Nirogacestat hydrobromide, a gamma secretase inhibitor, is an antineoplastic agent.1
Nirogacestat is used for the treatment of adults with progressing desmoid tumors who require systemic treatment.1 Nirogacestat has been designated an orphan drug by FDA for this use.2
The current indication for nirogacestat is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled trial (DeFi).1, 3 In the trial, 142 adults with progressing desmoid tumors (≥20% progression according to the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1, within 12 months of screening) not amenable to surgery were randomized 1:1 to receive nirogacestat 150 mg or placebo twice daily until disease progression or unacceptable toxicity.1, 3 Imaging for tumor progression was performed every 3 months.1 The primary efficacy outcome was progression-free survival based on RECIST version 1.1 as assessed by blinded independent central review, or on clinical progression (worsening of symptoms causing global deterioration of health status and need for emergent treatment and trial discontinuation) by the investigator and confirmed by independent review.1 Objective response rate was another efficacy outcome measure.1
The median patient age was 34 years (range, 18-76);1, 3 65% of patients were female, 83% were white, and 73 or 27% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, respectively.1 The majority of patients (77%) had extra-abdominal disease only; 41 or 59% of patients had multifocal or single focal disease, respectively.1 Twenty-three percent of patients received no prior therapy, and 44% received ≥3 lines of prior therapy (i.e., surgery, radiotherapy, or systemic therapy).1 At baseline, uncontrolled pain (Brief Pain Inventory-Short Form average worst pain intensity score >4) was reported by 39 or 43% of patients randomized to nirogacestat or placebo, respectively.3
The overall median follow-up for progression-free survival was 15.9 months at data-cutoff.3 Twelve events of disease progression or death were observed in the nirogacestat group, compared to 37 events in the placebo group.1, 3 Observed events were radiographic progression (in 11 and 30 patients who received nirogacestat and placebo, respectively), clinical progression (in 1 and 6 patients, respectively), and death (in 0 and 1 patient, respectively).1, 3 The median progression free survival was not reached for the nirogacestat group and was 15.1 months for the placebo group.1, 3 The objective response rate was 41 or 8% for nirogacestat or placebo, with median time to a confirmed first response of 5.6 or 11.1 months, respectively.1, 3 Change from baseline in patient-reported worst pain favored nirogacestat.1
The Desmoid Tumor Working Group, an international working group, describes desmoid tumors as a rare monoclonal, fibroblastic proliferation, which may occur at abdominal, intra-abdominal, and extra-abdominal sites and with a varied clinical course.4 In general, active surveillance is considered the first step in treatment after diagnosis, with regular monitoring using magnetic resonance imaging.4 For persistent progressive disease or disease close to critical anatomical structures, active therapy (i.e., surgery, radiotherapy, and/or systemic treatment) may be used; treatment is guided according to the anatomical site.4 Systemic medical treatment consists of anti-hormonal agents, nonsteroidal anti-inflammatory drugs, tyrosine kinase inhibitors, and low-dose or conventional chemotherapy.4 The availability of nirogacestat predates the Desmoid Tumor Working Group guideline; the specific place in therapy of nirogacestat is therefore not addressed.4 Nirogacestat is the first approved treatment for desmoid tumors.5
Administer nirogacestat orally with or without food.1 Swallow tablets whole; do not break, crush, or chew prior to swallowing.1
Nirogacestat is available as tablets containing 50, 100, or 150 mg.1
If a dose is missed or vomiting occurs, instruct the patient to take the next dose at its scheduled time.
