Systemic Therapies for Patients With Desmoid Tumors

Desmoid Tumor Expert Roundtable - Part 3

In this expert panel series, moderator Mrinal Gounder, MD, Memorial Sloan Kettering Cancer Center, New York, New York, leads participants Rashmi Chugh, MD, University of Michigan Medicine, Detroit, Michigan, and Ravin Ratan, MD, MD Anderson Cancer Center, Houston, Texas, in a discussion on desmoid tumors.

In the third video, our experts discuss the options for medical treatment of desmoid tumors, such as cytotoxic chemotherapy, sorafenib, and nirogacestat. The participants also review the latest data from the phase 3 DeFi trial, evaluating nirogacestat among adult patients with progressing desmoid tumors compared to placebo.

For Part 4 of this roundtable, please click here.

Transcript:

Mrinal Gounder, MD: Welcome back to Oncology Learning Network. My name is Al Gonder from Memorial Sloan Care Cancer Center in New York. And today I'm joined by Dr Rashmi Chugh from University of Michigan and Dr Ravin Ratan from MD Anderson Cancer Center in Houston, Texas. In this segment of our roundtable discussion on desmoid tumors, we are looking at the latest data for systemic therapies.

First, we'll begin with Dr Chugh: Can you please briefly describe the drugs that we are no longer routinely using in desmoid tumor treatments?

Rashmi Chugh, MD: Of course. We have learned an incredible amount about desmoid tumors in a relatively short period of time. For decades really, we had been employing the use of less toxic agents, I guess I would say, such as nonsteroidal anti-inflammatory treatments, as well as hormonal therapies in the treatment of desmoid tumors without a clear understanding of their mechanism and their activity. Most of the reason we've been using those is somewhat anecdotal, based on case series. And now that we've had the development of agents specifically in desmoid tumors, we've had a series of studies that have recognized that a lot of patients have this spontaneous regression of tumors. They're not that much different from what we have been observing for years with treating patients with anti-inflammatories and hormonal therapies.

We now have more clearly active agents. So our commonplace practice, which have been used in the past of using drugs like sulindac, tamoxifen, high dose tamoxifen, Celebrex [celecoxib], which were thought to be low morbid agents that may have some activity in desmoid, have called into question, are we really just treating ourselves in treating patients, knowing that we're not really necessarily having any anti-tumor effect, but really sometimes just improving symptoms with anti-inflammatories.

And if we really do need to treat a patient based on symptoms or progression, we have a lot more effective agents out there. So just as we've shifted from using surgery as an early tool for this disease, we've shifted from using hormonal therapies and anti-inflammatories essentially because their efficacy is questionable. And we know that these tumors often regress at a similar rate as we see benefit with those agents, and we have a lot more effective agents that we can utilize now.

Dr Gounder: Thank you. In terms of some of these anecdotal responses with NSAIDs or hormonal therapy, we now look back and say, “perhaps this was spontaneous regressions that were happening in these tumors.” To the audience here, spontaneous regression may sound really an odd concept. Can you please explain what spontaneous regression and how often we see this and what does that look like in desmoid tumors?

Dr Chugh: Yeah, absolutely. And I guess I'll give you a little anecdote here. I remember I had one of my patients who was coming to Michigan for college and was moved from Boston and one of my colleagues there had been treating her, and he had started her on sulindac for a recurrent desmoid tumor. So the tumor was resected, came back and was growing and started her on sulindac and said, “here, she's moving to Michigan, you take over.” My first visit with her, I looked at her MRI and I was so excited. I was like, “okay, this is shrinking dramatically. Oh go colleague. I never use sulindac anymore. They were right to use that.” And I went to meet this patient, she's like, “yeah, I never started it.” So that's what we see sometimes. We don't even realize that this patient was having a nice spontaneous regression after her tumor had recurred after surgery and was progressing clearly on imaging.

We know based on randomized studies that we performed now, depending on where we mark the bar for progressive disease, we can see spontaneous regression rates anywhere from 10% to 20% formally in tumors that are progressing. But in tumors that are stabilizing, I suspect we see it more often than that. And stability is often very acceptable with this disease as well.

One thing I wanted to add from some of the other agents that we no longer use, the anti-inflammatories and hormonal agents, we do base a lot of our rationale from them based on case series, and responses for desmoid tumors were oftentimes not reported in a similar way that we do in our modern day clinical studies. Desmoid tumors are very difficult to measure, and now that we've standardized response rates and even looking at more things in addition to RECIST for response rates, looking at volume, it really does question if you see a case series of the past of anti-inflammatories and they report very high response rates, was it really evaluated rigorously to the same standards that we would now?

