(P 413) EFFICACY OF NIROGACESTAT IN PATIENTS WITH DESMOID TUMORS AND PRESENCE OR ABSENCE OF POOR PROGNOSTIC FACTORS: POST HOC ANALYSES OF THE PHASE 3 DEFI TRIAL

Author(s)

Rashmi Chugh, MD

Professor of Internal Medicine
University of Michigan Rogel Comprehensive Cancer Center
Ann Arbor, Michigan, United States

Co-Author(s)

Nam Q. Bui, MD

Clinical Assistant Professor
Stanford University
Stanford, California, United States
Noah Federman, MD (he/him/his)

Clinical Professor, Pediatrics and Orthopaedic Surgery
University of California, Los Angeles
Los Angeles, California, United States
Richard F. Riedel, MD

Medical Oncologist
Duke Cancer Institute
Durham, North Carolina, United States
Charlotte Benson, MD (she/her/hers)

Consultant Medical Oncologist
Royal Marsden Hospital
London, England, United Kingdom
Brian A. Van Tine, MD, PhD

Professor of Medicine
Washington University in St Louis School of Medicine
St. Louis, Missouri, United States
Bernd Kasper, MD, PhD (he/him/his)

Medical Director Mannheim Cancer Center (MCC)
Mannheim University Medical Center, University of Heidelberg
Mannheim, Baden-Wurttemberg, Germany
TB

Timothy Bell, MHA

Springworks Therapeutics, Inc.
Stamford, Connecticut, United States
YC

Yucheng Chu, MS

Director, Biostatistics
Sumptuous Data Sciences
Monmouth Junction, New Jersey, United States
RC

Rachel Cohen, PhD

Associate Director, Clinical Development
SpringWorks Therapeutics
Stamford, Connecticut, United States
Ana B. Oton, MD

Vice President Medical Strategy
SpringWorks Therapeutics
Centennial, Colorado, United States
BV

Bruno Vincenzi, MD, PhD

professor medical oncology
Policlinico Universitario Campus Bio-Medico
Rome, Lazio, Italy

Objective: Desmoid tumors (DT) are rare, locally aggressive, and invasive soft-tissue tumors, often associated with debilitating symptom burden. Nirogacestat (niro), a targeted gamma secretase inhibitor, is the only FDA-approved treatment for adults with progressing DT who require systemic treatment. In the global, multicenter, phase 3 DeFi trial (NCT03785964, data cutoff 07April2022), niro significantly improved progression-free survival (PFS; HR, 0.29 [95% CI, 0.15–0.55]; P<.001), objective response rate (ORR; 41% vs 8%; P<.001), and patient-reported outcomes (PROs; all P≤.01) vs placebo (pbo). Factors associated with poor prognosis in DT include larger tumor size, age ≤30, presence of S45F or T41A CTNNB1 tumor mutations, and presence of pain. This study assessed the efficacy of niro vs pbo in patient subgroups with or without a poor prognostic factor.

Methods: In DeFi, patients were randomized 1:1 to niro 150 mg BID (N=70) or pbo (N=72). Post hoc analyses of PFS, ORR, and PROs were conducted for subgroups with a poor prognostic factor (tumor size >10 cm, age ≤30 years, presence of somatic S45F or T41A CTNNB1 mutation, or baseline pain by Average Pain Intensity [API>0] of the Brief Pain Inventory–Short Form) and those without (tumor size ≤10 cm, age >30 years, and no baseline pain [API=0]). Other CTNNB1 mutations were not assessed due to small sample size. PROs were evaluated as change from baseline score.

Results: HRs for PFS ranged from 0.18–0.39 for subgroups of patients with poor prognostic factors, and 0.27–0.45 for those without (HRs < 1 favored niro over pbo). ORR group differences (niro–pbo) ranged from 18.1–56.0% for subgroups of patients with poor prognostic factors, and 31.1–45.8% for those groups without (values >0 favored niro over pbo). Overall, niro-treated patients reported greater improvement vs pbo from baseline through cycle 25 in PROs of pain, DT-specific symptom burden, physical and role functioning, and overall QoL, regardless of subgroup. PRO improvements were observed early and sustained on treatment with niro vs pbo.

Conclusion: Niro was associated with consistent improvement in PFS, ORR, and PROs vs pbo regardless of the presence or absence of DT poor prognostic factors.