Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors

Abstract

Background: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.

Methods: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival.

Results: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%).

Conclusions: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Figure 1. Progression-free Survival and Subgroup Analysis.

Panel A shows Kaplan–Meier estimates of progression-free survival. Progression was determined through blinded, independent, central review and included imaging-based progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and clinical progression. Panel B shows a forest plot of progression-free survival in prespecified subgroups. FAP denotes familial adenomatous polyposis, NE not estimable, and TKI tyrosine kinase inhibitor.

Figure 2. Change in Tumor Size and Best Overall Response.

Panels A and B show waterfall plots of the best percent change at any time point from baseline in target-tumor size per patient according to RECIST, version 1.1, through blinded independent central review in each trial group. Values for best percent change were averaged between the two independent reviewers unless a reader was selected for adjudication, in which case only the adjudicated value is presented. Panels C and D show swimmer plots of duration of exposure and response status in each trial group. Colors indicate the best overall response according to RECIST, version 1.1, through blinded independent central review.

Figure 3. Patient-Reported Outcomes.

Shown are least-squares (LS) mean changes from baseline over time in patient-reported outcomes; the vertical bars indicate 95% confidence intervals. Brief Pain Inventory–Short Form (BPI-SF) average worst pain intensity scores (Panel A) range from 0 to 10, with higher scores indicating worse pain; scores represent a 7-day average of daily scores for worst pain. Gounder–Desmoid Tumor Research Foundation Desmoid Symptom/Impact Scale (GODDESS) Desmoid Tumor Symptom Scale (DTSS) total symptom scores (Panel B) range from 0 to 10, with higher scores indicating a more severe symptom burden. GODDESS Desmoid Tumor Impact Scale (DTIS) physical functioning domain scores (Panel C) range from 0 to 4, with higher scores indicating worse functioning. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) physical functioning scores (Panel D), role functioning scores (Panel E), and global health status–quality of life scores (Panel F) range from 0 to 100, with higher scores indicating better functioning or better quality of life. Mean (±SD) scores at baseline were as follows: BPI-SF average worst pain intensity score, 3.2±3.3 in the nirogacestat group and 3.3±3.3 in the placebo group; GODDESS DTSS total symptom score, 3.4±2.3 and 3.5±2.6, respectively; GODDESS DTIS physical functioning domain score, 2.8±1.1 and 2.7±1.2, respectively; EORTC QLQ-C30 physical functioning score, 77.5±22.4 and 77.1±22.0, respectively; EORTC QLQ-C30 role functioning score, 65.2±32.7 and 65.7±30.2, respectively; and EORTC QLQ-C30 global health status–quality of life score, 60.0±24.5 and 63.3±20.7, respectively. C denotes cycle.