Remarkable Success with Immunotherapy in Early-Stage MSI-Positive Colon Cancer

Preoperative tumor-shrinking treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), two different immunotherapy drugs called immune checkpoint inhibitors, produced a major pathological response in early-stage colon cancer patients with DNA mismatch repair deficiency, in %100of these patients, according to results presented at the ESMO 2018 Congress.

Neoadjuvant (preoperative tumor-shrinking) treatment with nivolumab and low-dose ipilimumab, in a study whose results were presented at ESMO 2018, a phase-2 clinical trial, was evaluated in patients whose DNA mismatch repair deficiencies resulted in high microsatellite instability (MSI-H, genomic instability) and achieved major pathological responses in % 100 of early-stage colon cancers with this feature.

What Are DNA Mismatch Repair Deficiency and Microsatellite Instability (MSI)?

DNA is copied by placing the matching nucleotide opposite each nucleotide (for example, thymine (T) opposite adenine (A); guanine (G) opposite cytosine (C)). When 3 billion nucleotides are paired during DNA replication , some errors (such as mismatches) may occur. Normally these are identified by DNA mismatch repair enzymes and repaired. However, when mutations occur in the genes encoding mismatch repair enzymes, mismatches cannot be repaired, and faulty DNA sequences called microsatellites accumulate, causing genomic instability. This is called mismatch deficiency (deficiency mismatch repair, dMMR), resulting in high microsatellite instability (microsatellite instability high, MSI-H). The greater the genetic instability in a tumor, the more easily its cancer cells are detected by the immune system .

New-generation immunotherapies classified as checkpoint inhibitors are a treatment strategy that activates the patient's immune response against cancer cells and has now become standard for some types of cancer. Immunotherapies are particularly effective in MSI-H tumors. They had previously been shown effective in metastatic (stage 4) MSI-H colorectal cancersand had received FDA approval for second-line treatment.

Study Details and Results

In this phase-2 clinical trial, 14 patients with early-stage colon cancer were treated before surgery with nivolumab (on days 1 and 15, two doses of 3 mg / kg) and ipilimumab (on day 1, a dose of 1 mg / kg).

According to the study results;

• All 7 of the 7 patients with dMMR (that is, MSI-H) had a major pathological response to treatment. A major pathological response means that viable tumor cells account for less than %5 of the tissue removed at surgery.
• Of 7 patients, 4 (% 57) had a pathological complete response, meaning all cancer cells had died.
• In contrast, patients with tumors that were dMMR negative showed no major pathological response, although there were significant increases in T-cell infiltration.
• The immunotherapy regimen was well tolerated, and all patients underwent their oncological operations without delay.

Conclusion

This clinical trial is the first study of immune checkpoint inhibitors in early-stage colon tumors. These data suggest that neoadjuvant immunotherapy in dMMR colon cancer warrants further investigation and has the potential to change the standard of treatment. The response obtained in as little as 4 weeks is also surprising because it is much greater than in metastatic disease; immunotherapies have generally been found to have higher response rates in metastatic cancers until now. One reason may be that dMMR positivity occurs in around % 15 of early-stage colon cancers, while in stage 4 colon cancer it occurs in around % 5.

In conclusion, this early clinical trial places immunotherapy earlier in the disease course for colon cancer patients with localized (regional, early-stage) tumors and, interestingly, as neoadjuvant treatment rather than adjuvant (postoperative preventive) treatment, as approved in melanoma and non-small cell lung cancer.