100% Disease-Free Survival with Preoperative Immunotherapy in MMR-Deficient Colon Cancer

The Importance of MMR Deficiency and Neoadjuvant Immunotherapy

Mismatch repair (MMR = MisMatch Repair) deficiency is an important biomarker in colon cancer, and these tumors’ sensitivity to immunotherapy has been recognized for a long time.

NOTE: approximately 15% of colon cancers are DNA mismatch repair (MMR)-deficient tumors, meaning they have dMMR (deficient mismatch repair) status. These tumors have impaired DNA repair mechanisms and consequently a high mutation burden. This is particularly important for sensitivity to immunotherapy, because dMMR tumors may respond better to treatments such as immune checkpoint inhibitors. dMMR tumors are also called microsatellite instability-high (MSI-H).

Neoadjuvant immunotherapies are given before surgery to shrink tumors and improve disease-free survival. The NICHE-2 and NICHE-3 studies provide the latest encouraging results in this area, showing substantial benefits from immunotherapy in this patient group. Their findings strengthen the place of immunotherapy in treatment strategies and make important contributions to clinical practice.

The NICHE-2 Study: Three-Year Disease-Free Survival Data

The NICHE-2 study included 111 patients with locally advanced dMMR colon cancer, who received a single dose of ipilimumab and two doses of nivolumab before surgery. After surgery, three-year disease-free survival was 100%, exceeding the prespecified success threshold of 93%.

These results clearly show that neoadjuvant immunotherapy improves disease-free survival in dMMR colon cancer. In addition, clearance of ctDNA (circulating tumor DNA) played an important role in predicting treatment response. Among 102 patients who started treatment, 45% showed ctDNA clearance on day 15 after treatment. ctDNA remained positive before surgery in 16 patients, but 5 of them achieved a pathological complete response (pCR), and 8 a major pathological response (MPR). Minimal residual disease analysis at week 3 after surgery found all patients to be ctDNA-negative. This was the postoperative finding.

Chart explanation: in the NICHE-2 study of neoadjuvant ipilimumab plus nivolumab in dMMR colon cancer, 94% of patients with a pathological complete response had clearance of circulating tumor DNA before surgery. The chart shows presurgical circulating tumor DNA (ctDNA) clearance rates and their relationship with pathological response. Three response categories (partial response, major pathological response, and pathological complete response) were examined, with the proportions of patients showing early clearance, late clearance, or no clearance presented statistically for each group.

The NICHE-3 Study: Results of Nivolumab Plus Relatlimab

The NICHE-3 study used two doses of nivolumab and relatlimab as the neoadjuvant immunotherapy regimen. Among the 59 participants, the pathological response rate after surgery was 97%, with pCR in 68% and MPR in 92%. These results further reinforce immunotherapy’s effectiveness in dMMR colon cancer.

However, some treatment-related adverse effects were also reported. Grade 3-4 immune-related adverse events occurred in 10% of patients and caused surgery to be postponed in three patients. Long-term endocrine disorders were also observed, particularly thyroid dysfunction and adrenal insufficiency.

Circulating Tumor DNA (ctDNA) Clearance and Response

The NICHE-2 data presented above suggest that ctDNA can serve as an important biomarker of treatment response. Presurgical ctDNA clearance stands out in particular as a determining factor in assessing treatment effectiveness. In the study, ctDNA clearance occurred in 94% of patients with a pathological complete response and 70% of those with a major pathological response. These findings represent an important step toward identifying patients at risk of minimal residual disease and offering them more targeted treatments.

Safety Profile: Adverse Effects of Immunotherapies

In both studies, immunotherapy adverse effects were largely manageable. In NICHE-2, grade 3-4 immune-related adverse events occurred in only 4%. In NICHE-3, more serious adverse effects were reported in 10%, with endocrine disorders — particularly thyroid dysfunction and adrenal insufficiency — prominent. Such adverse effects are important considerations when using immunotherapies.

Conclusion: Neoadjuvant Immunotherapy in Clinical Practice

The NICHE-2 and NICHE-3 studies clearly show the important role of neoadjuvant immunotherapy in dMMR colon cancer treatment. Very high three-year disease-free survival rates of 100% strongly support the effectiveness of this approach. The role of ctDNA clearance in predicting treatment response also suggests that this biomarker may be used more widely in clinical practice in the future. However, treatment-related adverse effects must be carefully monitored and managed.

These findings represent important progress in immunotherapy, broadening the range of treatment options for patients with dMMR colon cancer. Neoadjuvant immunotherapy offers an effective strategy to reduce tumor burden before surgery and improve disease-free survival.