Multicenter randomized phase 2 trial of addition of celecoxib to neoadjuvant toripalimab for dMMR/MSI-H, locally advanced colorectal cancer

Neoadjuvant immune checkpoint blockade has shown remarkable activity in dMMR or MSI-H, locally advanced colorectal cancer (LA CRC). Preclinical studies suggest that COX-2 inhibition might modulate the inflammatory tumor microenvironment. The randomized phase 2 PICC-2 trial, at three centers in China, evaluated addition of the COX-2 inhibitor celecoxib to neoadjuvant toripalinab for dMMR/MSI-H LA CRC. Eligible patients were aged 18-75 years, had clinical stage T3-T4 or any clinical T stage with lymph node positivy (N+), and had ECOG performance status 0 or 1. Participants were randomly assigned (1:1), stratified by tumor location and clinical T stage, to receive neoadjuvant toripalimab plus celecoxib (n=55) or toripalimab monotherapy (n=55) every 14 days for 12 cycles, followed by surgery. At the data cutoff date, median follow-up was 18.1 months. In each of the groups, 49 of 55 patients completed all 12 planned cycles of neoadjuvant therapy. Surgery was done in 53 of 55 patients (89%) in the toripalimab plus celecoxib group and 36 of 55 (69%) in the monotherapy group. Pathologic complete response (pCR) was observed in 49 of 55 patients (89%; 95% CI 78-96) in the toripalimab plus celecoxib group versus 38 of 55 (69%; 55-81) in the monotherapy group (p=0.014). Grade 3 treatment-related adverse events occurred in 5% and 7%, respectively. No grade 4 or 5 treatment-related adverse events occurred. The authors conclude that addition of celecoxib to neoadjuvant toripalimab resulted in significant increase in the proportion of dMMR/MSI-H LA CRC patients achieving pCR, without compromising safety.