DeFi Study Establishes Role of Nirogacestat in Desmoid Tumors

Richard F. Riedel, MD

Professor of Medicine

Duke University School of Medicine

Member, Duke Cancer Institute

Durham, NC

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

Targeted Oncology: How did the DeFi trial (NCT03785964) investigate nirogacestat (Ogsiveo) in patients with desmoid tumors?

This was a randomized phase 3 study for patients with progressing desmoid tumors. They were randomized to either nirogacestat, a γ-secretase inhibitor, at a dose of 150 mg twice daily, compared with a match of placebo. They were followed up to the double-blind portion [followed by] open-label extension. The primary end point was progression free survival [PFS]. There were quality of life measures and there were patient-reported outcomes [PROs]. This study in particular did a wonderful job of looking at PROs, which is important because overall survival is not a reasonable end point because [all the patients] are going to live.

What baseline characteristics were important in this study?

Sixty percent of the patients in both arms had some prior systemic therapy, so 40% were treatment naive from a systemic therapy standpoint.¹ The vast majority had extra-abdominal [tumors]. We would expect that the vast majority, 60%, had mutations in CTNNB1 which [encodes] β-catenin. Less than 20% had [family history of] familial adenomatous polyposis; we would expect that. If you add it all up, half had surgery, about one-quarter had radiation therapy, and over 60% had some form of systemic therapy. That systemic therapy could have been chemotherapy, it could have been tyrosine kinase inhibitor—it could have been sorafenib [Nexavar].

What were the outcomes of the study?

The primary end point was impressive. PFS was not reached in the nirogacestat arm, [whereas] in the placebo arm, it was about 15 months. It has an HR of 0.29 [95% CI, 0.15-0.55; P < .001]. That means that there was a 71% reduction in the risk for progression or death with the use of nirogacestat. That's an impressive number.

There were only 12 progression events for the nirogacestat in the double-blind portion, and there were close to 40 events in the placebo arm. The chance of being disease-free at 2 years in the nirogacestat arm was about 76%, quite a bit less in the placebo arm [44%]. So clearly an agent with activity, and remember, these were patients who were progressing prior to study entry. So [we are not concerned that] they were already progressive; they've already progressed.

[Looking at] the waterfall plots, there's 1 patient with progression on nirogacestat and the vast majority of patients had some degree in tumor reduction, even if it didn't meet partial response. What's interesting is the placebo group. The response rate here for placebo is 8%, so 8% of patients had spontaneous shrinkage enough to meet partial response, per RECIST. In the sorafenib data, it was 20%.² This is a different population than the sorafenib group, because [in the DeFi trial] they were progressing prior to entry whereas with sorafenib they weren't. This just speaks to the fact that with no intervention, up to 20% of patients can have significant shrinkage of at least 30% to meet partial response per RECIST. The overall response rate was 40% with nirogacestat vs 8% in placebo. The median time to response was less than 6 months, so if you're going to get shrinkage, it happens early. There was a complete response rate of 7% and a partial response rate of 34%, with a disease control rate of 90%.

How long should patients receive nirogacestat?

Recently, a landmark analysis looked at longer-term data for patients who stayed on the drug up to 4 years.³ As you move from year 1 to 2 to 3 to 4, you start seeing an occasional complete response, and partial response gets added with longer treatment. We don't know what the optimal duration of treatment is. The way the study was designed was that you continued until you had progression. In clinical practice, many [physicians] will treat to maximum response and then consider taking a break. It's hard to tell a [patient in their 20s or 30s] that they’re going to be on this drug for the rest of their life. Many of us, admittedly in the absence of data, will treat to maximum response for a year or two, and then pull back and watch.

What is the adverse event (AE) profile with nirogacestat?

The AE profile [includes] gastrointestinal adverse events. It's hypophosphatemia, rash, fatigue, nausea, diarrhea, all of which we see in our day-to-day practices for the other myriad of malignancies that we treat.¹

I'm going to highlight an important AE that was identified in nirogacestat which is ovarian dysfunction. There is female predominance for desmoid tumors. There's a predominance of younger patients being affected. In this study, 75% of the women who were of childbearing potential, 27 of 36, had ovarian dysfunction. If you look at the study, that was a vague term, and it included things like hot flashes, early menopause, ovarian dysfunction, and some hormonal abnormalities. The effect was seen by investigators on the study. I had a patient who developed ovarian dysfunction and a colleague at UCLA had a patient, and we notified [the sponsor] at the same time. They took a step back, and put in some hormone measurements to try to get a sense of this. The feeling is that this is a class effect from γ-secretase inhibitors, in part because the NOTCH signaling pathway is involved with ovarian function.

It appears to be reversible, but you need to have a conversation. [A patient may not] want nirogacestat because they wanted to have children. One of the first patients that I put on was a 22-year-old, and she got hot flashes. She wanted to have children, and we didn't know at the time if it was reversible or not, and she stopped the drug. You have to be aware of this because it's more likely than not that it's going to happen.

Can you give agents to preserve ovarian function as with breast cancer treatment?

It’s a great question. I don't think we know the answer to that. I will get our gynecologist involved, and some of them have recommended leuprolide [Lupron]. It's not clear to me that we have any robust data to guide us in that regard.

DISCLOSURE: Riedel previously reported funding to the institution for clinical trial support from Aadi Bioscience, Adaptimmune, AROG, Ayala, BioAtla, Blueprint, Cogent, Daiichi-Sankyo, Deciphera, GlaxoSmithKline, InhibRx, NanoCarrier, Oncternal, PTC Therapeutics, SARC, SpringWorks, TRACON, and Trillium; consulting fees from Aadi Bioscience, Adaptimmune, Bayer, Blueprint, Boehringer Ingelheim, Daiichi-Sankyo, Deciphera, GSK, NanoCarrier, and SpringWorks; honoraria for lectures from SpringWorks; travel support for advisory board participation for Deciphera.

REFERENCES:

1. Gounder MM, 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

2. 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

3. Kasper B, Ratan R, Alcindo T, et al. Long-term nirogacestat treatment in adult patients with desmoid tumors: updated efficacy and safety from the phase III DeFi trial. ESMO Open. 2025;10(suppl 3):104381. doi:10.1016/j.esmoop.2025.104381

4. 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