Evaluating Survival, Long-Term Use of Nirogacestat in Desmoid Tumors

Nam Quoc Bui, MD

Clinical Associate Professor of Medicine

Stanford Cancer Institute

Stanford, CA

Please discuss the design of trial of nirogacestat (Ogsiveo) for patients with desmoid tumors.

Nam Quoc Bui, MD: The DeFi trial [NCT03785964], a phase 3 clinical trial…was published in the New England Journal of Medicine before it was presented at the 2024 Connective Tissue Oncology Society Annual Conference.¹ This trial involved 142 patients across North America and Europe. The trial enrolled patients who had progressive desmoid tumors, meaning patients who had documented 20% growth within the past 12 months.

This was a very strict inclusion criterion because many patients have desmoid tumors that are not growing, or the tumors are so large that 20% growth is a [significant amount]. These were patients with the highest-risk desmoid disease, which had grown by 20%. There was a double-blind portion followed by an open-label extension. Patients were randomly assigned to receive either nirogacestat vs placebo, and it was blinded so neither patients nor physicians knew who was receiving what. Patients on placebo who experienced progression could cross over to nirogacestat.

The primary end point was progression-free survival [PFS]. Secondary end points included objective response rate [ORR] and patient-reported outcomes [PROs]. Patients used a tablet or phone app to log their [symptoms], and we received emails if they didn’t adhere, so we had to ensure they were adherent. [The logs] included pain symptom burden, physical function, and overall quality of life. We looked at tumor response, durability, PROs…and safety, which was reported as treatment-emergent adverse events [AEs].

What were the baseline characteristics of this trial population?

Tumor locations were evenly split, with about 75% being extra-abdominal. Most tumors were single, though about 40% were multifocal. These were large tumors, with a median size of about 91.6 mm for nirogacestat and 115.7 mm for placebo. About 16% to 18% had risk of familial adenomatous polyposis, which aligns with the expected rate. Sixty percent had CTNNB1 mutations, though a quarter had no mutations analyzed.

Many patients were pretreated—about 74% in the nirogacestat arm and 81% in the placebo arm. The median number of prior therapies was 2, and patients had previous local treatments, including surgery at 44% and 61% with nirogacestat vs placebo respectively. With radiation, it was 23% and 22%, and other systemic therapies, such as chemotherapy and tyrosine kinase inhibitors [TKIs], were also used. Many patients had uncontrolled pain—39% and 43% for the 2 groups respectively.

What were the efficacy outcomes in the DeFi trial?

There was an impressive Kaplan-Meier plot demonstrating that median PFS significantly improved with nirogacestat compared with placebo, with an HR of 0.29 [95% CI, 0.15-0.55], which is very impressive. The P value was less than .001, and the median PFS was not reached for nirogacestat, whereas it was 15.1 months for placebo. It took a while for the placebo group to progress—this isn’t like a metastatic lymphoma trial where progression happens at 3 months. Desmoid tumors can be slow-growing, even in patients who had 20% growth in the past year. It can still take 15 months for them to grow another 20%.

The likelihood of being progression free at 2 years was 76% for nirogacestat and 44% for placebo. At 2 years, 12 patients on nirogacestat and 37 on placebo met the event, meaning the placebo group had triple the likelihood of progression.

Nirogacestat had much better responses, with many partial responses and even some complete responses. Very few patients had true progression on nirogacestat. Most had minor shrinkage or stable disease. In the placebo group, there was more progression or minor growth. Interestingly, some patients had spontaneous regression. This is why access to trials is important, even for patients who had 20% regression and enrolled in this trial.

Did patients continue nirogacestat indefinitely, and when would you consider stopping nirogacestat?

They were supposed to continue; there was no stopping. The median treatment duration [was 20.6 months (range, 0.3-33.6)], so patients were on the drug for a long time.

The question is, when do you stop these drugs? These questions aren’t answered in these pivotal trials. It will require post-marketing data and collaborations between investigators to pool data and figure it out. But that won’t be published for a while, until we have more time with patients on this drug in a larger population.

How did patients respond to nirogacestat over time compared with placebo?

The ORR was much higher for nirogacestat—41% vs 8% for placebo [P < .001]. The time to response was also quicker with nirogacestat—5.6 months vs 11.1 months. Most responses were partial, at 34%, though some were complete, at 7%. The disease control rate was 91% for nirogacestat and 85% for placebo, which is pretty high. Most patients, even on placebo, were stable at 12 weeks.

The landmark analysis showed the response rate deepened over time.² At year 1, only 30% had partial response, but that increased to 34.3% [by year 4], and complete response went from 4.3% to 11.4%. So, the longer patients are on the drug, the more likely they are to respond. But this still doesn’t answer how long patients should stay on it.

What are the AEs seen with nirogacestat for patients with desmoid tumors?

If patients are on this drug for 3 years or more, we need to know what they’ll be dealing with. Overall, it’s relatively well tolerated.¹ It’s a TKI, not chemotherapy, so patients won’t lose their hair or get neutropenic fever. They can work and do daily activities. The most common AE is diarrhea. We counsel patients that they may have diarrhea, but it’s manageable with loperamide or diphenoxylate/atropine, or we can dose reduce. The rate is high—84%—but it’s manageable. About 20% discontinued nirogacestat due to AEs vs 1% on placebo. Other AEs include nausea, fatigue, and hypophosphatemia. Patients are generally asymptomatic from hypophosphatemia, but we check it regularly, and some patients need phosphate supplements. Rash is another AE. Some patients have had whole-body rashes within the first couple of weeks, though most have milder rashes.

Patients on nirogacestat had significant improvement in symptoms, including pain…. I’ve noticed that pain improves very quickly—within 2 weeks, patients are off opioids and feeling better. The MRI may not change much initially, but it does over time. Pain scores improved by cycle 2, with most patients responding by the second scan at 6 months.

Can you discuss the ovarian toxicity in more detail for these patients?

As oncologists, we give many toxic treatments like chemotherapy or TKIs that impair ovarian function, but we don’t always think about it because patients are often focused on life-threatening malignancies. But with desmoid tumors, these are young women in their 20s and 30s who may want to have children. We realized that many were becoming postmenopausal or entering menopause while on this drug. Their menstrual cycles became irregular, then they became amenorrheic, and some had postmenopausal symptoms like hot flashes.³

In terms of ovarian dysfunction, serum hormone levels were collected at baseline and cycles 1, 2, and 4. About 75% of patients on nirogacestat had ovarian dysfunction vs 0% on placebo. The median time to onset was 8.9 weeks, and the median duration was 21 weeks. Of the 11 patients who stopped nirogacestat, all recovered ovarian function, so this is not permanent. We can tell patients it’s unlikely they’ll be permanently postmenopausal.

DISCLOSURE: Nam Quoc Bui, MD, has no known disclosures.

_References:

_{1. 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}

_{2. SpringWorks Therapeutics announces long-term efficacy and safety data from phase 3 defi trial of OGSIVEO® (nirogacestat) in adults with desmoid tumors to be presented at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting. News release. SpringWorks Therapeutics. Accessed March 5, 2025. https://tinyurl.com/4tydvsw4}

_{3. Loggers ET, Chugh R, Federman N, et al. Onset and resolution of ovarian toxicity with nirogacest at treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study. Cancer. 2024;130:2812–2821. doi:10.1002/cncr.35324}