Treatment options for patients with metastatic osteosarcoma who progress on first-line chemotherapy are limited, and prognosis for these patients is extremely poor. The activity of second-line chemotherapy in osteosarcoma is marginal, and treatment with checkpoint inhibitors, unfortunately, also appears ineffective. More promising results were reported with targeted therapy, in particular with agents targeting angiogenesis and other signaling pathways. Regorafenib is an oral multikinase inhibitor of multiple protein kinases involved in the regulation of tumor angiogenesis, oncogenesis, and the tumor microenvironment. It is an established treatment for patients with pretreated gastrointestinal stromal tumors, colorectal cancer, and hepatocellular carcinoma and has demonstrated important antitumor activity in nonadypocitic soft-tissue sarcomas . More recently, this agent was evaluated in the noncomparative, double-blind, placebo-controlled, multicenter, phase II REGOBONE trial in patients with bone tumors including osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. Results from the osteosarcoma cohort were recently published in Lancet Oncology.
Patients with metastatic osteosarcoma (N = 43) who had progressed on one to two lines of prior chemotherapy received either regorafenib (160 mg/day for 21 days in a 28-day cycle) or placebo. The primary endpoint (proportion of patients without disease progression at 8 weeks) was evaluated in 38 patients who received treatment without major protocol violations. At 8 weeks post-treatment, 17 of 26 patients (65%) receiving regorafenib remained progression free, compared to 0 of the 14 patients (0%) receiving placebo. Two patients in the regorafenib group achieved partial response, with durations of 6.2 months and 12.9 months. The median progression-free survival (PFS) was 16.4 weeks for patients receiving regorafenib and 4.1 weeks for patients receiving placebo. The median overall survival (OS) was 11.3 months and 5.9 months with regorafenib and placebo, respectively.
The adverse events (AEs) seen in patients receiving regorafenib were consistent with the known safety profile of this agent. Serious treatment-related AEs occurred in 24% of patients receiving regorafenib and 0% of patients receiving placebo. The most common grade 3/4 AEs associated with regorafenib treatment included hypertension in 24% of patients and hand-food skin reaction, fatigue, hypophosphatemia, and chest pain each in 10% of patients.
The investigators concluded that regorafenib demonstrated meaningful antitumor activity in patients with advanced osteosarcoma who have progressed on chemotherapy and that these results support investigations of regorafenib in a larger patient cohort and potentially in earlier lines of treatment. In an accompanying editorial, the authors commented that although this trial was statistically noncomparative, there was a clear benefit for regorafenib over placebo, highlighting the potential benefit of treatment in this setting. However, they indicated that ‘’identifying the targets of regorafenib is essential to moving towards better stratification of the patients enrolled in future clinical trials’’.
For additional information about the role of multikinase inhibitors in solid tumors including sarcomas, please see the prIME Oncology Expert Review on Multikinase Inhibitors.