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The oral multikinase inhibitor sorafenib significantly extended overall survival by 44%, compared with placebo in patients with hepatocellular carcinoma in a phase III trial in the plenary session. The results are being hailed by some as a major breakthrough for patients with primary liver cancer, the third leading cause of cancer deaths worldwide.
"It's the first time we have a positive trial in terms of survival with a systemic treatment for HCC [hepatocellular carcinoma]," coprincipal investigator Dr. Josep M. Llovet said at a press briefing. "This is a breakthrough in terms of the management of this disease. The standard of care will become sorafenib for advanced stage for sure."
Bayer HealthCare Pharmaceuticals Inc. and Onyx Pharmaceuticals Inc. announced on Aug. 20 that the Food and Drug Administration has granted priority review status to a supplemental new drug application for an indication for sorafenib (Nexavar) in hepatocellular carcinoma. If approved, sorafenib would be the first FDA-approved therapy for this disease, according to the announcement. The companies also filed a marketing authorization application with the European Medicines Agency based on the trial data.
Sorafenib is currently approved in more than 50 countries, including the United States, for the treatment of advanced kidney cancer.
The results will likely trigger immediate off-label use of sorafenib in HCC—even with a $5,000 per month price tag—simply because there are no other good options, said Dr. A. William Blackstock, professor of radiation oncology at Wake Forest University, Winston-Salem, N.C., and press briefing moderator.
He stopped short of calling it a breakthrough, saying instead that the results set a baseline against which all other compounds will be evaluated. The trial could never have been conducted in the United States, he added, because Americans would not consent to randomization to placebo.
Discussant Dr. Philip James Johnson said sorafenib may be of particular use fighting HCC in the West. Hepatitis B virus infection is responsible for 60%-80% of all HCC cases worldwide, and prevalent in developing countries, he noted. However, rising levels in the West are attributable to hepatitis C virus infection, usually contracted in the 1960s and 1970s and for which no vaccine is available.
"The message here for the West is that HCC will be a therapeutic challenge for several years, and that is where sorafenib may have a role," said Dr. Johnson, professor of oncology and translational research, and director of the clinical trials unit in cancer research at the UK Institute for Cancer Studies, University of Birmingham.
In the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, 299 patients were randomized to continuous dosing with sorafenib 400 mg twice daily, and 303 patients to placebo. An intent-to-treat analysis found median overall survival was 46 weeks for sorafenib compared with 34 weeks for placebo (hazard ratio 0.69, P = .00058). Median time to progression was 24 weeks with sorafenib and 12 weeks with placebo (hazard ratio 0.58, P = .000007). Investigators calculated a 73% prolongation of time to progression.
Sorafenib was well tolerated with manageable side effects, said Dr. Llovet, director of HCC research, Mount Sinai School of Medicine, New York, and professor of research at Barcelona Clinic Liver Cancer Group, Hospital Clinic, Barcelona, Spain. There were no significant differences in serious adverse events. The most common in the sorafenib arm were hand-foot-skin reaction and diarrhea.
Bayer and Onyx halted the trial in February 2007 when a prescheduled analysis determined that the overall survival end point had been met.
Dr. Johnson said the study has several limitations, including failure to clarify the impact of sorafenib on quality of life, a primary end point. Efficacy was only demonstrated for patients with good liver function and who were predominantly European. Expense will be a limitation in many parts of the world. Finally, no attempt was made to identify who would benefit from the drug.
Among the trial's "considerable strengths," he said sorafenib is clearly the first convincing, rigorously tested treatment to show enhanced survival in advanced HCC. Some people will see only a modest absolute improvement in survival, he said. Others will see the relative improvement in survival as dramatic. "To my mind, both of these are true and I do think that this now constitutes the dawn of a new era for HCC," Dr. Johnston said. "I use the word 'dawn' advisedly. At dawn not everything is clear. But I think in the years to come, light will be thrown upon these limitations and we will begin to see that a new era for HCC therapy has really arrived."
Llovet J. et al. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial) Abstract LBA1.
Commentary |
The era of molecular therapy is now clearly upon us. The data on sorafenib in hepatocellular carcinoma enhances an already impressive list of new agents that have demonstrated survival benefits in a broad range of indications. Sorafenib is a multikinase inhibitor originally developed as an inhibitor of Raf kinase; it is likely, however, that sorafenib's effects on tumor angiogenesis account for the clinical effects seen in hepatic and renal cancers. This is a landmark trial and was appropriately selected for the plenary session at ASCO 2007. It does establish a new standard of care in hepatocellular carcinoma and a reference standard for future clinical investigation. The survival benefit is clinically significant, but advanced hepatocellular cancer remains a serious and inevitably fatal disease for which better therapies are desperately needed. Just as important as the clinical benefit of sorafenib is how these findings will energize clinical and translational research in hepatocellular carcinoma. This disease is a major health problem worldwide, but to date has received less attention in the gastrointestinal oncology research community than have colorectal, pancreatic, or gastroesophageal cancers. In diseases such as gastrointestinal stromal tumors (GIST) and renal cell cancer in which traditional cancer therapies were ineffective, the identification of an active, targeted therapy has not only established a new standard of care, it has also markedly increased clinical trials in these diseases and subsequently resulted in other new active agents being identified. We should look forward to a similar future in hepatocellular cancer. — Malcolm J. Moore, M.D.
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