Study Protocol of A Phase II Study to Evaluate Safety and Efficacy of Neo-adjuvant Pembrolizumab and Radiotherapy in Localized Rectal Cancer

Background Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve the treatment of cancers. Nevertheless, responsiveness to these treatments is often correlated with the extent of the T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor infiltration and, therefore, do not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy may have profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immunotherapy was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immunotherapy have never been tested in these tumors. Methods Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized microsatellite stable rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5Gy x 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed after three weeks from the last pembrolizumab injection. Our clinical trial also includes an extensive research program involving the transcriptomic and proteomic analysis of blood and tumor samples throughout the course of the treatment. Discussion Our study is the first clinical trial to provide with safety and efficacy information of this novel treatment approach in rectal cancer, leading to a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer better insight into immunological changes within the tumor and blood during treatment. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients. Trial registration This study was registered with www.clinicaltrial.gov NCT04109755 . Registration date: June, 2020.