Clinical activity of chidamide-containing regimens after prior PD-1-based therapy in two patients with microsatellite-stable metastatic colorectal cancer: a case series and narrative review
Abstract
Background More than 90% of metastatic colorectal cancers (mCRC) are microsatellite-stable (MSS), an immunologically “cold” subtype characterized by low neoantigen burden, impaired antigen presentation, and poor responsiveness to immune checkpoint inhibitors (ICIs). Epigenetic aberrations—including aberrant DNA methylation and histone deacetylation—drive immune evasion in MSS CRC. Histone deacetylase inhibitors (HDACi) can restore major histocompatibility complex class I (MHC-I) expression, reshape the immunosuppressive tumor microenvironment (TME), and synergize with ICIs to enhance antitumor immunity. This retrospective study evaluated chidamide (a selective HDACi) plus a PD-1 inhibitor in two MSS CRC patients with prior ICI progression, with a mechanistic discussion informed by published evidence. Case presentation Case 1: A 60-year-old woman with BRAF V600E-mutant, right-sided, MSS mCRC received third-line surufatinib plus camrelizumab, with a best response of stable disease (SD) and a progression-free survival (PFS) of 5 months. After subsequent disease progression, fifth-line chidamide plus sintilimab achieved a partial response (PR), with a PFS of 6 months. Case 2: A 43-year-old man with recurrent RAS/BRAF wild-type MSS mCRC received fifth-line surufatinib plus sintilimab (PR, PFS 8.5 months) and, after progression, seventh-line chidamide plus sintilimab plus bevacizumab (SD, PFS 5.5 months). No grade 3–4 AEs occurred. Conclusion This retrospective two-patient case series observed one PR and one SD in heavily pretreated MSS mCRC patients with prior ICI failure who received chidamide plus a PD-1 inhibitor (Case 1: primary resistance; Case 2: acquired resistance). As descriptive observations, these findings are hypothesis-generating only and are insufficient to demonstrate reversal of immunotherapy resistance or survival benefit. Prospective biomarker-driven studies are warranted to evaluate epigenetic-immunotherapy combinations in this subgroup.