Store nirogacestat tablets at 20-25°C (excursions permitted between 15-30°C).1
Dosage of nirogacestat hydrobromide is expressed in terms of nirogacestat.1
For the treatment of adults with progressing desmoid tumors who require systemic treatment, the recommended dosage of nirogacestat is 150 mg orally twice daily until disease progression or unacceptable toxicity occurs.1 Each 150 mg dose of nirogacestat consists of three 50-mg tablets or one 150-mg tablet.1
Dosage Modification for Toxicity
See Table 1 for recommended nirogacestat dosage modifications for selected severe adverse reactions.1
For other severe adverse reactions, life-threatening adverse reactions, or persistent intolerable grade 2 adverse events, withhold nirogacestat until resolution to grade ≤1 or baseline.1 Only restart nirogacestat at a dosage of 100 mg twice daily after considering the potential benefit and likelihood of recurrence of the adverse reaction.1 Permanently discontinue nirogacestat for recurrence of severe or life-threatening reaction upon rechallenge at the reduced dosage.1
Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
Diarrhea persisting for ≥3 days despite maximal medical therapy | Grades 3 or 4 | Withhold nirogacestat until resolution to grade ≤1 or baseline, then restart at a dosage of 100 mg twice daily |
Increased ALT or AST | Grade 2 (≥3-5 times upper limit of normal [ULN]) | Withhold nirogacestat until ALT, AST, or both are resolved to <3 times ULN or baseline, then restart at a dosage of 100 mg twice daily |
Increased ALT or AST | Grades 3 or 4 (>5 times ULN) | Permanently discontinue |
Hypophosphatemia persisting for ≥3 days despite maximal replacement therapy | Grades 3 or 4 | Withhold nirogacestat until resolution to grade ≤1 or baseline, then restart at a dosage of 100 mg twice daily |
Hypokalemia dispite maximal replacement therapy | Grades 3 or 4 | Withhold nirogacestat until resolution to grade ≤1 or baseline, then restart at a dosage of 100 mg twice daily |
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1 However, hepatotoxicity during treatment requires dosage modification (See Table 1).1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Diarrhea, sometimes severe, can occur in patients treated with nirogacestat.1
In the nirogacestat clinical trial, diarrhea occurred in 84% of patients, including grade 3 events in 16% of patients.1 The median time to first diarrhea event was 9 days (range, 2-434 days).1
Monitor patients and manage using antidiarrheal medications.1 Modify dosage as recommended (See Dosage Modification for Toxicity).1
Female reproductive function and fertility may be impaired in patients treated with nirogacestat.1 Impact on fertility may depend on factors including the duration of therapy and the state of gonadal function at the time of treatment.1 The long-term effects of nirogacestat on fertility have not been established.1
Before initiating nirogacestat, advise females of reproductive potential of possible risks for ovarian toxicity.1 Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency (e.g., hot flashes, night sweats, vaginal dryness).1
Hepatoxicity can occur in patients treated with nirogacestat.1
Elevations in ALT or AST occurred in 30 or 33% of patients who received nirogacestat in the clinical trial, respectively.1 Grade 3 ALT or AST elevations (>5 times ULN) occurred in 6 or 2.9% of patients, respectively.1
Monitor liver function tests regularly and modify dosage as recommended.1
New non-melanoma skin cancers can occur in patients treated with nirogacestat.1
In the clinical trial, cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9 and 1.4% of patients, respectively.1
Perform dermatologic evaluations prior to initiation of nirogacestat and routinely during treatment.1
Electrolyte abnormalities can occur in patients treated with nirogacestat.1
In the clinical trial, decreased phosphate and potassium levels were observed in 65 and 22% of patients, respectively.1 Phosphate levels <2 mg/dL occurred in 20% of patients treated with nirogacestat, and grade 3 decreased potassium occurred in 1.4% of patients.1
Monitor phosphate and potassium levels regularly and supplement as necessary.1 Modify nirogacestat dosage as recommended.1
Fetal/Neonatal Morbidity and Mortality
Nirogacestat use during pregnancy can cause fetal harm based on findings from animal studies and the mechanism of action of the drug.1
Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryofetal toxicity and death at maternal exposures below the human exposure at the recommended dosage of 150 mg twice daily.1 Animal studies also indicate that nirogacestat may impair female and male fertility.1
Verify pregnancy status in females of reproductive potential prior to initiating nirogacestat.1 Apprise pregnant women of the potential hazard to a fetus.1 Advise females and males of reproductive potential to use effective contraception during treatment with nirogacestat and for 1 week after the last dose.1
