Abstract IA10: Preemptive or reactive? Drug development strategies in cancers resistant to targeted agents

Development of strategies to prevent or overcome resistance to targeted therapy is predicated on a common definition of clinical drug resistance. This may not be as easy as it seems. While clear tumor growth or the appearance of new metastatic disease is typically the hallmark of clinical drug resistance, different mechanisms may be at work depending upon 1) when it occurred in relation to treatment (i.e., during, shortly after, or long after); 2) whether or not treatment was administered on time and at full doses; and 3) the site of tumor growth (i.e., at a pharmacologically privileged site). In addition, new technologies – such as the detection, quantification, and molecular characterization of circulating tumor cells – stand to redefine how, what, and when we determine the appearance of “resistant” disease. It is also important to appreciate that although cancer is a genetic disease, the development of resistance may involve processes that extend beyond the tumor cell compartment and include tumor blood vessels, stem cells, stroma, and/or the immune system, making the design of an effective strategy to overcome resistance even more challenging. Another key variable to consider in the approach to resistant disease is when to intervene: before resistance has occurred or afterwards. Implementing strategies aimed at the prevention or delay of resistance has the advantage of earlier intervention, when the tumor burden is likely to be lower, with the chance that greater tumor cell kill could result in complete eradication and cure of the cancer. Intervening only after the tumor has developed resistance has the advantage that the measures implemented could be reserved for those patients whose tumors actually become resistant and that those measures are tailored to the escape pathway that has been activated. The design of clinical trials aimed at overcoming resistance to targeted therapies poses a number of practical challenges in terms of size, duration, definition of endpoints, and demonstration of clinical relevance. Trials to evaluate resistance-prevention measures would require a large number of subjects followed for a prolonged period of time since not all patients will develop resistance and those that do can do so at highly variable time points. Tumor progression – as a baseline variable and as an endpoint – can be defined in a variety of ways, from standard RECIST criteria to the re-appearance or increase in the number of circulating tumor cells. However, the clinical relevance of a numerical increase in would have to be clearly demonstrated. Lastly, should we consider tumor progression that is due to a mechanism other than the one targeted a success or failure of that approach? In summary, the development of strategies to prevent or reverse resistance to targeted therapies in the clinic will be quite challenging and require close collaboration between basic scientists, clinical investigators, statisticians, drug sponsors, and regulatory agencies. Nevertheless, the potential benefit – in terms of longer survival or survival without progression – makes this a worthwhile effort.