Project Optimus for Radiation Therapy-Drug Combinations: Moving Beyond the Maximum Tolerated Dose

The development of effective radiation therapy (RT)-drug combinations has been slow, largely because early-phase trial designs have mirrored systemic drug development paradigms based on the maximum tolerated dose (MTD). The U.S. Food and Drug Administration's Project Optimus advocates replacing the MTD approach with the identification of an optimum biologically effective dose, integrating both efficacy and tolerability. Applying these principles to RT-drug development could accelerate the establishment of safe and effective combinations.

An international panel of experts examined how Project Optimus principles could be adapted to RT-drug development. We discuss: (1) the legacy of the MTD in RT-drug development; (2) adapting Project Optimus principles to RT-drug trials; (3) key considerations for safety and efficacy assessment; (4) trial design innovations; and (5) future directions for implementation.

The panel identified key limitations of the traditional MTD approach, including inadequate capture of delayed and cumulative adverse events and a lack of biological relevance for radiosensitization or immune modulation. The proposed RT-Optimus framework redefines dose-finding objectives to identify the Optimum Radiation Therapy Combination Regimen-the combination of drug dose, schedule, and RT parameters that optimizes tumor control while minimizing normal tissue side effects. Implementation of this approach requires extended windows to assess side effects, incorporation of patient-reported outcomes, intermediate efficacy endpoints (eg, circulating tumor DNA clearance, radiomics), and use of adaptive, model-informed trial designs to efficiently evaluate multiple agents and schedules.

An RT-Optimus framework offers a biologically and ethically grounded pathway to modernize early-phase RT-drug trials. By focusing on the Optimum Radiation Therapy Combination Regimen rather than MTD, and embedding mechanistic, biomarker-informed, and patient-centered endpoints, this approach could improve the efficiency, reproducibility, and clinical relevance of RT-drug development, helping to avoid failures seen in previous RT-drug combinations and ultimately accelerating progress toward safer and more effective multimodality cancer treatments.