Radiation Therapy Enhances Immunotherapy Response in Microsatellite-stable Colorectal and Pancreatic Adenocarcinoma in a Phase II Trial

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer remains challenging. We conducted a single-arm, non-randomized, Phase 2 trial (NCT03104439) combining radiation, ipilimumab and nivolumab in patients with metastatic MSS CRC (n=40) and PDAC (n=25) with an ECOG performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCR was 25% for CRC (10/40; 95% CI: 13–41%) and 20% for PDAC (5/25; 95% CI: 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (10/27; 95% CI: 19–58%) in CRC and 29% (5/17; 95% CI: 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples, but higher expression of NK cells and the HERVK repeat RNA in patients with disease control. This study provides proof-of-concept of combining radiation with immune checkpoint blockade in immunotherapy resistant cancers.