Applying Desmoid Tumor Treatment Strategies and Data in Practice

Desmoid tumors can present management challenges due to their unpredictable behavior. Steven I. Robinson, MBBS, an associate professor of oncology and medical oncologist at the Mayo Clinic in Rochester, Minnesota, reviewed consensus guidelines recommending active surveillance as the initial approach for desmoid tumors in a virtual Case-Based Roundtable with participants from the Great Lakes and Great Plains regions. Robinson also highlighted efficacy data and toxicity profiles from key clinical trials of systemic therapies like sorafenib (Nexavar) and nirogacestat (Ogsiveo) for progressive or symptomatic disease.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What do you think of the guidelines from the Desmoid Tumor Working Group?

Steven I. Robinson, MBBS: The article from Kasper, et al, on behalf of the Sporadic Desmoid Tumor Working Group in JAMA Oncology in 2024 is a useful paper to read.¹ It helps me counsel when I share with patients the consensus guideline approach, when I'm walking through what my plan will be, to explain the evidence and what we recommend.

We should biopsy them; it should be reviewed by a pathologist who has experience in bone and soft tissue tumors. You do want to involve a sarcoma center, either directly or liaising with your sarcoma physician. You want to assess if the tumor is threatening to their life, to their function, or to their quality of life. If the answer is yes, then we want to treat. If the answer is no, then we want to do frontline active surveillance. If the tumor then changes in its character and becomes threatening, whether to their quality of life or their function, we want to pivot to treat. But if it's growing and that answer is no, we want to continue to observe. Not included in the fine print, the Sporadic Desmoid Tumor Working Group recommends waiting until third progression to treat.

How do the NCCN guidelines differ from the Desmoid Tumor Working Group, and what is their suggested approach?

The NCCN guidelines have a slight difference [where] they highlight the importance of looking for familial adenomatous polyposis and thinking about it if it's an intra-abdominal tumor, if there's a strong family history, and then the impact this will have on referring for genetics and screening for the other family members.²

The present version of the NCCN guidelines on desmoid tumors similarly align with the Sporadic Desmoid Tumor Working Group consensus statement advising to consider active surveillance up front, and if someone is symptomatic or requires treatment, then treat.

Can you discuss the trials that have been conducted in desmoid tumors?

The first trial that was published by Mrinal M. Gounder, MD, in The New England Journal of Medicine in 2018 was the Alliance A091105 trial [NCT02066181] of sorafenib for the treatment of advanced and refractory desmoid tumors. These patients had to have a confirmed desmoid tumor. They had to be symptomatic or have mild progression, described as a 10% increase in size within 6 months of registration, and they did follow symptoms. What was novel about this study is that they utilized the 50% lower dose than is standard for sorafenib. Rather than 800 mg; they went with 400 mg daily in a 2:1 fashion vs placebo. If you were on placebo at progression, you were allowed to cross over to sorafenib.³

The baseline characteristics were fairly evenly matched. For the primary tumor site, there were very similar rates of extra-abdominal vs intra-abdominal tumors. Similarly, 36% vs 41% of patients had prior therapy in the sorafenib and placebo arm, respectively.

What was the efficacy and toxicity with sorafenib in these patients?

Sorafenib had a significant improvement in progression-free survival, which was the primary end point. There was an HR of 0.13 and a significant P value [P <.001].

When I'm counseling my patients on upfront surveillance, I show them that in this study where patients had slight growth in their desmoid tumor and were symptomatic and were randomly assigned to get sorafenib or placebo, the sorafenib worked.

Above 30% of patients hit that 30% response rate, but we also saw a 20% [response rate] for patients on placebo. In patients who are on the fence, when I share this with them, it helps them get over that hesitancy with active surveillance.

As expected with sorafenib, with its use in other malignancies, we saw the typical adverse events [AEs] we might see, albeit slightly less than with the 800-mg dose. The study team was lauded for considering that lower dose.

Which other trials showed positive data in the desmoid tumor population?

