Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma

Abstract

Purpose: SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort.

Patients and methods: This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS.

Results: Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation.

Conclusion: The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

Trial registration: ClinicalTrials.gov NCT02048371.

FIG 1.

SARC024 study schema. Imaging occurred every 8 weeks for the first 32 weeks and then every 12 weeks.

FIG 2.

CONSORT diagram. (*) Physician decision (n = 1), second cancer (n = 1), noncompliance (n = 1), and alternate therapy (n = 2). (†) Physician decision (n = 1) and financial reason (n = 1).

FIG 3.

Kaplan-Meier estimates for (A) progression free survival (PFS), (B) overall survival (OS), and (C) OS after crossover from placebo to regorafenib. HR, hazard ratio.