Randomized phase 2 trial of sintilimab plus chidamide with or without bevacizumab for advanced MSS/pMMR colorectal cancer

Epigenetic modification of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. The randomized phase 2 CAPability-01 trial, at Sun Yat-sen University (Guangzhou, China) evaluated sintilimab (anti-PD-1) plus chidamide (histone deacetylase inhibitor) with or without bevacizumab (anti-VEGF) for unresectable chemotherapy-refractory locally advance or metastatic microsatellite stable/proficient mismatch repair colorectal cancer. The primary endpoint of progression-free survival rate at 18 weeks was met with a rate of 43.8% across both groups. The median PFS was 3.7 months, the ORR was 29.2%, and the DCR was 56.3%. The triplet group had significantly improved outcomes compared to the doublet group: 18 weeks PFS rate 64.0% versus 21.7% (p=0.003), ORR 44.0% versus 13.0% (p=0.027), and median PFS 7.3 versus 1.5 months (p=0.006). The most common treatment-emergent adverse events in both groups were proteinuria, thrombocytopenia, neutropenia, leukopenia, and diarrhea.Two of 48 patients died of treatment-related causes (hepatic failure and pneumonitis). The authors conclude that the combination of a PD-1 antibody, an HDAC inhibitor, and a VEGF antibody could be a promising treatment regimen for MSS/pMMR advanced colorectal cancer.