LBA2 - Search: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients with Hepatocellular Carcinoma (HCC)

Abstract

ABSTRACT Background Sorafenib is the only systemic agent to show statistically significant overall survival (OS) benefits in advanced HCC. Erlotinib is a direct and reversible EGFR tyrosine kinase inhibitor. Combining sorafenib and erlotinib in HCC patients may result in synergistic or additive antitumor effects. Methods Patients ≥18 years with advanced HCC, ECOG PS 0–1 and Child-Pugh class A, and stratified by ECOG PS (0 vs 1), macroscopic vascular invasion and/or extrahepatic spread (yes vs no), smoking status (current vs former vs never) and region (Americas vs Europe and South Africa vs Asia-Pacific), were randomized 1:1 to oral sorafenib 400 mg bid plus erlotinib 150 mg qd or sorafenib 400 mg bid plus placebo 150 mg qd. Treatment was on a continuous basis, with scans performed every 6 weeks. The primary endpoint was OS, with secondary endpoints including time to progression (TTP), disease control rate (DCR), and safety. Results Of 720 randomized patients, 362 received sorafenib plus erlotinib and 358 received sorafenib plus placebo. Median OS (9.5 vs 8.5 mo; HR 0.929; 95% CI 0.781–1.106, p = 0.204) and TTP (3.2 vs 4.0 mo; HR 1.135; 95% CI 0.944–1.366, p = 0.91) did not differ significantly in the two arms. There were no significant differences in OS or TTP between arms by region. The median daily doses of sorafenib in the sorafenib plus erlotinib and sorafenib plus placebo arms were 768 and 773 mg, respectively, while the median daily doses of erlotinib and placebo were 142 and 143 mg, respectively. DCR (43.92% vs 52.51%) and median treatment duration (2.8 vs 4.0 mo) were lower in the sorafenib plus erlotinib arm, while the percentage withdrawing after ≤1 treatment cycle was greater (34.0% vs 23.8%). Rates of treatment-emergent (100% vs 99.2%) and drug-related (95.0% vs 95.2%) AEs and treatment-emergent (58.0% vs 54.6%) and drug-related (21.0% vs 22.8%) serious AEs were similar. No new or unexpected toxicities were observed compared with sorafenib or erlotinib alone. Conclusions Erlotinib, when added to sorafenib as standard of care in advanced HCC, did not prolong OS or TTP. Safety profiles were consistent with those of the individual agents. NCT0901901, EudraCT-2008-006021-14. Disclosure A.X. Zhu: Dr. Zhu has received research support from Bayer, Onyx, Imclone-Eli Lilly and Novartis has received been an advisor/consultant for Abbott Laboratories, Bristol-Myers Squibb, Eisai Pharmaceuticals, and Sanofi-Aventis. J. Evans: Dr. Evans has received consultancy fees, honoraria, speaker's fees, support to attend conferences, and support costs for clinical research trials (including this study) from Bayer Healthcare Pharmaceuticals, Roche and Bristol Myers Squibb. P. Ross: Dr. Ross has received honoraria from Bayer HealthCare Pharmaceuticals, Merck Serono, Roche, Sanofi Aventis and has received consulting fees from Bayer Health Care Pharmaceuticals and Bristol-Myers Squibb and a grant from Merck Serono. A. Santoro: Dr. Santoro has received consulting/advisory fees from Bayer HealthCare Pharmaceuticals. F.J. Carrilho: Dr. Carrilho has received payments from Bayer HealthCare Pharmaceuticals for participating and enrolling patients in this study M. Leberre: Dr. Leberre is an employee of Bayer HealthCare. M. Jensen: Dr. Jensen is an employee of, and owns shares in, Bayer Healthcare G. Meinhardt: Dr. Meinhardt is an employee of, and owns shares in, Bayer HealthCare. Y. Kang: Yoon-Koo Kang has received honoraria and research funding from Bayer Healthcare Pharmaceuticals All other authors have declared no conflicts of interest.