REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis

Abstract

Background: In a placebo-controlled, randomized phase 2 trial (ClinicalTrials.gov identifier NCT01900743), regorafenib improved progression-free survival (PFS) for patients with doxorubicin-pretreated advanced nonadipocytic sarcoma. A quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) post hoc exploratory analysis was applied to provide an integrated measure of its clinical benefit.

Methods: In the base-case analysis, each patient's overall survival (OS) was partitioned into 3 mutually exclusive health states: the time with a grade 3 or 4 adverse event (TOX), the time without symptoms of disease or grade 3 or 4 toxicity from treatment, and the time after tumor progression or relapse. The time spent in each state was weighted with a health-state utility associated with that state and was summed to calculate the Q-TWiST. The stability of the base-case analysis was explored with several sensitivity analyses.

Results: In nonadipocytic sarcoma, the PFS was (4.0 months [2.6-5.5 months] with regorafenib vs 1.0 month [0.9-1.8 months] with a placebo; hazard ratio, 0.36 [0.25-0.53]; P < .0001); the OS was 13.4 months (8.6-17.3 months) with regorafenib and 9.0 months (6.8-12.5 months) with a placebo (hazard ratio, 0.67 [0.44-1.02]). With the classic definition of TOX (including all grade 3 and 4 clinical adverse events), the Q-TWiSTs were 8.0 months (7.0-9.0 months) with regorafenib and 5.7 months (4.9-6.4 months) with a placebo (P < .001).

Conclusions: For patients with doxorubicin-pretreated soft-tissue sarcoma, regorafenib significantly improved quality-adjusted survival in comparison with a placebo. Cancer 2017;123:2294-2302. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Keywords: metastatic soft-tissue sarcoma; placebo; quality-adjusted survival; quality-adjusted time without symptoms of progression or toxicity (Q-TWiST); regorafenib.

© 2017 American Cancer Society.

Figures

Figure 1

(A) Q‐TWiST: base‐case analysis of a placebo versus regorafenib. These graphs express the mean survival over time. The upper survival curves represent overall survival. The middle survival curves represent progression‐free survival. The lower survival curves represent survival without unacceptable treatment‐related toxicity. Between the overall survival curves and the progression‐free survival curves, the black represents the mean time spent between documented disease progression and death. Between the progression‐free survival curves and the curves of survival without unacceptable treatment‐related toxicity, the dark gray represents the Q‐TWiST. The light gray represents the mean time with unacceptable toxicity. (B) Threshold utility analysis. This graph depicts a utility analysis in which the utility of disease progression and the utility of treatment‐related toxicity vary from 0 to 1. The time horizon has been set at 15.5 months, and the utility of toxicity is constant (ie, 1). The horizontal axis represents the different values of disease progression from 0 to 1. The vertical axis represents the different values of treatment‐related toxicity. The dark gray represents a scenario in which regorafenib is superior to the placebo. On the contrary, the light gray represents a different scenario in which there is no significant difference between the placebo and regorafenib. There is no scenario in which the placebo is superior to regorafenib. (C) Difference in Q‐TWiST between the 2 treatment groups according to the time from randomization. This graph shows the difference in Q‐TWiST between the 2 arms over time and its 95% confidence interval. The horizontal axis represents the time spent from the date of randomization. The vertical axis represents the difference in Q‐TWiST between the 2 arms. This difference constantly increases over time, and this demonstrates that the gain in Q‐TWiST constantly increases with exposure to regorafenib. Q‐TWiST indicates quality‐adjusted time without symptoms of progression or toxicity; REL, time spent without disease progression; TOX, time with a grade 3 or 4 adverse event; TWiST, time spent without toxicity or disease progression.