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Neoadjuvant bevacizumab, when added to standard chemotherapy for operable breast cancer, improved the rate of complete pathological response in two large, well-conducted trials. However, the modest incremental benefits, combined with uncertain long-term effects on disease recurrence, mean that this approach remains experimental until follow-up data are available.
In the CLASSIC study, capecitabine–oxaliplatin was an effective chemotherapy after D2 gastrectomy for stage II–IIIB gastric cancer. We compared these data with the ACTS-GC study, which was the only pivotal study proving the benefit of adjuvant chemotherapy in these patients. Long-term survival data from CLASSIC are awaited with interest.boxed-text
Demonstration of the clinically significant activity of bevacizumab in advanced-stage ovarian cancer has attracted a great deal of interest. Here, we summarize the two positive phase III trials that led to EMA approval of bevacizumab as first-line therapy and discuss the optimum use of the drug in this disease.boxed-text
Recent neoadjuvant studies have examined the effects of adding single or dual agents targeting HER2 to chemotherapy, finding unanimously that dual HER2 targeting markedly improves pathologic response. These findings have significant implications for future trial designs, particularly if the impact on pathologic response is accompanied by improved disease-free survival or overall survival.
The size, length and cost of phase III clinical trials are prompting oncology researchers and pharmaceutical companies to look for other options. This Review outlines adaptive clinical trial designs that can address many questions at once. A wholly new paradigm for drug development exemplifying personalized medicine is evinced by an adaptive trial called I-SPY2, in which drugs from many companies are evaluated in the same study and are matched with their biomarker signatures.
If a targeted therapy demonstrates convincing efficacy in early clinical testing, can randomized phase III trials be avoided? Sharma and Schilsky discuss when it is reasonable to consider foregoing randomized phase III trials before drug approval and also highlight the caveats. They explore the consequences of such an approach and propose criteria that the drugs must meet to be approved without a phase III trial.
The current system for the development of anticancer drugs is not fit for purpose. In this Review article, this system is examined from the perspective of the drug company, offering a fresh look at development from target identification up to registration.
Is there a precise end point that could enable us to compare neoadjuvant and adjuvant endocrine therapy outcomes? A reliable short-term surrogate to assess the potential of endocrine drugs in the adjuvant setting? In this Review, Goncalves et al. summarize the studies in which the proliferation marker Ki 67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting.
Randomized controlled trials (RCTs) pose dilemmas in terms of the tension between the therapeutic obligations of the physician and the scientific obligations of the investigator. Clinical equipoise is often regarded as a solution to this problem. The authors critically evaluate clinical equipoise and highlight its flaws as an ethical requirement for RCTs and propose an alternative method of risk–benefit assessment.
In terms of drug development, the main driving force should be optimized benefit–risk to patients; however, no drug can be of real benefit unless it has achieved approval from the regulatory agencies. This Perspectives allows us a peek behind the door of one of those agencies (EMA) and outlines the hurdles that exist and that need to be overcome before we can have an efficient, biomarker-driven drug development program. Points for discussion in the community are raised and suggestions are put forward.
Nature Reviews Clinical Oncologyis proud to feature a Focus on clinical trials. The April 2012 issue includes discussion on the recent and ongoing challenges of undertaking clinical trials in patients with cancer. This special issue comprises four Reviews and two Perspectives by key opinion leaders in the field.
