Oncologists Consider Treatment Duration and New Options in Progressive Desmoid Tumors

During a live event, Brittany Siontis, MD, a sarcoma oncologist at Mayo Clinic, and participants examined how to choose between the systemic options for progressive desmoid tumors, how long to continue treatment in a responding patient, and what emerging data from the RINGSIDE trial (NCT04871282)of varegacestat (AL102) may eventually add to the therapeutic toolkit.

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This is part 2 of a 2-part series. Read part 1.

CASE SUMMARY

• A 50-year-old man presents with intermittent abdominal pain.
• The patient denies prior trauma to the site or gastrointestinal symptoms.
• Past medical and social history: denies chronic comorbidities and concomitant medications; no known family history of familial adenomatous polyposis (FAP) or colorectal cancer (CRC)
• Focused physical examination: abdominopelvic: tender to palpation in the right mid-abdomen
• Diagnostic studies: MRI showed mass measuring 5 cm; suggestive of desmoid fibromatosis; post-MRI biopsy confirmed; no sign of bowel compression; in retrospect, had been present for at least 6 months

EVENT RECAP

The second case patient’s intra-abdominal location and documented growth over 6 months put him in a category where observation alone carries real risk, but the absence of bowel compression created genuine ambiguity about when to act. When asked for their initial treatment preference, nearly 60% of participants chose active surveillance and others chose nirogacestat (Ogsiveo) or sorafenib (Nexavar), but the participant discussion captured the uncertainty practitioners feel. Siontis said that if symptoms are clearly attributable to the desmoid tumor and worsening, therapy is appropriate; whereas if there is any doubt about the source, a 3-month rescan is justifiable.

CASE UPDATE

• Based on the presence of symptoms, active growth, and multiple treatment options, the patient and his physician agreed to proceed with treatment.​
• As they discussed potential treatment options, the following concerns were brought forward:​
  • His concerns about active surveillance are related to disease progression and worsening symptoms​.
  • He was concerned about sorafenib treatment due to risk of abdominal complications and adverse events.​
• Based on these concerns, nirogacestat 150 mg twice daily was given.
• He generally tolerated the oral treatment well, with his only complaint being occasional (grade 1) diarrhea.
• With 2-mg loperamide as needed, diarrhea resolves; no dosing adjustments were necessary. ​
• After 6 months of treatment, another MRI was done and showed that the tumor had shrunk from 5 cm to 2 cm.​
• The treatment plan is to continue treatment to reach maximal tumor reduction.

Siontis described this outcome as typical: as responses to nirogacestat accumulate over months, the plan is to continue toward maximal tumor reduction. “I think you could probably ask 10 sarcoma oncologists and get 15 different answers to how long they treat patients,” she acknowledged. She observed that the DeFi trial (NCT03785964) investigators reported 4-year treatment outcomes for 15 patients, but these data could not show how those patients would have fared had they discontinued nirogacestat earlier.¹

Balkrishna N. Jahagirdar, MBBS, raised the challenge of maintaining adherence through a response timeline that may not arrive until month 5 or 6, noting that reinforcing that expectation is part of the conversation. He added that sorafenib does not carry an FDA label for desmoid tumors whereas nirogacestat does, but both are now NCCN category 1 recommendations, a distinction that matters for community prescribers facing payer scrutiny.²

Siontis reviewed the A091195 trial (NCT02066181), which randomly assigned patients with progressive or unresectable desmoid tumors 2:1 to sorafenib 400 mg once daily vs placebo, showing an HR for investigator-assessed progression-free survival (PFS) of 0.13 (95% CI, 0.05-0.31; P <.001).³ Although the HR appears more impressive than the 0.29 seen in DeFi comparing nirogacestat with placebo, Siontis and Jahagirdar both cautioned against a direct cross-trial comparison, noting that A091195 did not require documented radiographic progression at enrollment, whereas DeFi required confirmed RECIST progression before randomization, creating a meaningful difference in the trial populations.

The practical comparison that most shaped the group’s discussion was tolerability. Siontis described palmar-plantar erythrodysesthesia, or hand-foot syndrome, as her most persistent challenge with sorafenib, and said she is more cautious initiating it in younger, physically active patients for whom it would be particularly disruptive. The diarrhea associated with nirogacestat, which occurred at an 84% any-grade rate among DeFi patients, is generally manageable with antidiarrheals and dose adjustment.⁴

Siontis said she has rechallenged patients who came off therapy and subsequently progressed, and that prior response is a reasonable basis for reinitiating the drug. Nicole Jacobi, MD, asked whether stopping at plateau, surveilling, then restarting at progression might spare cumulative toxicity; Siontis agreed it is a reasonable strategy, and that she approaches the decision collaboratively with each patient. Yan Ji, MD, asked if there are trials using nirogacestat as neoadjuvant/adjuvant therapy in combination with resection; Siontis said there is likely some interest in this approach but it currently lacks supporting data.

Siontis also presented findings from the RINGSIDE trial, a phase 2 study of varegacestat, another gamma-secretase inhibitor like nirogacestat, in 42 patients with desmoid tumors.⁵ Three dose schedules were evaluated before the 1.2-mg once-daily cohort was selected for expansion. Any-grade treatment-emergent adverse events were universal, with no grade 4 or 5 events; common toxicities included gastrointestinal effects, fatigue, dry skin, stomatitis, and alopecia; the last occurring more frequently than with nirogacestat. Ovarian toxicity was observed in 67% of women of reproductive potential in the 1.2-mg cohort. Among 9 patients at that dose, 75% achieved a partial response with a median time to objective response of approximately 7 months. Siontis told the group that the phase 3 readout included a PFS HR of 0.16 (P <.0001) and all key secondary end points were met, including an objective response rate of 56%. Following the live event, the full results were presented at the American Society of Clinical Oncology Annual Meeting.⁶

In the final thoughts from the discussion, Jahagirdar credited the DeFi trial success to the patients and families who pushed to improve clinical trial enrollment in this rare disease. “They are the ones who actually rallied, and got all the support, and enrolled all the patients,” he said. Siontis agreed, pointing to the Desmoid Tumor Research Foundation as a model of patient advocacy in an ultra-rare disease, and noting that the ability to quickly enroll and complete randomized phase 3 trials in single sarcoma subtypes is due in no small part to the infrastructure of patient advocacy groups.

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_{DISCLOSURES: Siontis previously disclosed consulting for Deciphera and institutional support from Ratio Therapeutics.}

REFERENCES

1. Ratan R, et al. Efficacy and safety of long-term continuous nirogacestat treatment in adults with desmoid tumors: results from the DeFi trial. J Clin Oncol. 2025;43(34):3646-3651. doi:10.1200/JCO-25-00582

2. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 3.2026. Accessed July 6, 2026. https://tinyurl.com/2tha348t

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. Kasper B, Gounder M, Chugh R, et al. Updated results of the RINGSIDE phase II trial and open-label extension of AL102 for treatment of desmoid tumors. Ann Oncol. 2024;35(suppl 2):S1051-S1052. doi:10.1016/j.annonc.2024.08.1857

6. Gounder M, Rutkowski P, Jones RL, et al. RINGSIDE: A phase 3 randomized, placebo-controlled trial of varegacestat for treatment of progressing desmoid tumors. J Clin Oncol. 2026;44(suppl 16):11506. doi:10.1200/JCO.2026.44.16_suppl.1150