Targeted Therapy Trials: Approval Strategies, Target Validation, or Helping Patients?

We are witnessing the coming of age for molecular-targeted agents as a treatment strategy for malignancies in general and metastatic colorectal cancer (MCRC) in particular. We can now select from three different monoclonal antibodies (MoABs), targeting either the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) for MCRC. However, the excitement associated with the availability of these new drugs has to be tempered by the fact that the longest median survival reported in any large randomized trial in MCRC remains less than 24 months, regardless of treatment regimen, and suggests that we maybehittingaceiling. 1 Furthermore,toourknowledge,thereare nocompletedtrialsthathaveactuallydemonstratedtheadditionof the EGFR-targeted MoABs results in a significant increase in median overall survival (OS) compared with chemotherapy alone in any line of therapy, in part due to cross-over study design and the use of new agents outside of clinical trials. In the past, the US Food and Drug Administration (FDA) approved most new agents based on improvements in OS. However, the availability of multiple lines of effective therapy results in a confounding effect on any single regimen’s real impact on OS. In addition, better regimens meant that the duration of trials would have to increase to reach a primary end point of OS, a significant problem in a rapidly evolving field. Slowly, a consensus has been achieved, whereby a significant improvement in progression-free survival(PFS)isanacceptablesurrogateendpointforanimprovement in OS, and the FDA has accepted it as the primary end point in registration trials. Both EGFR-targeted MoABs currently available (cetuximab and panitumumab) were approved by the FDA based on improvements in PFS, without having demonstrated a statistically significant benefit in OS. InthisissueoftheJournalofClinicalOncology,VanCutsemet