Bevacizumab plus temsirolimus as second-line treatment for advanced hepatocellular carcinoma (HCC).

Abstract

e14567 Background: The mTOR pathway has a central role in HCC not only in the tumor growth but also in the insulin driven hepatocarcinogenesis and is reported activated in 40-50% of HCC patients. Temsirolimus is an mTOR inhibitor with proven efficacy in renal cell carcinoma. The angiogenesis inhibitor bevacizumab has shown promising activity in HCC. Sorafenib represents the only drug with proven efficacy in HCC but currently there is no standard 2nd line treatment for patients who progress on sorafenib. Therefore, we performed a phase II study to determine the activity of a bevacizumab plus temsirolimus combination in second-line HCC. Methods: Patients who had progressed on sorafenib were eligible. Other eligibility criteria included ECOG PS 0-2 and Child- Pugh score A. The combination consisted of bevacizumab 10 mg/Kg plus temsirolimus 25 mg (total dose) given i.v. biweekly. After the enrolment of the 1/3 of the preplanned 40 patients (n=13) an interim analysis had to be performed to evaluate biologic activity. Biologic activity was defined either as a partial response by RECIST criteria or a > 50% decline in AFP in at least 2 of 13 patients. An expanded panel of possible biomarkers of response including VEGF, HGF, FGFb, TSP-1 and others, were measured at baseline. Results: The median age of the first 13 patients was 67 years (53-79 years) . The patients performace status was 0 (n=3), 1 (n=4) and 2 (n=6) and 11 of 13 patients had extrahepatic disease. Four patients had radiographic partial responses and five patients had > 50% reduction in AFP. Seven patients (53,8%) showed bioactivity. It is of note that two of them experiencing durable and long lasting partial remissions of 20 and 16 months respectively are still on treatment. One patient developed reversible posterior leycoencephalopathy syndrome (Grade 4 ) and one grade 4 hypertension. Grade 3 non-hematologic toxicities included hyperglycemia (n=3), hyperlipidemia (n=2), diarrhea (n=2) and infection (n=2). Conclusions: The combination of bevacizumab plus temsirolimus is well tolerated with encouraging activity. The study's preplanned criteria for activity have been met and the study continues accrual.