CHICAGO—Except for patients with liposarcoma, regorafenib is associated with improved progression-free survival (PFS) in pretreated patients with advanced refractory soft-tissue sarcomas, according to findings from an international, randomized, double-blind, placebo-controlled phase II trial, presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 11003).
Patients with advanced soft-tissue sarcoma previously treated with doxorubicin have a median overall survival time of approximately 12 months, but no consensus exists for second-line therapies, explained lead study author Nicolas Penel, MD, PhD, of the department of medical oncology at Centre Oscar Lambret in Lille, France.
Tumor angiogenesis plays a key role in soft-tissue sarcomas. Regorafenib is an oral multikinase inhibitor with antiangiogenic activity tied to dual targeting of VEGFR2 and TIE2.
The REGOSARC trial included four independent parallel cohorts of a total of 175 patients with advanced refractory soft-tissue sarcomas. Participants had been diagnosed with liposarcomas (n = 50), leiomyosarcomas (n = 50), synovial sarcomas (n = 25), and other sarcomas (n = 50). For each cohort, patients were randomly assigned 1:1 to receive best supportive care plus either regorafenib (160 mg once daily) or placebo, with optional crossover for placebo-group patients upon disease progression. Patients were treated 3 weeks on and 1 week off therapy.
Patients were well-balanced among the eight study groups except in the leiomyosarcoma cohort, in which 50% of patients in the regorafenib arm had grade 3 tumors, compared with 25% of patients in the placebo group.
No patients in the study experienced complete response, but 8% of regorafenib-treated patients with synovial sarcoma and 11% of regorafenib-treated patients with other sarcomas experienced partial responses, vs 0 patients in those cohorts’ placebo groups.
Regorafenib was associated with longer PFS, the primary study endpoint, in all cohorts other than liposarcoma. The study was not designed to demonstrate overall survival (OS) improvement.
In the leiomyosarcoma cohort, regorafenib was associated with better PFS (3.7 months vs 1.8 months; hazard ratio [HR], 0.46 [95% CI, 0.26–0.80]; P = .005), and a trend toward better OS (21 vs 9 months; HR, 0.50 [95% CI, 0.24–1.03]; P = .06).
For the synovial sarcoma cohort, PFS was also better in the regorafenib arm (5.6 vs 1.0 months; HR, 0.09 [95% CI, 0.02–0.35]; P < .00001), but the difference in OS did not achieve statistical significance (13.4 vs 6.7 months; HR, 0.87 [95% CI, 0.32–2.35]; P = .79).
Similarly, for other soft-tissue sarcomas, regorafenib was associated with longer PFS (2.9 vs 1.0 months; HR, 0.45 [95% CI, 0.26–0.80]; P = .006), but that was not the case for OS (12.1 vs 9.5 months; HR, 0.50 [95% CI, 0.24–1.03]; P = .38).
In a subsequent pooled analysis of non-adipocytic sarcoma, regorafenib was associated with improved PFS (HR, 0.36 [95% CI, 0.26–0.53]; P < .0001).
The most frequent regorafenib-associated adverse events were asthenia, anorexia, diarrhea, mucositis, arterial hypertension, phosphatemia decrease, and hand-foot skin reaction.
“One toxic death occurred due to hepatitis,” Penel noted.