Modified-dose capecitabine plus bevacizumab for the treatment of advanced metastatic hepatocellular carcinoma: a phase II single-arm study

Abstract

Background: The oral fluoropyrimidine capecitabine (X; Xeloda®) has anti-tumor activity in metastatic colorectal, breast, gastric cancers and HCC. The humanized monoclonal antibody bevacizumab (A; Avastin®) targets VEGF and limits tumor angiogenesis. The combination of X+A is active in breast cancer xenografts and increases the objective response rate (ORR) in patients (pts) with anthracycline- and taxane-resistant breast cancer. X+A also appears to be highly active when administered with irinotecan as first-line treatment for metastatic colorectal cancer. We report data from a multicenter, Ensign’s 3-stage design, open-label phase II trial of X+A as first- line treatment for HCC. Methods: Pts with untreated, histologically confirmed advanced HCC received X 800mg/m2 orally bid d1–14 and A 7.5mg/kg i.v. infusion d1. Treatment was repeated q3w x6 cycles in the absence of disease progression or unacceptable toxicity. Pts without progressive disease after 6 cycles of X+A could continue on the same doses of X+A. Primary endpoint was ORR (RECIST); secondary endpoints were disease control rate, progression-free survival (PFS), overall survival, and safety. Results: 45 patients were enrolled. By Dec 2006 the 25 patients (male, 88%; median age 52 years; Child-Pugh A) enrolled in Stages 1 and 2 of the study had completed at least 6 months’ follow-up and were assessed for efficacy and safety. ORR (CR+PR) was 16% (95% CI 4.5–36.1%) and disease control rate (CR+PR+SD) was 60% (95% CI 38.7–78.9%). Median overall survival was 10.7 months (95% CI, 5.3–14.7) and median PFS was 4.1 months (95% CI, 1.6–6.2); the PFS rate (i.e. the event (PD or death) free rate) at 3 and 6 months was 64% (95% CI 45.2–82.8%) and 34% (95% CI 15.1- 53.2%), respectively. Median number of cycles per patient was 5 (range 1–6). The most common treatment-related grade 3 toxicities included hand-foot syndrome (n=2), nail changes (n=1), diarrhea (n=1), nausea/vomiting/hiccups (n=1), gastric ulcer hemorrhage (n=1). Conclusions: X+A appears to be both effective and well tolerated as first-line treatment for HCC, providing support for further evaluation of this combination in this difficult-to-treat cancer.