Cracking Open Window of Opportunity Trials

Despite an increase in investment, only one in every 10 new molecular therapeutic agents that enters clinical development receives US Food and Drug Administration approval. The sequential phase I/II/III model that was developed in the 1960s for cytotoxic chemotherapy remains a common pathway for drug development, with anticancer agents often being investigated in metastatic disease before operable disease. However, with many new targeted therapies, there are limitations in measuring response by traditional methods, such as response rate defined by RECIST criteria, which may lead to erroneous conclusions about a drug’s benefit. Evaluating molecular end points can be hindered by difficulties in procuring tumor tissue before and after drug administration and by heterogeneity in previous exposure to cancer therapies. A method to circumvent this issue is to assess novel agents in presurgical (window of opportunity or phase 0) trials. In this model, women with newly diagnosed breast cancer, for instance, receive a study drug between the diagnostic breast biopsy and planned surgical resection. The goals of these trials include evaluation of target modulation after drug exposure and pharmacokinetic assessment of a potential anticancer agent. This is in comparison to neoadjuvant trials, in which an investigational agent is commonly given preoperatively along with cytotoxic chemotherapy or hormonal therapy for a longer period of time than in a presurgical trial, and the primary end point is often, but not always, pathologic or clinical response. The ultimate hope is that presurgical studies can expedite the drug development process by improving the understanding of an agent’s biologic effect early in its development, validating markers that may predict subsets of patients who will benefit, and targeting select patients in subsequent clinical trials that are powered to detect changes in clinical outcome. In the article by Bonanni et al that accompanies this editorial, 200 Italian, nondiabetic women with early-stage invasive breast cancer were randomly assigned to receive metformin or a placebo for 4 weeks before surgery. The authors should be commended on completing a large, randomized, double-blind presurgical trial, given the challenges in conducting these studies. Coordinating enrollment between diagnosis and surgery requires close collaboration between academic disciplines, including medical oncologists, surgeons, pathologists, and laboratory scientists. The authors chose to evaluate the effect of metformin on the basis of the benefit observed in preclinical population-based and retrospective singleinstitution studies. Proposed mechanisms of action include reduction in serum insulin levels, direct modulation of cellular protein synthesis, and growth through changes in AMP-activated protein kinase (AMPK) pathway signaling. In addition, metformin has a well-defined toxicity profile, is safe in healthy patients, does not interfere with surgery or wound healing, and reaches pharmacologic levels within a short intervention period. This is in comparison to drugs that have been evaluated in other presurgical trials, such as poly (ADPribose) polymerase and epidermal growth factor receptor inhibitors, which did not yield the same amount of safety data as metformin in healthy patients with cancer and in patients with other disease states. One must always balance the risks of treating curable patients with the potential yield of new information when designing presurgical trials with less well-studied pharmaceutical agents. The primary end point in the presurgical trial by Bonanni et al was reduction in the post-treatment mean of the proliferative marker Ki-67 (log transformed: lnKi-67) in surgical resection tissue. No difference in the lnKi-67 was observed between groups. Thus, this is a negative study for the primary end point. One may ask whether Ki-67 was the best end point to select. Ki-67 modulation has clearly been shown to be an appropriate end point for preoperative studies involving hormonal therapies. In the neoadjuvant, randomized, double-blind Immediate Preoperative Anastrazole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial, anastrazole was associated with a significantly greater reduction in tumor Ki-67 at 2 and 12 weeks compared with tamoxifen and the combination. The geometric mean percentage change in Ki-67 at 2 weeks strongly mirrored the results of the large, adjuvant Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. It has been argued that the ATAC trial could have been designed differently, potentially excluding the combination arm and reducing the sample size and expense. Although a decrease in the presurgical levels of Ki-67 serves as an appropriate surrogate marker for outcome in patients who are administered antiestrogen therapy, its usefulness in predicting disease-free survival outcome remains unproven with other targeted therapies. In addition, variability in results can come from the lack of uniformity for measuring Ki-67, particularly with a small sample size. Variability in Ki-67 staining can occur as the result of a number of factors, including the duration of ischemia, formalin quality, and time of fixation. There is also potential variability in the evaluation of Ki-67 staining by pathologists, with some estimating the percentage of nuclei staining and others counting hundreds of consecutive nuclei in different tumor locations to determine an overall average index. In this trial, there was a numerical increase in the overall lnKi-67 score in both the placebo and metformin groups, which emphasizes JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 21 JULY 2