Dr Gounder: Excellent. Thank you so much. That's really super-detailed. Dr Ratan, if you could maybe explain to the audience how you integrate or what is the role of cytotoxic chemotherapies for desmoid tumor treatment? What is your clinical practice? How do you use this drug along with many of the other drugs that we'll be soon talking about?

Ravin Ratan, MD, MEd: It's a really important question because I think that, in contrast to some of the NSAIDs and hormonal therapies that Dr Chugh mentioned, cytotoxic chemotherapy probably still has a role for some patients under some circumstances. And when we talk about cytotoxic chemotherapy, we're largely talking about two groups of treatments. One is the methotrexate and vinca alkaloid combination, and the second is anthracycline based, either single agent or combination chemotherapy. And that's things like Doxil [liposomal doxorubicin], conventional doxorubicin, or doxorubicin-based combinations.

I think that it's quite clear that these agents probably have even in single-arm series or non-randomized experiences, probably higher activity than the baseline that we see in most other desmoid experiences. And so I think there's an agreement that these are active, and I think the amount of data, especially for the Doxil and doxorubicin-based treatments, is continuing to accumulate.

We have novel agents now that have been the subject of randomized controlled trials, specifically sorafenib and nirogacestat, and then in a non-comparative randomized study, pazopanib, all of which have strong evidence for their activity. But these are not medicines that are universally available. And so certainly in parts of the world where some of these novel therapeutics are not available, cytotoxic chemotherapy has a role.

And the other place where I think that you would say that cytotoxic chemotherapy remains a standard is in children. Methotrexate and vinblastine has been used in children for a very long time because of the limited long-term toxicity in contrast to doxorubicin-based therapies where there is a concern for secondary malignancies, a concern for cardiac toxicity. Methotrexate and vinblastine or methotrexate-based regimens tend to have less long-term toxicity have been tried and true. Important to say, they work slowly. Methotrexate based regimens do not typically cause rapid reduction in tumors. Ten years ago we would've used a doxorubicin-based therapy for any patient that needed a fast response for their desmoid tumors. And while there's no randomized experience, it's not entirely clear that doxorubicin works faster than some of our more novel agents. These agents also work quite quickly, and so we're using much less of it as time goes on.

Dr Gounder: Excellent, thank you. In your own practice, you practice at a major cancer institute here in the US with access to all of these drugs. Where do you position cytotoxic chemotherapies, in relation to the other drugs that we will soon talk about in greater detail, but is this first line, second line, third line?

Dr Ratan: I would say at this point in my practice, uncommonly used. I think we have other options that are well tolerated that have the convenience of being oral, and so for several years now, I would say that we've reserved these therapies for patients that either have failed more sort of novel agents, or for one reason or another do not wish to take them.

Dr Gounder: Thank you. Dr Chugh, I'm going to ask you about sorafenib, but before moving, how do you position cytotoxic chemotherapies in your practice in relation to the tyrosine kinase inhibitors or the gamma-secretase inhibitors?

Dr Chugh: Similar to my colleague here, we tend to reserve cytotoxic chemotherapies for specific situations. Most of the time it's for refractory disease, but every situation is a little bit different and that's why we talk about the desmoid tumor journey a bit. Sometimes there's situations where oral medications are not the best option, so choosing something intravenous is helpful. Sometimes compliance is an issue, and giving a regimen that we deliver ourselves is helpful. And certainly, some of these agents, even though we are able to get access for most of our patients to the oral agents, but sometimes we have challenges there too, and we have to resort to intravenous treatments.

Dr Gounder: Excellent, thank you. So DrChugh, what about sorafenib and to our audience, can you also perhaps shed some light on the mechanism of action and side effects of this drug and how you position this in desmoid tumor treatments?

Dr Chugh: Yes, I’d be happy to. Sorafenib is a very effective agent and I feel a little phony speaking about it because my colleague, Dr Gounder himself, is the lead on this study that really showed the benefit of sorafenib in a randomized study versus placebo. Just so all of you know, as we discussed, because of the very reasonable option of active surveillance, placebo-controlled studies are very acceptable in the management of desmoid tumors. Sorafenib is a multi-tyrosine kinase inhibitor and there's actually a lot of different hypotheses about the mechanism of action and we could debate that a little bit, but certainly, the anti-VEGFR therapy as well as anti PDGFR activity is probably an interplay of why it is effective. Although, correct me if I'm wrong, we haven't quite developed a biomarker, an exact way to predict whether or not that this will be an effective strategy in the exact mechanism of how it behaves in desmoid tumors. But we do know it can be a very effective agent.

