Sorafenib for Advanced and Refractory Desmoid Tumors

Abstract

Background: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care.

Methods: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated.

Results: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%).

Conclusions: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Figure 1.

Randomization and Follow-up among the Patients in the Trial.

Figure 2.. Kaplan–Meier Estimates of the Duration of Progression-free Survival at the Time of the Last Assessment.

Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, were used by the investigators to identify disease progression. Data from patients who did not have progression or who had died were censored and marked by a tick. NE denotes not estimable.

Figure 3.. Tumor Responses and Clinical Outcomes.

Panel A shows waterfall plots of percentage changes from baseline in tumor size as assessed by investigators according to RECIST, version 1.1. Each bar represents one patient. Horizontal dashed lines indicate the changes in tumor size that would represent a partial response (30% decrease) or progressive disease (20% increase). One patient in the sorafenib group had a complete response, defined as total disappearance of tumor. Panel B shows swimmer plots of the duration of response and clinical outcomes among patients during the trial. “Progression nonmeasure” denotes clinical progression without radiographic progression (20% growth). One patient in the sorafenib group died from disease-related intestinal perforation. Duration of response was calculated as the time between the first objective response and disease progression; data from patients with ongoing responses were censored at the most recent disease assessment. Time to response during the time of the blinded trial intervention was calculated from the start of the intervention to the date of the first objective response or to the most recent disease assessment (for patients without a response). Time to progression was the time to disease progression or to the most recent assessment if the patient did not have disease progression.