Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting

Purpose: Only one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site.Patients and methods: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n = 66), we sought to validate data from a U.S. cohort, and performed pooled analysis (n = 104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and with progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates.Results: Objective responses were achieved in 38/66 (58%) of patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis (P = 0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P = 0.01).Conclusions: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients.