TACE 2: A randomized placebo-controlled, double-blinded, phase III trial of sorafenib in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma


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Tim Meyer1,Richard Fox2,Yuk Ting Ma2,Paul Ross3,Martin James4,Richard Sturgess5,Clive Stubbs2,Lucy Wall6,Anthony Watkinson7,Nigel Hacking8,Jeffry Evans9,Peter Collins10,Richard Hubner11,David Cunningham12,John Primrose13,Philip Johnson14,Daniel Palmer14
1UCL Cancer Institute,2University of Birmingham,3Guy's Hospital,4University of Nottingham,5Aintree University Hosptial,6Western General Hospital,7The Royal Devon and Exeter Hospital,8Southampton University Hospitals NHS Trust,9Beatson West of Scotland Cancer Centre,10Bristol Royal Infirmary,11Christie Hospital NHS Foundation Trust,12Royal Marsden Hospital,13University of Southampton,14University of Liverpool

Abstract

Background

TACE is the standard-of-care for patients with intermediate stage HCC while sorafenib (S) is the current standard for advanced disease. TACE 2 was designed to determine whether TACE + S improves progression free survival (PFS) compared to TACE alone

Method

Patients were randomised 1:1 to continuous S (400mg BD) or placebo (P). Inclusion criteria included; unresectable HCC, ECOG PS ≤1 and Child Pugh A liver score. Study-drug was commenced at randomisation and TACE performed at 2-5 weeks using drug eluting beads (DEB) loaded with 150mg doxorubicin. Further TACE was performed on demand. Primary outcome measure (OM) was PFS. Secondary OM included overall survival (OS), response rate and safety. Target recruitment was 412 to detect a (Hazard Ratio) HR of 0.72 with 2-sided significance α=0.05 and 85% power. A planned interim futility analysis (IFA) was performed at 45% of trial events.

Results

At the IFA, 294 had been randomised from 20 UK sites. Median age 67 yrs, 169 (58%) PS 0. In 229 cirrhotic patients, liver disease was: 43% alcohol, 24% HCV; 13% HBV; 38% other. Median PFS for the S and P group was 7.8 (95% CI 5.9, 10.0) and 7.7 (95% CI 5.9, 10.5) months; (HR) of 1.03 (95% CI 0.75, 1.42 p=0.85). For the S and P groups: median OS was 18.8 (95% CI 12.3, 24.0) and 19.6 (95% CI 14.8, 24.0) months; there were 77 and 78 SAEs; 195 and 256 TACE procedures. Median duration of S and P was 5.9 and 7.7 months; median of patient average daily dose was 649mg and 800mg.

Conclusion

The TACE 2 trial provides no evidence that addition of S to DEB-TACE improves PFS or OS in European patients with intermediate HCC. Alternative systemic therapies need to be evaluated in combination with TACE to improve outcomes for this patient population.