Feasibility of an Evolutionary Tumor Board for Generating Novel Personalized Therapeutic Strategies

Abstract

Abstract The current paradigm of clinical trials treating patients until disease progression using maximum tolerated dose does not account for the dynamic tumor-host-drug interactions that result in acquired resistance. Here, we present the concept of an Evolutionary Tumor Board (ETB) and report interim results from a prospective, non-interventional pilot study in which novel therapeutic strategies based on evolutionary principles were developed under the ETB framework. The ETB approach relies on an interdisciplinary team that integrates clinical, preclinical, and theoretical knowledge and the application of mathematical modeling to predict patient responses to different therapies, including novel approaches derived from eco-evolutionary first principles. We have previously proposed several evolutionary therapies that aim to enhance the efficacy of an overall treatment regimen, using existing agents for a given disease. Key among these evolutionary therapies is the idea of “first-strike second-strike”, where different agents are administered in sequence, and new strikes are applied as soon as the efficacy of the previous strike is nearing a minimum, as opposed to waiting until progression is identified on periodic imaging. This approach requires careful analysis of longitudinal patient data coupled with predictive dynamics generated by mathematical models. Here we describe the ETB process and the interim results from 15 patients enrolled in the feasibility trial. In addition, we describe the challenges faced as well as the solutions that can be implemented via improved modeling approaches, better patient data collection, and a reassessment of how we understand tumor dynamics in the light of evolutionary principles.