Rationale and clinical results of multi-target treatments in oncology.

During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti- EGFR mechanisms of action.

Rationale and clinical results of multi-target treatments in oncology.

During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti- EGFR mechanisms of action.

Cetuximab for treatment of metastatic colorectal cancer.

In the past decade the median overall survival of patients with metastatic colorectal cancer has increased from 12 to more than 20 months, mostly due to the new chemotherapeutic agents, irinotecan and oxaliplatin. Most recently, targeted therapies, that inhibit specific cancer pathways and molecules, have shown promising results in the treatment of patients with metastatic colorectal cancer and other solid tumors. One of the most studied targets for anticancer therapy is the epidermal growth factor receptor (EGFR), which is overexpressed in a variety of malignancies. Cetuximab, an anti-EGFR chimeric monoclonal antibody, has shown clinically meaningful antitumor activity in patients with metastatic colorectal cancer in several clinical trials. Efforts of physicians and researchers are currently directed towards the identification of predictive factors (clinical or molecular) of clinical outcome, with the aim of both optimizing the therapeutic index and dealing with increasing costs of these new compounds.