FDA approves nirogacestat for desmoid tumors

What is the potential role for nirogacestat in the treatment of desmoid tumors?

  • Desmoid tumors are non-malignant, rare tumors that develop anywhere in the body that has soft, connective tissue. Although they are not cancerous, since they do not metastasize, desmoid tumors can grow quickly and affect nearby organs and tissues potentially leading to severe pain and disability. A majority of patients are women who are usually diagnosed as young adults especially those with familial adenomatous polyposis (FAP). In the past, there was no standard treatment option for desmoid tumors. Surgery and systemic treatment with liposomal doxorubicin or sorafenib were the main treatment modalities. Systemic therapy was often reserved for patients with obstructive or heavily symptomatic disease.2
  • Nirogacestat is a first in class gamma secretase inhibitor that blocks activation of the Notch receptor. Desmoid tumors have been found to produce high amounts of the Notch protein, which promotes the growth of the tumor. Nirogacestat can specifically block the activity of gamma secretase, which is an enzyme that helps activate the Notch pathway.1
  • Nirogacestat was FDA approved in November 2023 for the treatment of adults with progressing desmoid tumors that require systemic treatment, which was based on the findings of the DeFi Trial.3
  • This international, randomized, multicenter, double-blind, placebo-controlled, phase 3 trial evaluated 142 adult patients with progressing desmoid tumors who were not candidates for surgery. Patients were randomized to receive nirogacestat 150 mg orally twice daily or placebo until disease progression or toxicity. The primary endpoint was progression-free survival.4
  • A progression-free survival benefit was seen in the nirogacestat group over placebo and was considered statistically significant (HR=0.29; 95% CI, 0.15 to 0.55; P<0.001) with 76% of patients being event-free at 2 years. Nirogacestat also had a significantly higher percentage of patients who had an objective response when compared to placebo (41% vs. 8%; P<0.001) with a median time to response of 5.6 months versus 11.1 months. The most common adverse effects that occurred were: diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). In addition, ovarian dysfunction occurred in 75% of women of childbearing potential, and resolved among 74% of those women.4 Ovarian dysfunction is defined by the MedDRA preferred terms of amenorrhea, premature menopause, menopause, and ovarian failure. The median time to first onset was 8.9 weeks and the median duration was 19.1 weeks. Resolution of ovarian dysfunction was defined on the basis of the investigator’s assessment of symptoms, reproductive hormone values, or both.
  • Overall, the authors concluded that nirogacestat had significant benefits in regards to progression-free survival, objective response, pain, and overall quality of life in patients who had progressing desmoid tumors.4
  • The National Comprehensive Cancer Network (NCCN) guidelines have now incorporated nirogacestat as a category 1 preferred agent for adult patients with progressing desmoid tumors.5

What role can the pharmacist play in the management of patients on nirogacestat?

  • Indications:
  • Adult patients with progressing desmoid tumors that require systemic treatment1
  • Dosing:
  • The recommended dosing is 150 mg orally twice daily with or without food until patient has disease progression or toxicity1
  • Renal Dose Adjustments:
  • None1
  • Hepatic Dose Adjustments:
  • There are no dose adjustments provided on the manufacturer label, however, if acute hepatoxicity occurs during treatment, refer to the table below to make appropriate dose modifications.1

  • Dosing Modifications for Adverse Effects:
Adverse Effect1 Grade1 Recommended Modification1
Diarrhea that persists for ≥3 days despite maximal medical therapy 3 or 4 Hold until resolved to Grade ≤1 or baseline, then restart at 100 mg twice daily
Alanine Transaminase (ALT) or Aminotransferase (AST) increase 2 (≥3-5 x ULN) Hold until AST, ALT is resolved to <3 x ULN or baseline, then restart at 100 mg twice daily
3 or 4 (>5 x ULN) Permanently discontinue
Hypophosphatemia that persists for ≥3 days despite maximal medical therapy 3 or 4 Hold until resolved to Grade ≤1 or baseline, then restart at 100 mg twice daily
Hypokalemia despite maximal replacement therapy 3 or 4 Hold until resolved to Grade ≤1 or baseline, then restart at 100 mg twice daily
Other Adverse Drug Reactions Severe; OR Life-threatening; OR Persistent, intolerable grade 2 Withhold nirogacestat until resolved to grade ≤1 or baseline; resume nirogacestat at 100 mg twice daily only after consideration of potential benefit and likelihood of toxicity recurrence.  Recurrence of severe or life-threatening adverse reactions following rechallenge at the reduced dose: Permanently discontinue nirogacestat.

