Peers Weigh Efficacy vs Toxicity of Nirogacestat in Progressive Desmoid Tumors

Hari Deshpande, MD

Associate Professor of Medicine (Medical Oncology)

Clinical Research Team Leader, Sarcoma

Director, Medical Oncology Inpatient Consult Service

Yale Cancer Center

New Haven, CT

EVENT REGION Maine, Massachusetts, New Hampshire, New York, Ohio

PARTICIPANT LIST Tong Dai, MD | Susana M. Campos, MD, MPH | Dale Shepard, MD, PhD | Dipak B. Ramkumar, MD | Lan Mo, MD | Peter Georges, MD

CASE SUMMARY

• A woman aged 41 years presented to her gynecologist with a 6-month history of a discrete, tender, and enlarging mass in her right abdominal wall.
• Two prior pregnancies with cesarean delivery
• Denies chronic comorbidities and concomitant prescription medications
• Normal menses
• Report of latest Papanicolaou test: negative
• No known family history of familial adenomatous polyposis or colorectal cancer
• Focused physical examination, abdominopelvic: firm, well-defined, immobile mass tender to palpation in the right upper quadrant
• T2-weighted MRI: mildly hypertense mass measuring 4.5 × 3.7 cm along right rectus abdominis muscle with well-defined margins and vascular enhancement
• Biopsy showed desmoid tumor, and her gynecologist decided to observe the patient for enlargement of her abdominal mass and symptom onset. Management consisted of over-the-counter nonsteroidal anti-inflammatory drugs as directed.
• Four months later, the patient returned to her gynecologist with complaints of visceral pain and bloating, nausea, and constipation.
• Right upper quadrant mass now associated with muscular rigidity, localized edema, and pain upon palpation
• Follow-up T2-weighted MRI: mass has rapidly enlarged (15%), now measuring 4.2 × 5.7 cm with well-defined margins and vascular enhancement

DISCUSSION QUESTION

• What adverse events (AEs) reported in the phase 3 DeFi trial (NCT03785964) of nirogacestat (Ogsiveo) are of most concern?

Deshpande: Almost every patient had some kind of AE. That could be grade 1 to 4. Those who had grade 3 or greater were still quite significant: 55% of patients on the treatment arm and, surprisingly, 17% of patients on placebo, possibly due to the location and size [of the tumor].¹ AEs leading to early discontinuation of nirogacestat or placebo [occurred in] 20% in the nirogacestat arm [vs 1% with placebo]. That’s always a number to think about. You’re giving these patients a medication for a nonfatal disease, and why are they stopping the medication?

The [most common AEs] were diarrhea, [which occurred] in 84% of patients, nausea in 54%, and fatigue in 51%. We have seen some quite severe rashes, acneiform rashes, but also hidradenitis-type rashes, which I hadn’t seen since I was a medical student…. Low phosphate was seen, so that’s something that we have to monitor, as well as the complete blood count and chemistries. As oncologists, I know you’re very comfortable with many AEs. Dr Dai, what do you feel about these particular AEs? Would any of them worry you more than others?

Dai: Diarrhea is well known to be caused by γ-secretase inhibitors, so that might be the No. 1 issue.

Deshpande: Right. I typically give them loperamide [Imodium] and [diphenoxylate and atropine (Lomotil)] up front, just because we’re worried about significant diarrhea.

DISCUSSION QUESTION

• How does the ovarian toxicity reported in this trial affect your treatment approach?

Deshpande: Ovarian dysfunction was seen in 39% of patients, and in women of childbearing potential in the safety population, it was [seen in] 75% of patients who were exposed to nirogacestat. Dr Campos, I know you’re used to this in patients receiving chemotherapy, but does this worry you in a nonmalignant condition?

Campos: It’s interesting. What is the mechanism of action? Why is it causing ovarian dysfunction?

Deshpande: That’s a good question.… It’s not like chemotherapy, where we know what’s going on.

