Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc, recently announced that The New England Journal of Medicine published results of a phase III trial demonstrating that sorafenib(Drug information on sorafenib) (Nexavar) tablets decreased the absolute risk of death by 31% in patients with unresectable hepatocellular carcinoma (HCC) vs patients who received placebo. This represents a 44% improvement in median overall survival for patients treated with sorafenib.
Based on the strength of these data, sorafenib was approved for HCC by the European Agency for the Evaluation of Medicinal Products (EMEA) and by the US Food and Drug Administration (FDA) in October and November 2007, respectively.
New Standard of Care
"Despite advances in the management of many other cancers, liver cancer has remained a treatment challenge, due to a lack of systemic therapies to extend life and limited opportunity for surgical intervention," said Dr. Josep M. Llovet, coprincipal investigator of the study and professor of research, Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, Liver Unit, Hospital Clinic Barcelona; director of research, HCC Program, and associate professor of medicine, Mount Sinai School of Medicine, New York. "This landmark study reflects a new systemic standard of care using sorafenib in the first-line management of liver cancer."
"The number of lives lost to liver cancer continues to increase globally, due to the prevalence of hepatitis B and C infections," said Jordi Bruix, coprincipal investigator and director of the Barcelona Clinic Liver Cancer (BCLC) Group; and senior consultant, Liver Unit, Hospital Clinic of Barcelona. "We are encouraged that there is a new treatment option available for liver cancer that has clearly demonstrated a survival benefit in this patient population."
SHARP Trial Details
The international phase III double-blind, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial evaluated 602 liver cancer patients who had no prior systemic therapy. The primary endpoints of the study included overall survival and time to symptomatic progression in patients administered sorafenib vs those who received placebo. Secondary endpoints included time to progression, disease control rate, and safety.
Results were first presented at the American Society of Clinical Oncology annual meeting in June 2007.
Median overall survival was 10.7 months for patients who received sorafenib compared to 7.9 months for patients who received placebo (hazard ratio [HR] = 0.69; P = .0006). There was no difference in time to symptomatic progression between patient groups, based on a patient-reported assessment questionnaire.
Median time to tumor progression was 5.5 months with sorafenib vs 2.8 months with placebo (HR = 0.58; P < .001). The most common drug-related grade 3/4 events in patients receiving sorafenib were diarrhea and hand-foot skin reaction. No indication of imbalances was observed with regard to serious adverse events between the sorafenib and placebo-treated groups.
Sorafenib's Differentiated Mechanism
Sorafenib targets both the tumor cell and tumor vasculature. In preclinical studies, sorafenib has been shown to target members of two classes of kinases known to be involved in both cell proliferation and angiogenesis. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. Preclinical models have also demonstrated that Raf/MEK/ERK has a role in HCC; therefore, blocking signaling through Raf-1 may offer therapeutic benefits in HCC.
Sorafenib is currently approved in more than 40 countries for liver cancer and in more than 70 countries for the treatment of patients with advanced kidney cancer. Sorafenib is also being evaluated as a single agent or combination treatment in a wide range of cancers, including metastatic melanoma, lung cancer, breast cancer, and as an adjuvant therapy for kidney cancer.