  • Drug-Drug Interactions:
  • Nirogacestat is a substrate for CYP3A4, therefore, strong or moderate CYP3A4 inhibitors are recommended to be avoided since they can increase exposure and ultimately the risk of adverse effects. It is also recommended to avoid strong or moderate CYP3A inducers, because that will decrease effectiveness of nirogacestat by decreasing exposure.1
  • It is recommended to avoid any gastric acid reducing agents such as proton pump inhibitors or H2 blockers since nirogacestat is poorly soluble when a patient’s gastric pH is ≥6. If the use cannot be avoided, it is recommended to stagger the medications (ex: give nirogacestat 2 hours before or after antacid use).1
  • Adverse Effects:
  • The most common adverse effects are diarrhea, ovarian toxicity (hot flashes, night sweats, or vaginal dryness), embryo-fetal toxicity, rash, nausea, fatigue, headache, abdominal pain, cough, hair loss, upper respiratory tract infection, and dyspnea.1
  • The most common lab abnormalities are increased AST, ALT, urine protein, urine glucose, and decreased electrolytes (specifically potassium and phosphate).1.

Clinical Pearls

  • In the Phase III trial, 75% of women had adverse events consistent with ovarian dysfunction, symptoms of this have resolved in 74% of the women affected. At this time, there is no long-term fertility data published. This adverse drug reaction should be discussed with women who desire a pregnancy in the future.4
  • The duration of treatment of nirogacestat remains a question that needs to be studied. Especially because these tumors do not metastasize, it could be reasonable for treatment breaks and holidays – especially in those who desire childbearing.
  • This medication is supplied as 50 mg tablets, this could be a big pill burden since patients will be required to take up to 6 pills a day.
  • If diarrhea becomes significant, patients can take over the counter antidiarrheals to help with symptoms as well as maintaining adequate hydration. If symptoms persist, therapy may need to be withheld or warrant a dose adjustment.1
  • Monitor for signs and symptoms of electrolyte abnormalities, specifically phosphate and potassium; diarrhea, ovarian toxicity and nonmelanoma skin cancers; long-term effects have not been established.1
  • Routinely monitor electrolytes and liver function lab levels throughout treatment.1
  • Dermatologic evaluations need to be performed at baseline and routinely throughout treatment.1
  • Nirogacestat can cause fetal harm, patients of childbearing potential need to be advised of the risks and need to use effective contraception during treatment and up to one week after the last dose of nirogacestat.1
  • Alopecia (19%), fatigue (54%), and cold like symptoms, such as cough (20%), and upper respiratory infections (17%) occurred in the phase III clinical trial. Patients should be educated on these signs and symptoms.4
  • Nirogacestat needs to be stored at room temperature and out of reach of children.1
  • Patient Assistance:
  • Patients can be enrolled in the SpringWorks CareConnections Patient Support Program, this helps navigate insurance, answer questions, and helps patients get started and maintained on treatment. Patients can also call 844-227-3755 for more assistance.6
  • For commercially insured patients, there is also a copay card that patients may be eligible for. This can be found at: Commercial Copay Program | SpringWorks CareConnections™ (springworkstxcares.com)6


1.Nirogacestat [package insert]. FDA: SpringWorks Therapeutics Inc; 2023.

2.van Broekhoven, DLM; et al. Time trends in the incidence and treatment of extra-abdominal and abdominal aggressive fibromatosis: a population-based study. Ann Surg Oncol. 2015;22(9):2817-2823

3.Food and Drug Administration. “FDA Approves Nirogacestat for Desmoid Tumors.” FDA approves nirogacestat for desmoid tumors | FDA. 28 November 2023.

4.Gounder, M; et al. Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors. N Engl J Med. 2023 Mar 9;388(10):898-912. doi: 10.1056/NEJMoa2210140. PMID: 36884323.

5.NCCN Guidelines. Soft Tissue Sarcoma. Version 3.2023.

6.SpringWorks Therapeutics. Ogsiveo (Nirogacestat). OGSIVEO ™ (nirogacestat) | Official HCP Website. January 2024.

Brooke Lochridge

PharmD, PGY-2

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