Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC)

Abstract

LBA1 Background: HCC is the 3rd cause of cancer death globally with most deaths occurring within 1 year of diagnosis. No standard therapy exists for advanced HCC. Sorafenib (Sor) is a multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity, with clinical activity in a phase II HCC trial. This large, multicenter, randomized, placebo-controlled phase III trial evaluated the efficacy and safety of Sor vs placebo (P) in pts with HCC. Methods: Patients with advanced measurable HCC, no prior systemic treatment, ECOG PS 0–2 and Child-Pugh status A received Sor 400 mg bid or P. Primary efficacy endpoints were overall survival (OS) and time to symptomatic progression (TTSP). Time to progression (TTP) and disease control rate (DCR; CR+PR+SD for at least 2 cycles) were secondary endpoints.Treatment arms were compared for OS and TTSP using a 1-sided log-rank test [overall a of 0.02 (OS) and 0.005 (TTSP)] stratified by region, ECOG PS and tumor burden. An O’Brien-Fleming-type error spending function determined criteria for early stopping for efficacy. Results: 602 pts (Sor n=299; P n=303) were randomized. Baseline characteristics were similar for Sor vs P: median age (67 vs 68 y), male (87% vs 87%), ECOG PS 0 (54% vs 54%), Child-Pugh A (95% vs 98%), and BCLC stage C (82% vs 83%). Based on 321 deaths (Sor n=143; P n=178), the hazard ratio (HR) for OS (Sor/P) was 0.69 (95% CI: 0.55, 0.87; p=0.0006), representing a 44% improvement in OS vs P which met early stopping criteria. Median OS was 10.7 vs 7.9 mos (Sor vs P). Primary TTSP analysis demonstrated no statistically significant difference for Sor vs P. HR for TTP (independent assessment) was 0.58 (95% CI: 0.45, 0.74; p=0.000007). Median TTP was longer (5.5 vs 2.8 mos) and DCR was higher (43% vs 32%) with Sor vs P. Incidence of serious adverse events was similar for Sor vs P (52% vs 54%). The most frequent grade 3/4 events were diarrhea (11% vs 2%), hand-foot skin reaction (8% vs 1%), fatigue (10% vs 15%), and bleeding (6% vs 9%) for Sor vs P. Conclusions: Sorafenib was well tolerated and is the first agent to demonstrate a statistically significant improvement in OS for pts with advanced HCC. This effect is clinically meaningful and establishes sorafenib as first-line treatment for these pts. [Table: see text]

Synergistic antitumoral activity and induction of apoptosis by novel pan Bcl-2 proteins inhibitor apogossypolone with adriamycin in human hepatocellular carcinoma

“…Those agents have shown promising effects on liver cancer in clinical trials, such as the RAF/MAP kinase kinase (MEK)/extracellular signal-regulated protein kinase (ERK) pathway blocker Nexavar [6] , which is a multikinase inhibitor approved by the FDA for HCC therapy. Lifespan was prolonged by 44% in comparison with the placebo group according the data of a phase III clinical trial [7] .…”

Highlights from the 2008 Gastrointestinal Cancers Symposium

“…The SHARP Trial (Llouvet et al 2007) defined singleagent sorafenib as a new standard of treatment for intermediate/advanced liver cancer patients. In a multiinstitutional double-blind randomized phase II study (Abou-Alfa et al 2008), 96 Child-Pugh A patients were randomized to doxorubicin combined to sorafenib or placebo.…”

Hepatocellular Carcinoma: The Role of the North American GI Steering Committee Hepatobiliary Task Force and the Advent of Effective Drug Therapy

“…These encouraging phase II findings led to the initiation of an international phase III trial, the Sorafenib HCC Assessment Randomized Protocol (SHARP), which was presented at the 2007 Annual Meeting of the American Society of Clinical Oncology (ASCO) [25]. In contrast to the phase II study, the SHARP trial almost exclusively enrolled patients with C-P grade A cirrhosis, a requirement that resulted in exclusion of a large fraction of patients (approximately one third of the patients who were evaluated at participating centers) with advanced HCC.…”