Neoadjuvant ipilimumab-nivolumab combination induces major pathological response in mismatch repair-deficient colon cancer

MUNICH — Neoadjuvant treatment with nivolumab and ipilimumab induced major pathologic response in 100% of patients with early-stage, mismatch repair-deficient colon cancers, according to results of the phase 2 NICHE trial presented at European Society for Medical Oncology Congress.

Immune checkpoint inhibition has become a standard treatment approach for many cancer types.

These agents are of particular interest in mismatch repair-deficient tumors because they have high mutational load and upregulation of immune checkpoints, according to Myriam Chalabi, MD, PhD, oncologist in the department of molecular oncology and immunology at Netherlands Cancer Institute in Amsterdam.

Prior studies showed checkpoint inhibitors induce durable responses in patients with metastatic colorectal cancers. In their study, Chalabi and colleagues assessed whether such treatment in the neoadjuvant setting could lead to clinically significant response among patients with mismatch repair-deficient early-stage colon cancer.

The analysis included 14 patients with histologically confirmed, resectable, early-stage colon cancer, with no distant metastases and no signs of perforation or clinical bowel obstruction.

Seven (mean age, 60.9 years; 57% female; 67% clinical stage III) had mismatch repair-deficient tumors.

All patients received one dose of ipilimumab (Yervoy, Bristol-Myers Squibb) 1 mg/kg plus nivolumab (Opdivo, Bristol-Myers Squibb) administered at 3 mg/kg on days 1 and 15.

Surgery was planned for a maximum 6 weeks after informed content.

Safety and feasibility served as primary endpoints.

Secondary endpoints included efficacy assessed by pathological response criteria, and associations between response and tumor mutational burden, interferon-gamma gene signatures, T-cell infiltration and T-cell receptor clonality.

Treatment appeared well tolerated.

All patients underwent radical resection with no delays in surgery.

All seven patients with mismatch repair-deficient tumors achieved major pathological responses, defined as less than 5% viable tumor cells remaining, and four of seven (57%) achieved complete responses. Four of these tumors had been clinical stage IIIB or IIIC prior to treatment.

Researchers observed no major pathological responses among patients with mismatch repair-proficient tumors; however, they reported significant increases in T-cell infiltration — particularly CD8-positive T cells — after treatment among both patient subgroups, with a median 2.4-fold change in the mismatch repair-proficient group (P = .018) and 4.8-fold change in the mismatch repair-deficient group (P = .0009).

“This was a very short treatment course in which most patients were operated on within 4 weeks. We now wonder what would have happened with a longer treatment course,” Chalabi said.

Most (71%) patients experienced grade 1 or grade 2 adverse events. Five patients experienced grade 3 adverse events, and no grade 4 adverse events occurred.

Researchers observed no significant differences in pretreatment T-cell receptor clonality and interferon-gamma gene signatures. However, posttreatment interferon-gamma signatures increased the ability to differentiate responders from nonresponders.

“Although mismatch repair-deficient tumor status and tumor mutational burden were associated with response, pretreatment measures of tumor inflammation may have limited predictive value,” Chalabi said. – by Jennifer Southall

Reference:

Chalabi M, et al. Abstract LBA37_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Disclosures: Bristol-Myers Squibb provided funding for this study. The authors report no relevant financial disclosures.