Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And today, we're highlighting recent research on combination treatment for advanced sarcoma. Joining me is Dr. Seth Pollack. He's the Stephen T. Rosen Professor of Cancer Biology and a Professor of Hematology Oncology at Northwestern Medicine.

Dr. Pollack, thank you so much for joining us today. Can you start by telling us a little bit about leiomyosarcoma in general? As I understand it, this is a rare cancer. Tell us a little bit about the landscape of this particular type of cancer.

Seth M. Pollack, MD: Sure. Well, first of all, thanks so much for having me. It's really such a pleasure to be here. And it's really an honor for me to get a chance to talk about this research a little bit. You know, leiomyosarcoma is a rare cancer. And it's really sometimes hard to get the word out about rare cancers. They're rare, but they're actually not that rare. If you have your antenna up, if you are looking at your patient panels and seeing kind of who has what, you'll be surprised that these patients are out there.

Sarcomas are cancers of the bones and the soft tissues. They make up about 1% of all cancers, which is actually over 20,000 Americans affected with new cases of sarcoma a year. So, that's actually a lot of patients. One percent of all cancers is a lot of people, and leiomyosarcoma is one of the most common subtypes of sarcoma. I think a lot of people remember from medical school learning about uterine leiomyosarcoma. But actually, only a third of leiomyosarcoma start from the uterus.

Other locations that leiomyosarcoma can occur and it can occur actually cutaneous. Leiomyosarcoma can affect the deep, soft tissues, including of the extremities. And often, leiomyosarcoma, it can be retroperitoneal, usually starting from the great blood vessels, the IVC and other important retroperitoneal blood vessels that have a smooth muscle wall that gives them their shape.

There's about 2000 cases of leiomyosarcoma a year, which is actually not—it's rare, but you know, if you think about other rare diseases that you might encounter in your practice, like ALS or something like that, it's actually really on par with some of those other ones. So, even though we don't talk about it that much, it's an important disease. And it's really understudied. We're learning a lot about what the right treatments are for leiomyosarcoma. There was recently a study from the French group showing, in the metastatic setting, an overall survival benefit to upfront doxorubicin with trabectedin using trabectedin maintenance. So, we are improving our options.

But really, on average for somebody with metastatic leiomyosarcoma, the survival is about two years still. And that's despite other options like gemcitabine, docetaxel, like pazopanib, and we really need new options for these patients, especially in the advanced setting.

Melanie Cole, MS: Well, thank you for that. And so, that's so interesting that you mention it, that outcomes remain challenging despite these multiple available therapies. So, speak a little bit about combination therapy, where that fits in. Are we trying to improve response rates, durability, resistance? Tell us a little bit about why this is so challenging. And then, we can talk about that recent study.

Seth M. Pollack, MD: Yeah, I mean, it's really a challenge to figure out when you want to combine different agents, right? Because even though those sort of average numbers are really terrible for leiomyosarcoma, there's actually a lot of patients who do much better than that. And I have a fair number of patients in my panel who have had metastatic leiomyosarcoma for more than five years, and I've had some who have had leiomyosarcoma for more than 10 years. So, it's really about coming up with a strategy that will help patients live for a long time with their disease and with excellent quality of life. And it's less about the response rates, having the best response rate in the front line, having the best response rate in the second line. That's not as important.

Of course, it's nice when you see your patient's tumor shrink. It's nice if—and especially when patients are symptomatic, that's really good if you can relieve that burden. But in terms of longevity, in terms of having great quality of life, I think progression-free survival is really what I'm thinking of. And for that, combination therapies, we have to be really careful about what we're trying to get out of them. Because the classic combination is adriamycin and Ifosfamide, and that really does improve response rates. But I think it's been very controversial in terms of how much we're helping patients over the long-term with their disease, using that kind of intensive chemotherapy rather than sequential therapies that give good quality of life.

On the other hand, there probably are some really effective combination therapies, and that's kind of what we were trying to explore in this study.

Melanie Cole, MS: Okay. So, let's mention the study now. It suggests this oral combination therapy that you're just talking about. Supporting further investigation, Dr. Pollack, tell us a little bit about some of the specifics that you would like to mention and the population, the patient population, that this was intended for. Tell us about the study and the trial outcomes.

Seth M. Pollack, MD: Yeah. So, this was a trial and it included all soft tissue sarcoma patients. So, that would be leiomyosarcoma, which is one of the most common types of soft tissue sarcoma. But also, undifferentiated pleomorphic sarcoma, synovial sarcoma, all these different sarcomas. And there were two cohorts. One was leiomyosarcoma, and that included both uterine and non-uterine leiomyosarcoma and then other sarcomas. And by some accounts, there's over a hundred different soft tissue sarcoma subtypes. And some of them are rare, but not that rare. And some of them are really ultra rare, and those were in a basket.

And really, for the other sarcomas, I don't want to say that the patients did poorly. They did as we might expect for them to be just on any TKI. So, the patients got a treatment regimen of cabozantinib, which is an FDA-approved tyrosine kinase inhibitor, but it's not FDA-approved for sarcoma. It is something we'll use off-label sometimes for our refractory sarcoma patients.

