Parikh and Szabolcs et al. reported the efficacy of dual PD-1 and CTLA-4 blockade combined with radiation therapy in patients with metastatic microsatellite-stable CRC (n=40) and PDAC (n=25). In intention-to-treat analysis, the disease control rate (DCR) was 25% and the ORR was 10% for CRC, while the DCR was 20% and the ORR was 12% for PDAC, all of which increased by up to 1.5 fold in per-protocol analysis (patients treated with radiation therapy). Duration of control was noteworthy. Transcriptomic analysis of pretreatment biopsies showed elevated expression of multiple repeat RNA species and higher numbers of NK cells in patients with disease control.
Contributed by Shishir Pant
ABSTRACT: Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of 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.