It is typically used at a dose of 400 mg once daily, in contrast to the dose that's approved for hepatocellular and renal cell carcinoma, of twice daily. And because of that, it can be tolerable in our younger patients and still be able to be quite functional at that dose. Side effects can include, like most of our multi-TKIs, hypertension, fatigue, nausea, diarrhea, hand-foot syndrome is a big one as well. And each of these can be significant in some patients and not too significant in others it is very variable. We know that a lot of people have some really nice benefit and nice tolerance to sorafenib. The technical tumor shrinkage rate by RECIST criteria in the multicenter randomized study was about a third, or 33%, but we know it can be clinically impactful in a lot more patients, based on patient-related outcomes, and just our own personal experience. Even before the tumor has shrunk, patients can experience decrease in pain. So, I position sorafenib fairly highly. I usually consider it a second- or sometimes some situations a first-line agent, usually make sure to give a trial of it before I resort to cytotoxic therapies.

Dr Gounder: Brilliant, thank you. Okay, so Dr Ratan, we will shift to this new kid on the block, nirogacestat, or gamma secretase inhibitors to our audience. Can you describe the mechanism of action of this novel drug and how this came to be FDA approved for this disease?

Dr Ratan: It's a fascinating story. Gamma secretase is an enzyme that cleaves a number of substrates and initially the whole class of drugs actually developed to treat Alzheimer's disease where I thought it might interfere with the cleavage of that amyloid precursor protein (APP). It didn't work there, but it also is responsible for cleaving notch, which is a signaling protein that is implicated in many cancers. And so, it was being studied for cancer. In that initial phase 1 study, there were a couple of desmoid tumor patients that were serendipitously placed on the study and responded to treatment. And the subsequent phase 2 study continued to demonstrate efficacy. And so the phase 3 DeFi trial was done to confirm that finding. It's not entirely clear what the specific mechanism of action is. It's thought that there's crosstalk between the notch pathway and the canonical Wnt/beta-catenin pathway, but we're still learning about that.

That being said, that phase 3 confirmatory placebo-controlled randomized study was very positive. In patients who had 20% progression of their tumors in the 12 months prior to going on study, a very stringent entry criterion, 41% of patients had a response in the arm treated with nirogacestat in contrast to 8% for patients with placebo. So important to note, that even in that group of patients where the tumors were progressing when they went on the study, there were still responses seen to placebo, 8% by RECIST and then a larger percentage if you look at patients whose tumors shrank, but clearly nirogacestat had significant clinical activity. And I think importantly, a couple important points about it, one is that it works relatively quickly a time for response about 5.5 months.

But additionally, it seems to be quite well tolerated in a significant proportion of patients. It doesn't mean that it is free of side effects. The most common adverse event that we do see are often GI, so diarrhea, which is typically manageable with antispasmodics and supportive care. We do see rashes in the majority of patients, these can be quite mild, but then there is a subset of patients that develop a very significant hidradenitis as a consequence of taking gamma-secretase inhibitors and so either have to dose, reduce or stop the drug altogether.

And then I think an important novel finding that was unexpected in the phase 3 trial was that in women who are premenopausal, so of trial childbearing potential, there does appear to be effects on the hormonal axis, this was a group of side effects that was termed “ovarian toxicities.” So, typically sort of a more menopausal-appearing hormonal profile, hot flashes and sort of evidence of estrogen deprivation. And this was unexpected and ultimately the protocol was amended to try to follow that more carefully. But I think that's a story that's still being sort of told. As far as we can tell, patients who stopped the medication do seem to recover ovarian function. We don't yet have a full picture as to whether fertility is impacted, but I think we're cautiously hopeful that that may not ultimately be the case. But that being said, the side effect was a surprise and there's a subset of my younger patients that are not yet done with childbearing that are concerned about this and we'll elect to use a different therapy and we tend to be pretty transparent about that as we talk with patients about whether this drug might be right for them.

Dr Gounder: Dr Chugh, if I may stay on this topic of nirogacestat, what is your practice with this drug? You talked about sorafenib and also about cytotoxic chemotherapies. And one thing I really want to ask you is, this is a hot topic, I don't think anyone knows the answer, but what do you tell patients about the duration of treatment of not just nirogacestat but sorafenib or any of the other cytotoxic therapies?

