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.