NCCN Adds Nirogacestat to Guidelines for Patients With Soft Tissue Sarcoma

The National Comprehensive Cancer Network (NCCN) has updated their guidelines for soft tissue sarcoma to include the γ-secretase inhibitor nirogacestat (Ogsiveo) as a systemic therapy option for patients with desmoid tumors, granting the agent a preferred, category 1 recommendation.¹

In version 3.2023 of the soft tissue sarcoma guidelines, published on December 12, 2023, the guidelines state, “Based on FDA approval, nirogacestat has been included as a systemic therapy option for desmoid tumors [aggressive fibromatosis].”

On November 27, 2023, the FDA approved nirogacestat for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. Nirogacestat was the first agent to gain approval from the agency for the treatment of patients with desmoid tumors.²

“The FDA continues to address unmet medical need and advance the development of safe and effective therapies for the millions of Americans whose lives are affected by rare tumors,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release at the time of the approval. “Desmoid tumors are rare tumors that can lead to severe pain and disability. [This] approval will offer the first approved treatment option for patients beyond surgery and radiation.”

The regulatory decision was supported by findings from the phase 3 DeFI trial (NCT03785964), which evaluated nirogacestat in patients with desmoid tumors/aggressive fibromatosis. The international, double-blind, placebo-controlled trial enrolled patients who were at least 18 years of age who had not received previous therapy for progressing desmoid tumors who were not amenable to surgery or had relapsed/refractory desmoid tumors following a minimum of 1 line of treatment.³

Patients were randomly assigned 1:1 to receivenirogacestat 150 mg (n = 70) or placebo (n = 72) twice daily given continuously in 28-day cycles. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), health-related quality of life, and safety.

At the April 7, 2022, data cutoff, the median PFS in the nirogacestat arm was not estimable (NE; 95% CI, NE-NE) compared with 15.1 months (95% CI, 8.4-NE), conferring a 71% reduction in the risk of progression or death (HR, 0.29; 95% CI, 0.15-0.55; P < .001) in the investigational arm vs the control arm. The estimated 1-year PFS rates were 85% (95% CI, 73%-92%) vs 53% (95% CI, 40%-64%), respectively; the 2-year PFS rates were 76% (95% CI, 61%-87%) vs 44% (95% CI, 32%-56%), respectively. The median follow-up for PFS was 15.9 months.

Additionally, the confirmed ORR in the nirogacestat arm was 41% compared with 8% in the placebo arm (P < .001). Seven percent of patients in the investigational arm experienced a complete response (CR); there were no CRs in the placebo arm. The median time to confirmed first response was 5.6 months vs 11.1 months, respectively. At the data cutoff, 97% of responders in the nirogacestat arm remained in response compared with 83% of patients in the placebo arm.

In terms of safety, any-grade adverse effects (AEs) occurred at a rate of 100% vs 96% in the nirogacestat (n = 69) and placebo (n = 72) safety populations. AEs of grade 3 or higher severity (55% vs 17%, respectively) and AEs leading to discontinuation of treatment (20% vs 1%) were reported in both arms. One patient in the placebo arm died and there were no deaths in the investigational arm.

Common any-grade AEs in the nirogacestat arm included diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%). Common any-grade AEs in the placebo arm consisted of nausea (39%), fatigue (36%), diarrhea (35%), and vomiting (19%).

“Nirogacestat was associated with significant benefits with respect to PFS, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. AEs with nirogacestat were frequent but mostly low grade,” study authors wrote in conclusion.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 3.2023. Accessed January 9, 2024. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
2. FDA approves first therapy for rare type of non-cancerous tumors. FDA. November 27, 2023. Accessed January 9, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-type-non-cancerous-tumors#:~:text=Today%2C%20the%20U.S.%20Food%20and,subtype%20of%20soft%20tissue%20sarcomas.
3. 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