Dr Chugh: Excellent question, and this is where we get into a lot more individualization, as well as experience. It can be highly variable, depending on how well the patient tolerates their degree of symptoms, the rate of benefit. One thing that we've learned as well as we can see imaging characteristics that can suggest whether a tumor is active or inactive, particularly based on MRI and T2-weighted signal. And sometimes that helps play a part if we're seeing evidence of not just tumor shrinkage but actual decreased enhancement of the tumors with treatment.

I honestly try to be very vague when I talk to my patients, which doesn't always go over well for patients that want to know how their lives are going to play out and have a lot to do. I give oftentimes a rough estimate of 1 to 2 years, depending on how they're benefiting, their treatment side effects. We will definitely do an assessment at 6 months whether it's even worth continuing that long, but if a patient's having benefit, that's the kind of broad range that I discuss.

Dr Gounder: Thank you. And while we are on the topic of systemic therapies, we know that asthma tumors mostly affect young people of reproductive health. Can I ask you both in terms of your own practice in terms of conversations around fertility preservation, whether you're using cytotoxic chemo[therapies] or sorafenib or nirogacestat, do you routinely refer everyone to this? What is each of your practice? Maybe we can start with Dr Ratan first and then Dr Chugh.

Dr Ratan: I routinely do make a referral to have them speak to a fertility specialist, and we've had several patients who've ultimately elected to do egg retrieval before starting nirogacestat. Again, we don't know at this point whether that's necessary or not, but given sort of the paucity of experience, there's some patients who've chosen to do that. Notably, we've worked with fertility specialists that are sort of clued into some of the details of desmoid treatment. We don't use tamoxifen or anti-estrogenic agents to treat this disease anymore, but I think the jury is still out as to sort of whether a stimulation protocol, especially if there's a high-estrogen state, may sort of provoke different behavior. And so, our fertility specialists will often use a protocol that's aimed at sort of minimizing that estrogen spike. But we've had several patients who've chosen to do fertility treatment, and in many cases, desmoid tumor treatment isn't so urgent that that's not doable. My routine practice is to at least have the conversation and ultimately make sure the patient has had the options explained to them.

Dr Gounder: Wonderful. Dr Chugh?

Dr Chugh: Absolutely a hundred percent agree with your approach. A lot of our data is limited. We don't have a lot of long-term term data to share. I have patients that feel very strongly that they don't want to take any risk at all. I have other patients that feel comfortable when we go through the available data, and most of the time patients have been anecdotally able to conceive after. Whereas, I just had my first patient come in with their baby post gamma-secretase inhibitor and that made me feel good. But these are all anecdotes, and we can't guarantee what may happen as we learn more. So, offering, having that conversation is paramount for patients.

Dr Gounder: Brilliant. Thank you. Thank you for sharing. This was a complex topic and wide ranging. If I may just quickly summarize to our audience. The key takeaway is that for desmoid tumors, we have a lot of new drugs. We no longer are using NSAIDs and hormonal therapies for the treatment of desmoid tumors. We can certainly use NSAIDs and other things for pain management or other symptom relief, but not for the actual treatment of the desmoid tumor itself.

In terms of other options we have 3 major groups, 1 is cytotoxic chemotherapies, methotrexate, vinorelbine, or one of the vinca alkaloids, liposomal doxorubicin or any of the other antracyclines are reasonable approach. There's also the tyrosine kinase inhibitor sorafenib, not FDA-approved, although primarily because the study was not a registrational study, but still very effective and globally being used. And lastly, the gamma-secretase inhibitors, nirogacestat, which is FDA approved. Two of these are oral drugs, the others are intravenous.

They all have certain roles and positions they play, and really it's a very personalized approach to an individual patient in terms of their medical comorbidities as their preference, their convenience, and what else is going on. All of them are good options. It really comes down to an in-depth conversation with the patient.

I think we can stop there and I want to thank the audience for watching and I want to thank both of you for sharing your insights into your own practice and also in the evidence-based discussions. Please join us for part four of this discussion on potential future treatments of desmoid tumors, what lays ahead. Thank you.

For Part 4 of this roundtable, please click here.

Sources:

Gounder MM, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. Published online: March 8, 2023. doi: 10.1056/NEJMoa2210140.

Ratan R, Kasper B, Alcindor T, et al. Efficacy and safety of long-term continuous nirogacestat treatment in adults with desmoid tumors: Results from the DeFi trial. J Clin Oncol. Published online October 20, 2025. doi: 10.1200/JCO-25-00582