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

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. ### Competing Interest Statement HE holds U.S. Patent 63/279,994: Bayesian Framework to Augment Tumor Board Decision Making (provisional), U.S. Patent 62/040,579: Predicting glioma treatment response (provisional), and U.S. Patent 62/944,804: Methods for prostate cancer intermittent adaptive therapy (provisional). TB received Research funding support from Bristol Myers Squibb and has stock ownership in Ionis Pharmaceuticals. HS received honoraria from AstraZeneca, Seattle Genetics, Merck, and Novartis for serving in ad hoc scientific advisory boards. DRR received honoraria from Springworks and Eisai for serving in Data Safety Monitoring Committee. CHC received honoraria from Sanofi, Merck, Brooklyn ImmunoTherapeutic, Fulgent, and Exelixis for serving in ad hoc scientific advisory boards. All other authors declared no conflict of interest. ### Clinical Protocols ### Funding Statement This study was funded by Moffitt Cancer Center and the Center of Excellence for Evolutionary Therapy at Moffitt Cancer Center ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Protocol No.: 20417 Title: Feasibility of Generating Novel Therapeutic Strategies Based on Evolutionary Tumor Board in Cancer Patients Protocol Status.: IRB INITIAL APPROVAL PI: Chung, Christine Institution: Moffitt Cancer Center IRB No.: IRB Committee: Advarra Meeting Date: 04/07/2020 Review Reason: Initial Review Review Type: Expedited Action: Approved Action Effective Date: 04/07/2020 Action Expiry Date: 04/07/2021 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Most data produced in the present work are contained in the manuscript. All data produced in the present study are available upon reasonable request to the authors.