A Phase II and Biomarker Study of Sorafenib Combined with FOLFOX in Patients with Advanced Hepatocellular Carcinoma (HCC)

PURPOSE: Sorafenib is a standard first-line treatment for advanced HCC. The phase III SHARP trial showed a median time-to-progression(mTTP) of 5.5 months, overall response rate(ORR) of 2%, and median overall survival(mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study. METHODS: The study included Child-Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400mg BID for 2 weeks, followed by concurrent mFOLFOX (5-FUCI 1200mg/m²/day for 46 hours, leucovorin 200mg/m² and oxaliplatin 85mg/m² biweekly). The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers. RESULTS: The study enrolled 40 patients: HCV/Etoh/HBV, 43%/28%/13%; Child-Pugh A5, 70%. Notable grade 3/4 adverse events included AST/ALT elevation(28%/15%), diarrhea(13%), hyperbilirubinemia(10%), hand-foot syndrome(8%), and bleeding(8%). mTTP was 7.7 months[95%CI: 4.4-8.9], ORR 18%, and mOS 15.1 months[7.9-16.9]. Sorafenib+mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL-12p70 and CAIX and CD4+ and CD8+ effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and Tregs. Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56^Dim NK cells after sorafenib alone and plasma sMET after combination treatment (all p<0.05). CONCLUSIONS: Sorafenib+mFOLFOX met the pre-specified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between TTP and angiogenic biomarkers and circulating Tregs.

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