Shepard: I don’t think they’ve defined the actual mechanism, and I think it’s a complex issue. At the 2024 American Society of Clinical Oncology Annual Meeting [ASCO], they presented data, and approximately 70% of the patients who were on treatment had resolution of ovarian dysfunction. When patients discontinued, I think 100% of people went back to normal ovarian function.2 The other consideration is that they lumped a whole bunch of things into ovarian function. Part of it was biochemical abnormalities and changes in cycles. It was a catch-all category. In a lot of ways, in the trial they ended up measuring things that most trials don’t. I daresay that most drugs we give would have similar effects on ovarian function.

Deshpande: That’s a good point. Dr Campos, do you have any theories on that?

Campos: I think it’s interesting. In [gynecologic oncology], the ovaries are [removed], and so we don’t worry about ovarian dysfunction as it’s where it starts. From a breast cancer perspective, it’s interesting that you measured that. It is kind of a basket AE pool, and it would be interesting to see what happened to estrogen, estradiol, follicle-stimulating hormone, and luteinizing hormone. I doubt that they have that kind of data, but these have also been mentioned in younger women.

Deshpande: I think [the DeFi investigators] do have those data. I don’t know if it’s been released, but we had to collect it after a certain point for all women of childbearing age.

Ramkumar: The purported mechanism was related to off-target suppression of NOTCH signaling in ovarian follicle maturation that ultimately prevented ovulation from occurring.¹

Deshpande: I don’t know the exact mechanism, but that sounds as good a theory as anything I’ve heard. It was just so unexpected that people made a big deal out of it. Is that how you’re remembering it, Dr Ramkumar?

Ramkumar: Yes, I think that’s been my experience. The recent update that they presented at ASCO with [over] 75% resolution has mimicked my clinical experience as well.²

Deshpande: The quality of life scores were another main reason for doing the study. There was an improvement for patients receiving nirogacestat in terms of the worst pain intensity score [Table 1¹]. The GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale Desmoid Tumor Symptom Scale, or GODDESS DTSS, also [showed] an improvement for patients on the nirogacestat arm.

Looking at patients in subgroups who were felt to have a poor prognosis based on certain factors: large tumor size, the presence of particular CTNNB mutations, younger age, and the presence of pain at baseline.… For all of those different categories, it was in favor of nirogacestat, and in particular for the large tumors, the young patients, and the baseline pain scores, this was statistically significant.³

[Limitations of the trial included that] there was a broad definition of investigator-identified ovarian toxicity; there was a difference in clinical trial coding terms; there was a lack of menstrual diaries, at least at the beginning of the trial; and hormone assessments were incomplete for some patients, and they were only regularly collected after a certain point in the trial.²

Patients were identified with ovarian toxicity in 27 of 36 women, which was 75%. Eleven of [these 27] patients, or 41%, were off nirogacestat for any reason. Four of them stopped because of ovarian toxicity, and 7 stopped for other reasons, and in all of those, the ovarian toxicity resolved.

Fourteen patients had ongoing nirogacestat. To Dr Ramkumar’s point, the ovarian toxicity resolved even on treatment in 71% of patients but remained unresolved in 29%. Two patients [7%] were lost to follow-up after discontinuing nirogacestat, and their ovarian toxicity status is unknown. Dr Mo, does that help you in deciding to give this drug or not?

Mo: For young women, I will probably discuss this ovarian toxicity with them, because a patient younger than 30 years old has more benefit with this medication.

Deshpande: Absolutely, and that’s what I do as well. Most patients are happy to take the medication, because the patients who I see tend to be the more symptomatic ones. But it’s not something you can ignore, and I would definitely have this conversation.

Georges: We’re dealing with a disease that has a very low proliferation rate and is very slow growing with low risk of spread of metastases. I assume we’re going to initiate therapy in patients who have symptoms.… Is there a role of continuing therapy until disease progression, or do we treat to a certain time and stop and watch and use treatment intermittently in those patients, rather than keeping them on therapy ongoing and dealing with all those toxicities?

