No Survival Benefit of Adding Erlotinib to Sorafenib in Advanced Hepatocelluar Carcinoma


Key Points

  • The addition of erlotinib to sorafenib did not improve overall survival.
  • Median overall survival was 9.5 months in the erlotinib/sorafenib group vs 8.5 months in the control group, and median time to progression was 3.2 vs 4.0 months.

In the phase III SEARCH trial reported in the Journal of Clinical Oncology, Zhu et al found no overall survival benefit of adding erlotinib (Tarceva) to sorafenib (Nexavar) in patients with advanced hepatocellular carcinoma.

Study Details

In this double-blind trial conducted in 26 countries in Europe, North and South America, and the Asia-Pacific region, 720 patients with Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and no prior systemic treatment were randomly assigned between May 2009 and January 2011 to receive sorafenib 400 mg twice daily plus either erlotinib 150 mg daily (n = 362) or placebo (n = 358). The primary endpoint was overall survival.

The combination and control groups were generally balanced for age (median, 60 and 61 years), sex (80% and 82% male), cirrhosis (70% and 66%), ascites (10% and 11%), macroscopic vascular invasion (43% and 38%), extrahepatic spread (61% and 57%), etiology (hepatitis B in 37% and 34%, hepatitis C in 24% and 30%), Barcelona Clinic Liver Cancer stage (C in 87% and 83%), Child-Pugh score (5 in 70% and 68%, 6 in 26% and 30%), ECOG performance status (0 for 60% and 61%), smoking status (former or current for 70% and 69%), and geographic region (North or South America for 24% in both, Europe for 51% in both, and Asia-Pacific for 25% and 24%).

No Survival Difference

The median duration of treatment with sorafenib was 86 days in the sorafenib/erlotinib group and 123 days in the sorafenib/placebo group. Median overall survival was 9.5 with the combination vs 8.5 months in the control group (hazard ratio [HR] = 0.929, P = .408). Median time to progression was 3.2 vs 4.0 months (HR = 1.135, P = .18). Subgroup analyses showed no overall survival differences between treatments, including analysis by geographic region. The overall response rate was 6.6% vs 3.9% (P = .102), and the disease control rate was 43.9% vs 52.5% (P = .021).

Adverse Events

Rates of diarrhea (76% vs 59%), rash/desquamation (52% vs 40%), anorexia (43% vs 37%) of any grade were higher in the sorafenib/erlotinib group, and rates of alopecia (13% vs 24%) and hand-foot skin reaction (38% vs 48%) were higher in the control group. Grade 3 or 4 adverse events occurred in 65% vs 64% of patients; the most common in both groups were hand-foot skin reaction (10% vs 17%), fatigue (18% vs 17%), AST elevation (14% vs 12%), and diarrhea (19% vs 12%).

Serious adverse events occurred in 58% vs 55% of patients. Adverse events led to treatment discontinuation in 45% vs 46%, including discontinuation of sorafenib within the first three cycles in 27% vs 23% and discontinuation of erlotinib or placebo within the first three cycles in 28% vs 24%.

The investigators concluded: “[A]dding erlotinib to sorafenib was associated with a shorter sorafenib treatment duration and did not improve survival in patients with advanced [hepatocellular carcinoma]. Sorafenib remains the standard of care for first-line treatment of advanced [hepatocellular carcinoma].”

Andrew X. Zhu, MD, of Massachusetts General Hospital Cancer Center, is the corresponding author for the Journal of Clinical Oncology article. Dr Zhu and Yoon-Koo Kang, MD, PhD, of University of Ulsan College of Medicine, Seoul, contributed equally to the article.

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