Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity

Abstract

Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

“…The pharmacodynamic interactions demonstrated that the tolerable dose of bevacizumab used is half or less of the recommended dose in other solid tumour studies (Azad et al, 2008b). We were unable to escalate beyond 5 mg kg À1 every 2 weeks because of proteinuria (n ¼ 2), thrombocytopaenia (n ¼ 1), and hypertension in DL 5A (n ¼ 2).…”

“…There was a 6-week accrual pause between DLs to monitor for delayed toxicity. A history, blood pressure measurement, and urine protein/creatinine ratio were performed before each bevacizumab dose, with detailed history and physical examination every cycle (Azad et al, 2008b). If the urine protein/creatinine ratio was greater than 1.0 but less than grade 3, bevacizumab was given and a 24-h urine was collected for measurement of protein before the next cycle.…”

“…Sorafenib is a multikinase inhibitor that targets RAF kinase, VEGFR2, platelet-derived growth factor-a and -b, and c-KIT (Escudier et al, 2005;Llovet et al, 2008;Azad et al, 2008b). Sorafenib is approved for use in advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (Escudier et al, 2007;Llovet et al, 2008).…”

Antiangiogenic drugs in ovarian cancer

“…All perforations occurred in patients who had received three or more chemotherapy regimens and there was a trend towards higher perforation rates in patients with documented bowel wall involvement or bowel obstruction at study entry. Bowel perforations and enteral fistulae have also been reported in other phase II trials utilising bevacizumab in advanced ovarian cancer (Azad et al, 2008;Garcia et al, 2008). However, no definitive conclusions on aetiological factors can be drawn, due to the small number of patients in each group.…”

“…A phase I study of sorafenib and bevacizumab demonstrated durable partial disease responses (4 -22 þ months) in 6 of 13 ovarian cancer patients recruited. Toxicity appears higher than that with single-agent anti-VEGF therapy, with twothirds of the patients developing hypertension and 79% incidence of grade 1 -3 hand -foot syndrome (Azad et al, 2008). Enteral fistulae were also seen in 2 of the 13 ovarian cancer patients on study.…”