S. Qin

4000 Background: The oral multitargeted tyrosine kinase inhibitor Su had antitumor activity in phase II HCC trials, leading to a phase III open-label trial comparing the efficacy and safety of Su with So. Methods: Patients (pts) with advanced HCC, Child-Pugh A, ECOG PS 0/1 and no prior systemic chemotherapy were stratified by geographic region, prior TACE and tumor invasion. Pts were randomized 1:1 to Su 37.5 mg/day or So 400 mg BID. The primary endpoint was overall survival (OS; 1-sided log-rank test; α=0.025, 90% power) with 600 pts/arm required in this superiority/non-inferiority trial design. Secondary endpoints were progression-free survival (PFS), time to progression (TTP) and safety. Efficacy and futility boundaries were set using the Lan-DeMets and O’Brien–Fleming methods for interim analyses. Results: 1,073 pts were randomized (Su 529/So 544) from July 2008 to May 2010. An Independent Data Monitoring Committee stopped the trial early for futility and safety concerns. Pts were notified. Su discontinuation was recommended with the option for investigator discretion in cases of clinical benefit. For Su/So: median follow-up 7.4/7.8 mo; median age 59/59 yr; Asian 76/75%; male 82/84%; ECOG PS 0 53/53%; >3 prior TACE 16/17%; tumor invasion 79/76%; ≥1 dose interruption 69/55% and ≥1 dose reduction 47/69%. Median OS was 8.1/10.0 mo (HR 1.31 [95% CI: 1.13–1.52], P=0.0019); PFS was 3.6/2.9 mo (HR 1.12 [95% CI: 0.98–1.29], P=0.1386) and TTP was 4.1/4.0 mo (HR 1.13 [95% CI: 0.97–1.31], P=0.1785). OS for pts with hepatitis B (Hep B; Su 290/So 288; post hoc analysis) was 7.8/7.9 mo (HR 1.09 [95%CI: 0.9–1.32], P=0.236). In 526/541 pts evaluable for safety, all-causality, grade 3/4 adverse events (AEs) occurred in 82/73% of pts; the most common were thrombocytopenia (19%) and neutropenia (16%) for Su, and skin disorders (21%) for So. Discontinuations due to AEs occurred in 26/23% of pts. Serious AEs were noted in 44/36% of pts, with grade 5 AEs in 18/16%. Conclusions: In advanced HCC, Su failed its primary OS endpoint. However, PFS and TTP results were similar between Su and So. In a Hep-B pt subgroup, no significant difference in OS was detected between Su and So. Su was associated with more frequent toxicities vs So. 65 pts (Su 17/So 48) remain on study.