Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) Analysis of Nirogacestat in Patients With Desmoid Tumors
Author(s)
Shreena Malaviya, MHS1, Timothy Bell, MHA2, Hoora Moradian, MBA, PhD1.
1Cytel Inc., Toronto, ON, Canada, 2SpringWorks Therapuetics, Inc., Stamford, CT, USA.
1Cytel Inc., Toronto, ON, Canada, 2SpringWorks Therapuetics, Inc., Stamford, CT, USA.
OBJECTIVES: Desmoid tumors (DT) are rare, locally aggressive soft-tissue tumors that can cause debilitating symptoms. In the phase 3 DeFi trial, nirogacestat demonstrated significant improvement in progression-free survival (PFS), objective response rate, and patient-reported outcomes compared to placebo; 95% of all adverse events were low grade. To compare quality‐adjusted survival of nirogacestat treatment vs placebo, a Quality-adjusted Time Without Symptoms or Toxicity (Q‐TWiST) analysis was conducted.
METHODS: At the nirogacestat median treatment duration from the primary analysis (20.6 months), overall survival (OS) was partitioned into three health states: time with Grade ≥3 treatment-related adverse events (TRAEs) before progression (TOX); time without progression or symptoms of toxicity (TWiST); and time from progression until death or end of follow-up (REL). Mean Q‐TWiST was calculated by multiplying each health state’s duration with its utility (TWiST, 1.0; TOX, 0.5; REL, 0.5) and summing the utility‐adjusted time. Sensitivity analyses included 36, 48, and 60 months of follow-up by extrapolating OS, PFS, and TOX survival curves. The established threshold for clinically important Q-TWiST relative gain is ≥10%.
RESULTS: Patients on nirogacestat (N=70) versus placebo (N=72) had significantly longer mean restricted TWiST (+137.57 days; 95% CI, 70.56 to 204.58; P<.001) and TOX (+11.41 days; P<.001), as well as shorter REL (-143.33 days; P<.001). Patients on nirogacestat had significantly greater Q-TWiST gains of 71.60 days (P<.001) and clinically important relative gains of 11.52% versus placebo. Extending follow-up to 36, 48, and 60 months resulted in relative Q-TWiST gains of 16.58%, 19.09%, and 20.96%, respectively, in favor of nirogacestat.
CONCLUSIONS: Nirogacestat significantly improved Q-TWiST versus placebo. Q-TWiST gains with nirogacestat were primarily driven by time in the “good” health state (TWiST), which resulted from long-term PFS benefits and lower differences in Grade ≥3 TRAEs versus placebo. Sensitivity analyses show benefits of nirogacestat are maintained with longer follow-up.
METHODS: At the nirogacestat median treatment duration from the primary analysis (20.6 months), overall survival (OS) was partitioned into three health states: time with Grade ≥3 treatment-related adverse events (TRAEs) before progression (TOX); time without progression or symptoms of toxicity (TWiST); and time from progression until death or end of follow-up (REL). Mean Q‐TWiST was calculated by multiplying each health state’s duration with its utility (TWiST, 1.0; TOX, 0.5; REL, 0.5) and summing the utility‐adjusted time. Sensitivity analyses included 36, 48, and 60 months of follow-up by extrapolating OS, PFS, and TOX survival curves. The established threshold for clinically important Q-TWiST relative gain is ≥10%.
RESULTS: Patients on nirogacestat (N=70) versus placebo (N=72) had significantly longer mean restricted TWiST (+137.57 days; 95% CI, 70.56 to 204.58; P<.001) and TOX (+11.41 days; P<.001), as well as shorter REL (-143.33 days; P<.001). Patients on nirogacestat had significantly greater Q-TWiST gains of 71.60 days (P<.001) and clinically important relative gains of 11.52% versus placebo. Extending follow-up to 36, 48, and 60 months resulted in relative Q-TWiST gains of 16.58%, 19.09%, and 20.96%, respectively, in favor of nirogacestat.
CONCLUSIONS: Nirogacestat significantly improved Q-TWiST versus placebo. Q-TWiST gains with nirogacestat were primarily driven by time in the “good” health state (TWiST), which resulted from long-term PFS benefits and lower differences in Grade ≥3 TRAEs versus placebo. Sensitivity analyses show benefits of nirogacestat are maintained with longer follow-up.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO197
Topic
Clinical Outcomes
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
Oncology, Rare & Orphan Diseases