Citations

Abstract New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety. Clin Cancer Res; 19(11); 2817–23. ©2013 AACR.

Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.