Anti-tumor Effects Of Regorafenib Research Articles

Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma.

Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.

Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma.

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice.In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.