Targeted Therapy Advancements in Sarcoma Subtypes


Neeta Somaiah, MD: Switching gears from the immunotherapy now to recent advances in targeted therapy, the area of tazemetostat in epithelioid sarcoma. Again, a pretty neglected sarcoma till late, and till we started learning so much more about the epithelioid sarcomas, histopathology, the conventional versus the proximal type, and then detecting the INI loss and that pathway being involved in epithelioid sarcoma that came into prominence when EZH2 [enhancer of zeste homolog 2] inhibitors were being studied. What is your take on the recent approval for tazemetostat? And how do you think our treatment of patients with epithelioid sarcoma is going to change now?

Jonathan Trent, MD, PhD: I think that it’s remarkable in a lot of different ways. It’s remarkable that this is a rare type of sarcoma. Maybe 200, 300 new patients per year in the United States. So it’s very rare. And there is some activity of chemotherapy, but it’s really not a very chemosensitive tumor. And even when you have a small epithelioid sarcoma, a centimeter say, on the pinkie or finger, the local recurrence rate after surgery is very high. And it’s very frustrating as somebody who takes care of patients with epithelioid sarcoma to see multiple local recurrences time and time again, and not really being able to change the trajectory very much with chemotherapy. I think a new agent is clearly needed. Tazemetostat is an EZH2 inhibitor, so it binds to the complex that EZH2 and INI1 are a part of, and disrupts it.

This complex is very active in the setting of INI1 loss. And so a diagnostic test that our pathologists do in the sarcoma world is to test for INI1 expression in any tumor that resembles an epithelioid sarcoma.

Neeta Somaiah, MD: And that’s an easy test by immunohistochemistry.

Jonathan Trent, MD, PhD: Correct. And so if INI1 is lost, then this an opportunity to treat a patient with epithelioid sarcoma with a first-in-class, epigenetically active, EZH2 inhibitor that has clearly shown benefit in these patients.

The challenge remains, it’s a rare disease. This FDA approval is based on a phase I study. Response rates as defined by RECIST [Response Evaluation Criteria in Solid Tumors], which we all had struggle with and we think only shows part of the story, but nonetheless, the response rates were in the 15% to 20% range. So not the highest by RECIST, but these patients have such a need, and it’s such a logical, rational target, it makes a lot of sense. And so I think we’re going to use it. Looking forward to using it.

Neeta Somaiah, MD: Yes, and I think it really opens the field to discovering this epigenetic modulation further. Because this is the first EZH2 inhibitor, and we know that INI loss with SWI/SNF complex modulates the EZH2, but maybe there are other inhibitors in that pathway that probably can be modulated further down that have better efficacy. But you’re right, it’s 15% response and…part of them, they go up to 6 months, or at least a duration of response of 6 months. But most of them do end up progressing fairly quickly. But do you think they’re going to use this as frontline therapy for patients with epithelioid sarcoma with INI loss, or are you going to start them on chemotherapy and use this in later lines?

Jonathan Trent, MD, PhD: That’s a million-dollar question. We know that doxorubicin-based regimens have some activity, probably also in the 15% to 20% range. Gemcitabine-docetaxel combination has probably similar activity. Some people may say a little bit more activity.

Neeta Somaiah, MD: Yes, maybe.

Jonathan Trent, MD, PhD: In my practice we either start with gemcitabine-docetaxel, or we start with tazemetostat as their initial therapy. We prefer to do it in a patient with a measurable lesion so that we can assess response to therapy.

Tazemetostat is very well tolerated—adverse effects are very minimal. So if there’s somebody who has any comorbidities, is older, is frail, I may start with tazemetostat as their initial regimen.

Neeta Somaiah, MD: And you do the 800 mg twice-a-day dosing, the standard?

Jonathan Trent, MD, PhD: Yes, standard.

Neeta Somaiah, MD: In terms of monitoring, as you said, it’s well tolerated, some fatigue, ischemias, and GI [gastrointestinal] toxicity. But do you get them back every 2 weeks for laboratory tests initially, or how often are you following them in terms of monitoring?

Jonathan Trent, MD, PhD: We usually do every 2 weeks for the first month and then we start going to monthly after that. And if they’re doing great we even back off from that maybe every 2 months. But we still do follow their labs. I think that’s an important part of any new agent because it’s so new we still don’t know all of the long-term toxicities.

Neeta Somaiah, MD: Correct. Liver toxicities, and the CBC [complete blood count] needs to be monitored.

Jonathan Trent, MD, PhD: One thing I was wondering about is what your thoughts are on other types of sarcoma. EZH2 in this complex plays a role in other types of sarcoma, not just epithelioid sarcoma. It may be important in synovial sarcoma and some others.

Neeta Somaiah, MD: Right, because we do have INI loss in other tumors.

Jonathan Trent, MD, PhD: Yes.

Neeta Somaiah, MD: The question is, when it gets approved, if we do check for those subtypes with a higher percentage of INI loss and we detect it, or in that SMARC complex, other abnormalities, shouldn’t we be treating them with this? But I think more data would be needed. I think we need to be studying it further in those subtypes, and hopefully the next trial would be inclusive of those subtypes as well.

Jonathan Trent, MD, PhD: Yes. I’d like to see that type of trial where maybe we can expand the use of agents that target this pathway because it’s going to be important in other types of sarcoma as well.

Neeta Somaiah, MD: Correct. And as we see newer agents targeting epigenetics coming into the field.

Jonathan Trent, MD, PhD: Let me ask about using this. Are you using tazemetostat preoperatively? Are you using it adjuvantly? Do you think there’s any role in this situation, or is it relegated in the current environment as it’s approved for inoperable patients who cannot be cured by a definitive surgery? When we know the response rate is so high, what’s your thought about its role in this space?

Neeta Somaiah, MD: I know. So far I’m still using it as defined for inoperable disease. And the patients coming in, we might have that discussion. Because some patients might benefit and respond, but response rate is still like 15%. So if they’re clearly operable, I think that it’s still the standard, unless they’re borderline operable, one could make the case of giving them neoadjuvant treatment and seeing how they do. But you have to do a quick check to make sure that they don’t lose the window of surgical resection.

I think unless we get more data, and maybe there are studies to look at a higher dose, or we can basically better define the response rate and which patients might benefit more, it will be difficult to bring it up to the frontline setting.

Jonathan Trent, MD, PhD: Combinations with chemotherapy?

Neeta Somaiah, MD: Combinations with chemotherapy also. And then, of course, more is to be learned. There is a warning about, I know it’s less than 1%, but an increase in T-cell lymphoma, the MDS [myelodysplastic syndrome] and AML [acute myeloid leukemia]. So that needs monitoring as well. I think we’ll have to see how that adverse effect, or the secondary malignancy effect, plays out.

Jonathan Trent, MD, PhD: Great. Well, it’s certainly an exciting new drug with a great rationale that we now at least have in our arsenal to treat patients with epithelioid sarcoma.

Neeta Somaiah, MD: Yes. And we’re showing the world that in this rare, 1% of all sarcomas, that we can actually do trials and get a drug to approval, so that is very exciting.

Transcript Edited for Clarity

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