The DeFi clinical trial [NCT03785964], unlike the Alliance trial, was conducted on both sides of the Atlantic Ocean. There were 142 patients in 27 sites. This study was slightly more stringent in its inclusion criteria. You had to show within the preceding year that you had progression by RECIST criteria before you could enroll. Patients were randomly assigned to get nirogacestat at 150 mg twice daily vs placebo. This was a 1:1 randomization, unlike the sorafenib study.⁴

Similarly, they were fairly evenly matched, just like in the sorafenib study. The vast majority, as we expect, had sporadic desmoid tumors. They were fairly equally matched in size, and as we expect, the vast majority were extra-abdominal in location.

How did nirogacestat affect patients’ survival and response on the DeFi trial?

Nirogacestat met its primary end point, which ultimately led to its approval with a 71% improvement and increase in the likelihood of PFS as compared with the placebo arm [HR, 0.29; P <.001].

They were slightly more stringent in their inclusion criteria. You had to show that RECIST-level progression to enroll on this trial, but we still had 8% of patients in the placebo arm achieve a RECIST criteria response. More importantly, nirogacestat had more than a 40% objective response rate showing the activity of this drug in progressive, symptomatic desmoid tumors.

You don't always see these responses early. In fact, it took about just under 6 months to see the initial response on average for patients on nirogacestat. They had 3% to 4% additional responders when they went out to year 3 and year 4.⁵ There was an improvement in pain…but that RECIST criteria response might come later.

What was the AE profile of nirogacestat?

The vast majority of patients on this study had adverse events, and it should be noted that most of these were grade 1/2. But it's not insignificant, so when one considers counseling that patient, we have an option. If we think of our young [patients] who we advise for active surveillance, we want to justify the treatment and the adverse events that might come with it.⁴

If the patient's minimally symptomatic, consider the active surveillance, but at least know that, if you then proceed to treatment, that we do have an effective option.

A unique AE on nirogacestat was the impact on ovarian function. Quite a few patients, especially my younger patients of childbearing age, who are on the forums, who are part of the Desmoid Tumor Research Foundation and involved, will speak about their fear of that ovarian impact.

If it's a small tumor in the abdominal wall location, and they are hesitant about considering systemic therapy because of the AEs and the fear, in that multidisciplinary evaluation, if a local control option like ablation might be an option, that's something we sometimes consider for these patients who are afraid.

How did the ovarian toxicity affect patients over time and how do you discuss it with your patients?

There was a broad definition. This wasn't always adequately captured. Not every patient tracked their menstrual cycles, either at baseline or during the trial, and there were incomplete assessments on the study. So it was reported, was it under reported? Was it over reported? You'll be the judge, but I do think that for this recently approved drug, there's certainly this question out there. However, when we look at those that were captured with ovarian dysfunction, what I want you to note is that of 11 patients who came off nirogacestat for any reason, all of those patients recovered their ovarian function.⁶

In the patients who [stayed on treatment] with nirogacestat after showing evidence of some ovarian dysfunction, just over 70% had resolution in their dysfunction, and 2 patients were lost to follow-up, and their status was unknown. So while this is a concern, I can tell you, I've had this discussion multiple times in recent months, especially since the approval and the data are out there. I've shared with the female patients that the vast majority to date, who we know of, given the limitations that I spoke of in the study, appear to recover their ovarian function.

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DISCLOSURES: There are no relevant disclosures.

REFERENCES:

1. Kasper B, Baldini EH, Bonvalot S, et al. Current Management of Desmoid Tumors: A Review. JAMA Oncol. 2024;10(8):1121-1128. doi:10.1001/jamaoncol.2024.1805

2. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma; version 1.2025. Accessed September 22, 2025. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf

3. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379(25):2417-2428. doi:10.1056/NEJMoa1805052

4. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140

5. Ratan R. DeFi: long-term follow-up of nirogacestat for adults with desmoid tumors. Presented at: 2024 CTOS Annual Meeting; November 13-16, 2024; San Diego, CA. Abstract 103.

6. Loggers ET, Chugh R, Federman N, et al. Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: updated safety analyses from the DeFi phase 3 study. Cancer. 2024;130(16):2812-2821. doi:10.1002/cncr.35324