A new study indicated that neoadjuvant immunotherapy using immune checkpoint inhibition has the potential to be a new standard of care in early stage colon cancer in patients with mismatch repair (MMR)-deficient (dMMR) tumors and a subgroup of patients with MMR-proficient (pMMR) tumors.

To date, immunotherapy directed against PD-1 and CTLA-4 proteins has been highly effective in patients with dMMR colon cancer. However, these regimens have had poor results in patients with pMMR colon cancers.

“Recent studies in early-stage melanoma, lung cancer and bladder cancer have shown impressive and deep pathological responses to neoadjuvant immune checkpoint inhibition,” the study researchers wrote. “The higher response rates in early-stage disease compared with metastatic disease have been attributed to a difference in T cell infiltration, a lower degree of systemic immune suppression, the absence of visceral metastases and a lower tumor burden. Interestingly, in early-stage pMMR colon cancers, a substantial proportion of tumors has a high T cell infiltration compared with metastatic pMMR colon cancers.”

In this study, the researchers treated a group of 40 patients with colon cancer with a single dose of ipilimumab and 2 doses of nivolumab before surgery; 21 patients had dMMR and 20 patients had pMMR tumors. The primary objective was safety and feasibility.


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All patients underwent radical resection of their tumor, meeting the primary endpoint. Thirty-five of the 40 patients were evaluable for efficacy and translational endpoints.

All of the patients with dMMR tumors had pathological response, with 19 major pathological responses and 12 pathological complete responses. Among patients with pMMR tumors, 27% had pathological responses, with 3 major pathological responses and 1 partial response. Among those with pMMR tumors, CD8+PD-1+ T-cell infiltration was predictive of response.

The researchers acknowledged that the study was small and that larger studies with at least a 3-year follow-up for disease-free survival will be required to determine if the observed major pathological responses in both patient groups translate into improved disease-free survival and overall survival.

Reference

Chalabi M, Fanchi LF, Haanen JB, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566-576.