And then, they also received temozolomide. Temozolomide is an oral chemotherapy agent. It is used as standard of care for soft tissue sarcoma, although it's a really bad standard of care. We'll sometimes use it for our really refractory patients or, because it's very well-tolerated, we'll sometimes use it for patients who are older who have a poor performance status, who we don't think will be able to handle other sarcoma regimens.

There's been a lot of work on the lab side showing that TKIs, one of the ways that they work is by opening the blood vessels in the tumor and allowing chemotherapy to get inside the tumor. And we thought—or the group of investigators that were doing the trial thought that, by allowing this chemotherapy to get inside the tumor while we were holding the tumor at bay with the tyrosine kinase inhibitor, that we might have more activity.

Melanie Cole, MS: So interesting. And as you said, even though it's rare, this is a very interesting field of study. Dr. Pollack, I'd love for you to tell us about Northwestern's Sarcoma Program and why it's so important for sarcoma patients to be seen at a specialty referral center.

Seth M. Pollack, MD: Right. Yeah, it's a really important point. So, sarcomas are rare. And as I said, they're not that rare, but they are rare. And there's a lot of evidence that patients seen at a specialty center do better. They do better in terms of their surgical outcomes. They do better because the pathology, when it's reviewed by an experienced bone and soft tissue pathologist, is more accurate. We know that when sarcoma pathology is reviewed by a pathologist that does not look at a lot of sarcoma, they misdiagnose these frequently or they misclassify them frequently. They do better by having a medical-oncologist that's familiar with their disease that has seen a lot of not just sarcoma patients, but leiomyosarcoma patients. And they've seen a lot of patients with leiomyosarcoma that have been on this treatment, that treatment, have had this toxicity, et cetera, and are not just one of their few leiomyosarcoma patients a year. We see many, many leiomyosarcoma patients a year, me and my partner, Pedro de Viveiros.

And in many cases, we're able to help local physicians manage their patients. For example, certainly in the Northwestern network, we're working with a lot of the oncologists here. But even in the community, we're able to frequently help people manage their sarcoma patients. And let them know when there are trials available so that they can refer them for that. And then, we'll send the patients back to wherever they live so that it's convenient for the patient. So, it's really important.

Our team has weekly sarcoma-specific tumor boards that talk about sarcoma patients. We have a specific sarcoma trials program. We're, you know, I would say among the bigger sarcoma trials programs in the country. And we've got great orthopedic oncology, great surgical oncology with a focus on sarcoma, radiation-oncology, protons. Vinai Gondi is always at our tumor board for proton therapy for sarcomas. John Hayes is our radiation-oncologist with tons of sarcoma-specific experience. So, I think having this kind of very experienced group managing sarcoma patients makes a huge difference.

Melanie Cole, MS: Well, it certainly does. And it's very a comprehensive, multidisciplinary approach, Dr. Pollack. So, next steps, larger trials, biomarker-driven approaches or entirely new combinations. Are we moving toward a future where sarcoma treatment is more subtype-specific, personalized? If you had to look three to five years in the future, what gives you the most optimism in advancing outcomes for these patients? And what would you like the key takeaways to be?

Seth M. Pollack, MD: Right. Well, for this specific trial, the one that was published in Lancet Oncology recently, there was definitely a huge progression-free survival benefit over historical controls in refractory leiomyosarcoma patients. And I do think there is rumblings of a randomized trial that will arise out of this, either using cabozantinib or very similar TKI. So, I think that is definitely something that's on the horizon.

For sarcomas more broadly, I think sarcoma-specific treatment is the way things are already going. I mean, we already have a number of different sarcoma-specific FDA approvals. For example, trabectedin is FDA-approved for only leiomyosarcoma and liposarcoma, eribulin FDA-approved for liposarcoma, afami‑cel that is an engineered T-cell. People sometimes refer to it as a CAR T-cell. It's actually not technically a CAR, but it's a TCR-engineered T-cell. And that is something that at Northwestern, we're one of only a number of sites around the country where it's available for patients, it's afami-cel for synovial sarcoma patients. Fyarro is an FDA-approved treatment only for a rare type of sarcoma called PEComas.

So, in terms of FDA approvals, I think things are already in that direction. And we're really proud that we are the lead site on the study chair for ECOG‑ACRIN 7222. That's a national—actually it's an international US and Canada—randomized trial of doxorubicin plus pembrolizumab in undifferentiated pleomorphic sarcoma and related poorly differentiated sarcomas. And that is actively accruing now. Actually, we're over two-thirds of the way into accrual for that cohort. And actually, the accrual is going so well that we're about to open a new second parallel cohort for dedifferentiated liposarcoma.

So, you can see there's so much happening in sarcoma. We're really proud to be at the forefront of a lot of it. We've got a big clinical trials program with trials in a lot of these specific sarcoma subtypes, including GIST, the gastrointestinal stromal tumors, which is also a more common sarcoma subtype. So, things are moving in that direction of sarcoma subtype-specific treatment, and we're really proud to be at the forefront of it.

Melanie Cole, MS: Such an exciting time in your field. And I can hear the passion in your voice. Dr. Pollack, thank you so much for sharing your incredible expertise with other providers today. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/oncology to get connected with one of our providers. And that concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.