Soft Tissue Sarcoma: Unmet Needs


Neeta Somaiah, MD: I think that’s a good transition point to talk about what you think are the biggest unmet needs in patients with sarcoma. Again, I know this is a broad statement, and I’m sure there are unmet needs for patients with soft tissue sarcomas, and then unmet needs for patients with GIST [gastrointestinal stromal tumor], and we can probably divide it that way and talk about those 2 patient populations.

Jonathan Trent, MD, PhD: I agree with you completely. I think there’s a fairly long list of unmet needs for our patients who have been affected by soft tissue and bone sarcomas. And one of the unmet needs we discussed earlier is having centralized sarcoma pathology review. There’s a wealth of literature showing that an experienced sarcoma pathologist will change the diagnosis 20% to 25% of the time, meaning that there are patients out there who are getting the wrong treatment, getting the wrong surgeries, getting radiation therapy when they shouldn’t. And so I think that’s really a huge unmet need, being able to get a centralized pathology review by sarcoma expert pathologists. Another unmet need remains treatment. We need more effective therapies. We have 175 different sarcoma types, and angiosarcoma is as different from liposarcoma as breast cancer is from colon cancer.

Neeta Somaiah, MD: Until not many years ago, and even now sometimes, we treat patient subpopulations the same, but we do realize that they’re so different. So yes, I think the challenge is, being a rare disease, it’s difficult to study each subtype separately. But what we have seen over the past few years as the sarcoma community comes together, is you can actually run and complete trials in specific subtypes, and show a response. Whereas, when you put all of them together, the efficacy signal gets diluted, which is why we have lost so much time in actually getting effective therapies into the market.

Jonathan Trent, MD, PhD: Yes. A great example is avapritinib. Its recent approval by the FDA for the use of PDGFR [platelet-derived growth factor receptor]-D842V mutated GIST. This is maybe 5% of GIST patients, so that’s a very small number of people. There might be 250, 300 new cases diagnosed each year in the United States, yet we were able to come together, do a clinical trial, and show an almost 90% response rate in this subset.

Neeta Somaiah, MD: That’s amazing. Well, if it was last year, we would be calling that an unmet need because we didn’t have anything for patients with PDGFR-D842V mutated GIST, and now we do. I think you’re right, I think looking at subtypes and understanding their molecular background a little better, and then choosing treatments accordingly is hopefully going to help us move the needle forward a little bit more and help us with these patients.

Jonathan Trent, MD, PhD: I think another unmet need in the field of sarcoma, bone and soft tissue sarcomas, is the use of immunotherapy. We’ve seen immunotherapy and the successes in melanoma, in lung cancer, in a number of different cancers where it’s made a huge impact. And I feel like in sarcoma, maybe we’re a little behind there. We’ve been ahead with the targeted therapies, but I think we’re a little behind the other solid tumors in terms of immunotherapy. What are your thoughts about opportunities?

Neeta Somaiah, MD: This is a huge opportunity. Yes, we are behind, even though I think the first case of immunotherapy in tumors was described in a sarcoma patient way back when, right? The Coley toxin was a sarcoma patient, but we’ve done a couple of trials. The SARC028 trial reported on pembrolizumab, and we saw activity in UPS [undifferentiated pleomorphic sarcoma] and some de-diff [dedifferentiated] liposarcoma patients. And then we had a nivolumab versus nivolumab plus ipilimumab study. What’s become clear is again, all subtypes are not the same. They don’t respond the same, and what’s challenging is we still don’t have tailored treatments for all subtypes. We know the populations of patients who respond to immunotherapy now, but we don’t have a good way of picking out those patients up front who are going to respond to immunotherapy. But we did make some progress.

I think through the trials that have been published, and trials ongoing, there are some subtypes that have emerged as clear winners, even though without a good rationale for why it would probably work. There’s alveolar soft part sarcoma [ASPS], again a very rare sarcoma subtype with no standard treatment options. Chemotherapy does not work for ASPS, and that seemed to be the winner for immunotherapy. More than 50% response was reported with the axitinib plus pembrolizumab study. We ran a study with durvalumab and tremelimumab, and we saw the same thing, more than 50% response in ASPS and very durable and long responses. Again, this is a subtype that is translocation driven.

Jonathan Trent, MD, PhD: Low mutation burden.

Neeta Somaiah, MD: Low mutation burden, but these patients do have immune infiltrate, and that increases on therapy, and they have beautiful responses. There is still a lot more to be researched, and I think we can learn a lot from that subtype. But for the other subtypes, I think the data are still emerging. I think we need to select our patients better, and we still have to keep researching. Maybe it’s not just the anti—PD-L1 [programmed death-ligand 1] and anti–CTLA-4 [cytotoxic T-lymphocyte–associated protein 4], and we have to diversify into other inhibitors to treat. The other success we’ve had with immunotherapy is actually with tumor testis antigen directed therapy with the adoptive T-cells. Synovial sarcoma and myxoid/round cell liposarcoma have a very high expression of NY-ESO-1, a tumor testis antigen that is not expressed in your normal cells.

And TCR [T-cell receptor]-based technology is now published, and shown to have great responses. I think it’s again a niche field, and we still have more to learn about how to maintain these responses long term. I think we’re slowly making progress, but yes, we’re far behind the other cancer types. But I think we have to keep working and keep completing our clinical trials that are ongoing.

Jonathan Trent, MD, PhD: Yes, I think we are catching up. Another area is the angiosarcoma.

Neeta Somaiah, MD: Angiosarcoma, yes. Again, that’s very interesting because when you look at angiosarcoma, it’s the cutaneous angiosarcomas that respond.

Jonathan Trent, MD, PhD: Yes, exactly.

Neeta Somaiah, MD: And not all the primary breast angiosarcomas, but it’s the cutaneous, mostly head and neck sometimes, radiation-associated ones that respond to immunotherapy. And there seems to be something to do with either a high tumor mutational burden or the UV signature that’s probably in place in these cutaneous angiosarcomas that leads to this high response rate with checkpoint inhibitors. Again, yes, that’s another need.

Jonathan Trent, MD, PhD: Yeah, 70% response rate in

one study.

Neeta Somaiah, MD: Yes, that’s pretty interesting. And then again those recently published data with the T-VEC [talimogene laherparepvec], which is intratumoral injection, along with nivolumab, showing responses.

Jonathan Trent, MD, PhD: It looks promising, too.

Neeta Somaiah, MD: It looks promising, too, yes. So more to come with immunotherapy in the future.

Transcript Edited for Clarity

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