Exploring Resistance to Targeted Therapies in Cancer

Authors:

Ghassan Abou-Alfa, MD (USA)

Since sorafenib has been approved as a standard of care for the treatment of advanced hepatocellular carcinoma (HCC) there has been ever-increasing interest in exploring single or multiple agent venues to help further improve medial overall survival of patients with advanced HCC. Disappointingly several single agent anti-angiogenics as well as a combination of sorafenib plus erlotinib have failed so far the median overall survival beyond the close to 10 months ceiling of sorafenib. A possible synergy between sorafenib plus doxorubicin is awaiting evaluation in a randomised phase III study and a phase II in the first line and second line settings respectively. Apparent differences in outcome based on etiology and ethnicity with sorafenib raise the possible importance of its mutli- targeted nature, including raf-kinase inhibition. The advent of c-met inhibitors cabozantinib and tivantinib have opened another option to bypass the alleged anti-angiogenic ceiling and brought the concept of enriched high c-met population to the arena of treating HCC. While this flurry of research activity has been met with disappointment, we are undoubtedly closer to a custom-based therapy in treating advanced HCC that should soon lead to advances through the anti-angiogenic ceiling.