An overview of the published and running randomized phase 3 clinical results of radiotherapy in combination with immunotherapy.

Several studies have established that radiotherapy (RT) in combination with immunotherapy (IO) has a strong synergistic effect. RT changes the tumor microenvironment, generates local inflammation reactions, and enhances immunostimulatory effects, which are able to assist IO with improving local and systemic tumor control. In several pre-clinical reports, RT in combination with IO reveals regression of tumors locally (irradiated sites) and systemically (non-irradiated sites). Several clinical trials are currently running, mostly as phase I and II studies. This article provides an overview of the randomized, prospective reported and recruiting phase 3 clinical trials of RT in combination with IO. To date, three phase 3 trials have been published on RT and sequential IO with variable results, ranging from no significant difference (Kwon et al., START) to absolute differences in overall survival of 13.5% after 3 years (PACIFIC), respectively. No phase 3 randomized trials have been published on the simultaneous combination of RT with IO. Thirty trials are presently under way, and still recruiting patients to quantify the response to RT with IO. These studies fall into three categories of research interests: (I) to discover an enhancement effect of IO as induction therapy with RT; (II) to determine the additional effect of concurrent IO on the local effect of RT; and (III) to determine the additional effect of adjuvant or consolidation IO on the local effect of RT. Most of the ongoing studies are a combination of these interests, with 15 trials evaluating the concurrent RT+IO with IO consolidation strategy. The results in coming years will provide more insights in the role of RT as an activator of the immune system, the effect of IO as local sensitizer of RT, the optimal sequencing of IO with RT, and the total RT doses needed to obtain the optimal local and systemic effect.