cooperative groups and through collaborations. I think regardless of the challenges, I think we’re able to overcome those challenges. To date, we’ve run a number of studies that actually, I think, have improved upon the standard of care and offered alternative options for our patients.

But beyond that, the struggle in pediatric sarcomas is actually similar to the struggle that we’ve seen in adult sarcomas. But some of the markers that can help us identify patients that are most more likely to benefit, such as high tumor mutational burden or increased immune infiltrates, MSI high status, universally those are typically not found. When we focus on pediatric sarcomas, often I think about translocation-driven sarcomas.

So diseases such as Ewing’s sarcoma, Rhabdomyosarcoma, and then a completely different disease that’s not translocation-driven, but that also has proven to be difficult to treat in the context of immunotherapies, osteosarcoma. And so I think that there’s more work to be done in the pediatric space. And we work closely at our respective institutions with our pediatric colleagues to be able to design clinical trials that will allow pediatric patients to enroll in pediatric-specific cohorts, but certainly more work to be done as well on the field.

As already we discussed, you know, T cell therapy, ephamocel, and leticell, I think those are promising, probably promising drugs that are nearing, at least ephamocel is nearing approval, we hope, and then leticell hopefully next. In the context of checkpoint blockade, I think that perhaps we need to kind of think beyond these particular pathways. And there are some sort of new and promising agents, such as bi-specific antibodies that target numerous parts of the immune system that may be sort of coming to the future that may offer alternative options for patients with sarcoma.

And so, I sort of walked into Memorial and covered the night shifts for two weeks. And after that two-week experience, I said I would never come back to Memorial Sloan Kettering, because it was so challenging and so difficult and so stressful. But something drew me back, and I actually wound up doing some outpatient clinics.

And it’s really in the clinics where I was exposed to the promise of oncology. I think inpatient oncology is different than outpatient oncology. In the outpatient setting, I learned a few things.

One, that we provide an anchor and support patients through a very difficult journey. And patients rely on us to be part of their team and kind of guide their ship. The other thing is that we help patients through standard of care.

And chemotherapy and targeted therapy and immunotherapy has really changed our approach in how we care for patients. And then, sort of just as important, is really how research and clinical trials and advancements are sort of intimately integrated into the care of patients. And it was really that exposure at MSK that inspired me to want to contribute to those advancements and do more than standard of care.

And together, those things sort of inspired me to continue my training. And I continue my training at Memorial Sloan Kettering, and I’ve been working there since completing my therapy, my training. And so I’ve never left since that initial two-week period as an intern.

And I think it’s just been an exciting journey. Being surrounded by leaders in the field and those that have really had impact on patient care in a very promising and exciting way, I think continues to inspire me day to day.

And join us for our next episodes. Thanks a lot, and bye.

Previous episodes of  5 min Sarcoma Talk with Shushan Hovsepyan

Episode 1: Leo Kager

Episode 2: Rajkumar Venkatramani

Episode 3: Aaron Weiss

Episode 4: Leo Mascarenhas

Episode 5: Andrea Ferrari