Patients with advanced hepatocellular carcinoma show no benefit from adding erlotinib to sorafenib

Results of the phase III SEARCH trial

The researchers tested whether adjunct erlotinib, a direct and reversible EGFR tyrosine kinase inhibitor, could have synergistic or additive antitumour effects when used with sorafenib in patients with advanced hepatocellular carcinoma. The approach did not improve overall survival or time to progression according to the study report at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

This phase III, randomised, double-blind, placebo-controlled trial of sorafenib plus erlotinib enrolled 720 patients with advanced hepatocellular carcinoma aged 18 or more years, ECOG performance status (PS) 0–1 and Child-Pugh class A. Patients were stratified by ECOG PS of 0 or 1, macroscopic vascular invasion and/or presence of extrahepatic spread, smoking status (current, former or never) and by region: the Americas and Europe vs. South Africa and Asia-Pacific.

The patients were randomised 1:1 to receive either continuous treatment with oral sorafenib 400 mg bid plus erlotinib 150 mg daily or sorafenib 400 mg bid plus placebo 150 mg daily and monitored every 6 weeks by CT scans. The primary endpoint of the study, defined as 33% of increase in the overall survival, was not met in this study.  Median overall survival in the 362 patients receiving the sorafenib/ erlotinib was 9.5 months compared with 8.5 months in the sorafenib/placebo arm.

Time to progression also did not vary significantly between treatment arms and was 3.2 compared with 4.0 months, with sorafinib/erlotinib and sorafenib/palcebo, respectively. No significant regional differences in overall survival or time to progression were noted. The disease control rates of 43.92% and 52.51% favoured the sorafenib/placebo arm. The median treatment duration of 2.8 and 4.0 months was longer with sorafenib/placebo, which reflected the percentage of patients withdrawing after completing one or fewer treatment cycles; the withdrawal rate was 34.0% in the sorafenib/erlotinib arm compared with 23.8% with sorefenib/placebo.

The rates of treatment-emergent and drug-related adverse events were similar between arms; and treatment-emergent and drug-related serious adverse events were also similar (58.0% versus 54.6% and 21.0% versus 22.8% in the sorafenib/erlotinib and sorafenib/placebo arms, respectively). No new or unexpected toxicities were observed between combination treatment and sorafenib or erlotinib alone.

The results reported by Dr. Andrew Zhu and colleagues during Presidential Symposium of the ESMO 2012 Congress, indicate that erlotinib added to sorafenib do not improve overall survival or time to progression over sole sorafenib in patients with advanced hepatocellular carcinoma. Safety profiles were similar between the two treatment groups and consistent with those of each individual agent; however the withdrawal rate was higher in the erlotinib/sorafenib arm, with fewer patients completing one or more cycles. Discussing the abstract data, Dr Manfred Lutz - a member of the Scientific Committee of ESMO 2012 said that sorafenib remains the standard treatment for patients with advanced hepatocellular carcinoma. He suggested that a subgroup analysis of the SEARCH study is needed for further insight on combo failure. An investigation of combinations with less toxicity is warranted for potential improvements of the treatment outcome in this patient population.