Immunotherapy Is Active in MMR-Deficient and MMR-Proficient Colon Cancer

In advanced-stage colorectal cancer, immune-checkpoint blockade (ICB) with anti–PD-1 plus anti-CTLA4 has shown efficacy in mismatch repair (MMR)-deficient but not MMR-proficient disease. Hypothesizing that ICB might be effective in colon cancer at earlier stages—during which there is lower T-cell impairment, immunosuppression, and tumor burden as well as an absence of distant metastases—Chalabi and colleagues initiated a clinical trial of neoadjuvant ipilimumab (anti-CTLA4) plus nivolumab (anti–PD-1) in 40 patients with treatment-naïve stage I, II, or III colon cancer. Twenty-one patients had MMR-deficient tumors and 20 patients had MMR-proficient tumors, with one patient having both an MMR-deficient and an MMR-proficient tumor. Due to the lack of benefit from ICB previously observed in patients with MMR-proficient tumors, these patients also received the COX2 inhibitor celecoxib, which has been suggested to synergize with ICB. All patients underwent planned radical resections within six weeks of study inclusion. Treatment was generally well tolerated, with most side effects being grade 1 or 2, and no patients died due to treatment-related adverse effects. Of patients with MMR-deficient tumors, 100% had a pathologic response, of which 95% were major pathologic responses (defined as ≤10% residual viable tumor) and 60% were complete pathologic responses. Among patients with MMR-proficient colon cancer evaluable for response, 27% exhibited pathologic responses of any degree, with 20% experiencing major pathologic responses, a finding that contrasts with the lack of efficacy observed with ICB in advanced MMR-proficient colorectal cancer. Interestingly, biomarker analysis revealed that lower tumor mutational burden—suspected to be a cause of ICB failure—did not correlate with lack of response in patients with MMR-proficient disease. Instead, the analysis showed that greater CD8⁺PD-1⁺ T-cell infiltration was associated with a higher chance of response in these patients. Limitations of this study include the small number of patients enrolled and the short postoperative follow-up, which prevents evaluation of whether neoadjuvant ICB affects overall survival. However, the promising results presented in this work warrant follow-up in larger trials.

Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566–76.

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