Nirogacestat use during pregnancy can cause fetal harm based on findings from animal studies and the mechanism of action of the drug.1 Human data on nirogacestat use during pregnancy are not available.1 Daily oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in decreased fetal body weights, pre- and post-implantation loss, and fetal subcutis edema at doses ≥20 mg/kg per day (approximately 0.85 times the recommended dose of 150 mg twice daily based on AUC).1
Verify pregnancy status in females of reproductive potential prior to initiating nirogacestat.1 Apprise pregnant women of the potential hazard to a fetus.1
It is unknown whether nirogacestat or its metabolites distribute into human milk, or affects milk production or the breast-fed child.1
Because of the potential for serious adverse reactions in breast-fed children, advise women not to breast-feed during treatment with nirogacestat and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Nirogacestat can cause fetal harm when administered to pregnant women.1 Nirogacestat can also impair female and male fertility based on findings in animal studies.1 In nonclinical studies, nirogacestat has been shown to interfere with folliculogenesis and spermatogenesis resulting in changes such as ovarian atrophy.1
Verify pregnancy status in females of reproductive potential prior to initiating nirogacestat.1 Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with nirogacestat and for 1 week after the last dose.1
The safety and effectiveness of nirogacestat have not been established in pediatric patients.1 Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, has been reported in children with open growth plates treated with nirogacestat.1
Of the total number of patients treated with nirogacestat in the clinical trial, 4% of patients were ≥65 years of a none were ≥75 years of age.1 Experience in patients ≥65 years of age is insufficient to determine whether they respond differently to nirogacestat than younger adults.1
The mean nirogacestat AUC increased by ≤16% and the mean peak plasma concentration decreased by ≤39% in patients with moderate hepatic impairment (identified by Child-Pugh class B, or National Cancer Institute-Organ Dysfunction Working Group group C criteria) compared to patients with normal hepatic function.1 Data are insufficient to characterize nirogacestat pharmacokinetics in patients with severe hepatic impairment.1
Mild or moderate renal impairment (estimated glomerular filtration rate ≥41 mL/minute per 1.73m2) did not have a clinically important effect on the pharmacokinetics of nirogacestat.1
The most common adverse reactions reported in ≥15% of patients receiving nirogacestat were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.1
Nirogacestat is primarily metabolized by N-dealkylation via cytochrome P-450 (CYP) isoenzyme 3A4; secondary pathways include metabolism by CYP isoenzymes 3A4, 2C19, 2C9, and 2D6.1
Nirogacestat is a CYP3A substrate.1 Nirogacestat is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.1 Nirogacestat is an inducer of CYP2B6, 2C8, 2C9, and 2C19, but not an inducer of CYP1A2.1
Nirogacestat is a substrate of P-glycoprotein (P-gp), but not a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, or OATP1B3.1
Nirogacestat is an inhibitor of P-gp, but not an inhibitor of BCRP, multidrug and toxin extrusion (MATE) 1, MATE2K, OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT2, or OAT3.1
Drugs Affecting Hepatic Microsomal Enzymes
Strong or Moderate CYP3A Inhibitors
Concomitant use of nirogacestat with a strong or moderate CYP3A inhibitor increases nirogacestat exposure, which may increase the risk of nirogacestat adverse reactions.1
When itraconazole (a strong CYP3A inhibitor) was administered concomitantly with nirogacestat (single dose of 100 mg), nirogacestat peak plasma concentration and AUC increased by 2.5- and 8.2-fold, respectively.1 Nirogacestat AUC is predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with the strong CYP3A inhibitors itraconazole, ketoconazole, and clarithromycin, respectively.1
Nirogacestat AUC is predicted to increase by 2.73- and 3.18-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with the moderate CYP3A inhibitors erythromycin and fluconazole, respectively.1
Avoid concomitant use of nirogacestat with strong or moderate CYP3A inhibitors including grapefruit products, Seville oranges, and starfruit.1
Strong or Moderate CYP3A Inducers
Concomitant use of nirogacestat with a strong or moderate CYP3A inducer decreases serum nirogacestat exposure, which may reduce the effectiveness of nirogacestat.1
Nirogacestat AUC is predicted to decrease by 85% following coadministration of multiple doses of nirogacestat (150 mg twice daily) with rifampin, a strong CYP3A inducer.1
Nirogacestat AUC is predicted to decrease by 67% following coadministration of multiple doses of nirogacestat (150 mg twice daily) with efavirenz, a moderate CYP3A inducer.1
Avoid concomitant use of nirogacestat with strong or moderate CYP3A inducers.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Nirogacestat increases the exposure of certain CYP3A substrates, which may increase the risk of adverse effects related to these substrates.1
