Neoadjuvant therapy as a platform for drug development and approval in breast cancer.

The traditional drug development process in breast cancer based on large phase III studies has serious limitations and needs a major overhaul. Searching for new approaches, the testing of novel agents in the preoperative (neoadjuvant) setting approach offers a potentially rapid and efficient strategy for drug development utilizing pathologic complete response (path CR), a surrogate marker for survival, as the primary endpoint. In addition, neoadjuvant studies allow the assessment of drug effects on the target (pharmacodynamic response) and the development of predictive biomarkers of response. Molecular profiling of the residual tumor in the surgical specimen may also provide insights into actionable mechanisms of resistance. Recognizing the potential of neoadjuvant trials for drug development, the U.S. Food and Drug Administration (FDA) recently announced consideration of neoadjuvant trials for accelerated drug approval in early breast cancer, particularly for tumors with high risk of recurrence and unfavorable prognosis, and provided accelerated approval to neoadjuvant pertuzumab in September 2013. The FDA has emphasized that while improvement in path CR could be utilized for "accelerated" approval, improvement in survival will still need to be demonstrated for "regular" approval. Key considerations in conduct of such neoadjuvant drug development trials include (i) study design such as utilization of biomarker stratified design to evaluate a biomarker that could enrich response, (ii) definition of path CR, (iii) distribution of factors that influence path CR between the treatment arms, (iv) prespecified plan for follow-up to obtain data on survival, and (v) safety as it involves a patient population with curable disease. In the years to come, we anticipate an increase in the number of neoadjuvant trials testing novel therapies that hopefully will open a new path in bringing efficacious new therapies to patients with breast cancer. ©2013 AACR.