Innovative, early-phase clinical trials of drug-radiotherapy combinations

Over the past few decades, breakthroughs in cancer biology at the molecular level have revolutionised cancer treatment. Enhanced precision in radiotherapy has not only reduced patient side-effects, but also enabled the delivery of high-dose stereotactic extracranial irradiation with unprecedented accuracy. Simultaneously, the number of medical therapies available for clinical care continues to grow. Despite the progress made with combined chemoradiotherapy, only a few drug-radiotherapy combinations have received clinical approval, leaving a vast landscape of untapped opportunities for basic, translational, and clinical research, particularly in early-phase drug-radiotherapy trials. New and promising pharmaceutical therapies, paired with advanced radiotherapy technologies, are now being tested in innovative clinical trial designs. Moreover, the integration of biological and imaging markers-both tumour-specific and peripheral-holds the potential to personalise drug-radiotherapy combinations, thereby enhancing the therapeutic index for specific patient populations. In this Review, we highlight the latest developments and future directions for early-phase clinical trials that combine precision drug-radiotherapy strategies in adult patients, with the aims of improving outcomes and expanding treatment options.