Peak plasma concentration and AUC of midazolam (a CYP3A substrate) is predicted to increase by 1.77- and 2.07-fold, respectively, following concomitant use with multiple doses of nirogacestat (150 mg twice daily).1
Avoid concomitant use of nirogacestat with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions.1
Nirogacestat decreases the exposure of certain CYP2C19 substrates, which may decrease efficacy of these substrates.1
Drug interaction studies demonstrate that concomitant use of multiple doses of nirogacestat (150 mg twice daily) with a sensitive CYP2C19 substrate decreases the plasma concentrations of the substrate.1
Avoid concomitant use with nirogacestat where decreased concentrations of CYP2C19 substrates may lead to significant decreases in efficacy of the CYP2C19 substrate, unless otherwise recommended in the prescribing information for the CYP2C19 substrate.1
Drugs Affecting Gastric Acidity
Nirogacestat is poorly soluble at pH ≥6; gastric acid reducing agents may decrease serum nirogacestat exposure, which may reduce its effectiveness.1
Based on drug interaction studies, concomitant administration of proton pump inhibitors (e.g., omeprazole), histamine type 2 (H2) blockers (e.g., famotidine), or antacids (e.g., calcium) is expected to reduce plasma concentrations of nirogacestat.1
Avoid concomitant use of nirogacestat with proton pump inhibitors and H2 blockers.1 If concomitant use cannot be avoided, nirogacestat administration can be staggered with antacids (e.g., administer nirogacestat 2 hours before or 2 hours after the antacid).1
No clinically important differences in nirogacestat pharmacokinetics are predicted when used concomitantly with cimetidine (a weak CYP3A inhibitor).1
Concomitant use of nirogacestat and dabigatran (a P-gp substrate) did not affect peak plasma concentrations and AUC of dabigatran.1
No clinically important differences in the pharmacokinetics of rosiglitazone (a CYP2C8 substrate) are predicted when used concomitantly with nirogacestat.1
No clinically important differences in the pharmacokinetics of S-warfarin (a CYP2C9 substrate) are predicted when used concomitantly with nirogacestat.1
Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of Notch receptors.1 Notch is a signaling protein that, when dysregulated, can activate pathways that contribute to tumor growth.1, 6 It is thought that desmoid tumors produce high amounts of Notch, which may drive their growth.6 While the mechanism of action of nirogacestat in desmoid tumors is not yet fully elucidated, antitumor activity has been demonstrated in patients with such tumors.3
The absolute bioavailability of nirogacestat is 19%.1 The median time to peak plasma concentration of nirogacestat is 1.5 hours (range, 0.5-6.5 hours).1 When administered with food, the dose-normalized geometric mean ratio of nirogacestat peak plasma concentration and AUC is 93 and 114%, respectively.1 The time to steady state of nirogacestat is approximately 6 days.1 The median drug accumulation ratio is 1.6 (range, 1.3-4.6).1
Serum protein binding of nirogacestat is 99.6%; protein binding to human serum albumin and to alpha-1 acid glycoprotein is 94.6 and 97.9%, respectively.1 Nirogacestat is metabolized by N-dealkylation via cytochrome P-450 (CYP) 3A4 (85%; primary pathway) and by 3A4, 2C19, 2C9, and 2D6 (secondary pathways).1 Nirogacestat is excreted in the feces (38%), urine (17%, with <1% unchanged), and expired air (9.7%).1 The mean elimination half-life of nirogacestat is 23 hours.1 No clinically important differences in nirogacestat pharmacokinetics have been observed based on age (18-80 years), sex, or race (Asian, Black or African American, and white).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Nirogacestat is available through specialty pharmacies and specialty distributors.7 Consult the Ogsiveo®website ([Web]) for specific availability information.7
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 50 mg (of nirogacestat) | Ogsiveo® | SpringWorks Therapeutics |
100 mg (of nirogacestat) | Ogsiveo® | SpringWorks Therapeutics | ||
150 mg (of nirogacestat) | Ogsiveo® | SpringWorks Therapeutics |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. SpringWorks Therapeutics, Inc. OGSIVEO® (nirogacestat) ORAL prescribing information. 2024 April. [Web]
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Jun 22. [Web]
3. Grounder M, Ratan R, Alciindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388:898-912.
4. The Desmoid Tumor Working Group. The management of desmoid tumours: a joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020;127:96-107.
5. US Food and Drug Administration. FDA approves nirogacestat for desmoid tumors. From FDA website. 2023 Nov 28. Accessed 2024 Jun 22. [Web]
6. National Cancer Institute. Nirogacestat may offer hope to people with desmoid tumors. From NCI website. 2023 May 1. Accessed 2024 Jun 22. [Web]
7. Ogsiveo®Product Fact Sheet and Ordering Guide. From SpringWorks Therapeutics for Healthcare Professionals website. Accessed 2024 Jun 16. [Web]