Deshpande: I think that’s what a lot of oncologists are asking. There is a certain group who feel patients get all the benefit in the first 2 years, and whatever’s left is a shell which might involute and cause some of the responses going forward. There are others who feel you have to continue it because it’s working.

Georges: If you treat them, and you get a complete response, is there a point of continuing therapy in that patient? I know they will probably [have recurrence] at some point, but why not give them a treatment-free interval? Have them recover from the toxicities [so] they’re pain free at that point and they’re probably symptom free. Most of the symptoms at that point are probably related to drug toxicity more than anything. This is a disease that’s not going to spread to the liver or lung and kill you in the next 6 months, so why not give patients a break?

Deshpande: That’s important, and I don’t know the answer to that. Sometimes I wonder if they will [have recurrence], or how long it would take it to recur. I agree with you. There may be people for whom we would want to stop treatment sooner.

Georges: I would think if [there is recurrence], they would still be sensitive to the drug, so you can rechallenge with it later. I know there are no studies to look at that right now, but I wouldn’t think there are acquired mutations against the drug if we stopped it after response.

Deshpande: As far as I know, that’s correct. I don’t think there are any mutations that occur while taking the drug that would make it not respond later on. There is another drug that might be on the market soon, so there are other treatments that may become available soon.

Georges: With the ovarian toxicity, is there any role for ovarian suppression in those patients? Would that help mitigate that toxicity?

Deshpande: In the trial, that was not looked at. [Some physicians] might be doing that off-label. My feeling is, if most of them are going to recover their function anyway, then it’s probably not needed. It’s not chemotherapy, and the 71% resumption of ovarian function even in patients who continued suggests you probably don’t need that. But, if someone’s very concerned about ovarian toxicity, that might be something to think about. I don’t know how effective it would be.

CTNNB mutations accounted for 52% of patients with ovarian toxicity and 89% of patients without ovarian toxicity.2 But the numbers are pretty small. With more systemic treatments, there were 14 patients, or 52% who had ovarian toxicity, and 4 who did not have ovarian toxicity if they had more than 2 prior systemic treatments. The number is a bit lower when you look at more than 4 systemic treatments. I don’t know if we can get too much out of this [analysis]. The numbers, again, are very small, so you can’t predict too much about who’s going to get this toxicity.

In some of the patients who had the toxicity after it was being recognized, ovarian failure was noted in the majority of patients, followed by premature menopause, amenorrhea, and menopause [Table 2²].

The time to onset was 8.9 weeks, and the duration of ovarian toxicity was 19.1 weeks. The patients had dose modifications, either interrupted [7%], reduced [7%], or withdrawn [15%].

DISCLOSURES: Campos previously reported a consulting or advisory role with GlaxoSmithKline, Eisai, and AstraZeneca, and honoraria from AstraZeneca, Eisai, GlaxoSmithKline, Novartis, Merck, and Genmab. Deshpande previously reported consulting fees from Deciphera Pharmaceuticals and SpringWorks Therapeutics and fees for professional activities from Blueprint Medicines Corporation, Daiichi Sankyo Company, and Exelixis. Shepard previously reported consulting or advisory roles for AADi, Deciphera, Replimune, and Sanofi; honoraria for Deciphera; and research funding (institution) for Amgen, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Compugen, Genentech/ Roche, Harpoon Therapeutics, Inhibrx, Lilly, MabSpace Biosciences, Novartis, Pionyr, Shanghai Miracogen Inc, Tempus, and VBL Therapeutics.

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. 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

3. Vincenzi B, Bui NQ, Dileo P, et al. Efficacy of nirogacestat in patients with desmoid tumors and poor prognostic factors: patient-reported outcomes, progression-free survival, and objective response rate in the phase 3 DeFi trial. Presented at: Connective Tissue Oncology Society 2024 Annual Meeting; November 13-16, 2024; San Diego, CA. Paper 102.