Neoadjuvant Nivolumab/Ipilimumab Elicits Promising Pathologic Responses in dMMR Colon Cancer

Four weeks of treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) elicited major pathologic responses (MPRs) in 95% of patients with mismatch repair–deficient (dMMR) colon cancer, according to findings from the NICHE-2 trial (NL58483.031.16, EudraCT 016-002940-17) presented at the 2022 ESMO Congress.¹

“This stands in stark contrast to data from neoadjuvant chemotherapy in this same patient population [that had] only 7% pathologic responses,” Myriam Chalabi, MD, PhD, a medical oncologist at the Netherlands Cancer Institute, said in her presentation at the conference.

Additionally, 67% of patients demonstrated pathologic complete responses (pCRs) and none have disease recurrence to date. This treatment was also well tolerated, with investigators observing only 4% grade 3/4 immune-related adverse events (irAEs).

The non-randomized, multicenter NICHE-2 trial was initiated by investigators after 32 patients with nonmetastatic dMMR colon cancer in the NICHE-1 trial (NCT03026140) showed 100% pathologic responses and 60% pCRs to an immune checkpoint blockade.

In NICHE-2, the 112 patients in the intention-to-treat (ITT) population received 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab in the first cycle, then only nivolumab in the second cycle 2 weeks later, followed by surgery within 6 weeks of enrolling on the trial. The primary end points of this study were 3-year disease-free survival (DFS) and safety, and secondary end points included MPR and cPR. Safety and feasibility would be reached if surgery was performed on time, with no more than 2 weeks delay in 95% of patients. A 3-year DFS of 93% would also be deemed successful.

All patients underwent surgery and achieved tumor-free resection margins, with 98% of patients undergoing timely surgery and meeting the safety end point of the trial. The median time from the first dose with the combination to surgery was 5.4 weeks. No new safety signals were observed, however 21% of patients had any-grade surgery-related AEs. Thirteen percent of those were grade 3 or higher and 5% were anastomotic leakage or wound infections.

Pathologic response was defined as 50% or less residual viable tumor (RVT), MPR as 10% or less RVT including tumors with pCR in the primary tumor but RVT in the lymph node, and pCR as 0% RVT in both the primary tumor and lymph nodes.

In this trial, 107 patients were evaluated for efficacy and 106 patients (99%) showed a pathologic response. MPR was seen in 102 (95%), pCR in 72 (67%), and partial pathologic response in 4 (4%) patients. Only 1 patient did not experience pathologic response with 60% RVT upon evaluation. Of the 14 patients with positive lymph nodes after treatment, 3 received adjuvant chemotherapy¾1 non-responder, 1 partial responder, and 1 with MPR—5 patients were over 70 years old and could not receive chemotherapy, and 6 patients refused adjuvant chemotherapy. There has been no disease recurrence at a 13.1-month median follow-up (range, 1.4-57.4 months).

For the 97 patients in the per protocol population who had Lynch status available, 65 had a sporadic dmmR tumor and 32 had Lynch syndrome. Sporadic tumor patients had a 58% pCR rate and Lynch syndrome patients had a 78% pCR rate (P = .056).

In total, 61% of patients experienced any grade irAEs. Only 2 patients had irAEs leading to a delay in surgery more than 2 weeks. Infusion reactions, dry mouth, hyper- or hypothyroidism, and fatigue and flu-like symptoms were the most common grade 1/2 AEs.

“Only 4% of patients experienced grade 3 or 5 AEs. [There were] 5 events in 4 patients total,” Chalabi said. “These included 2 patients with amylase and lipase increase, which was asymptomatic and resolved without any intervention; 1 patient with hepatitis, 1 patient with myositis, and 1 patient with a rash that were treated with prednisone and the patient with myositis received mycophenolate [as well].”

Patients on the NICHE-2 trial had nonmetastatic, previously untreated dMMR colon adenocarcinoma, cT3 and/or node positive disease based on radiologic staging, no clinical symptoms or radiologic suspicion of perforation, and no clinical signs of obstruction. Patients could not have active autoimmune disease, or other medical conditions, requiring systemic steroid or immunosuppressive medications.

At baseline, there was a median age of 60 years (range, 20-82 years) and 58% of patients were female in the ITT population. Most patients (87%) had an ECOG performance status of 0, and 74% had radiologic stage of high risk III. Patients with right colon tumors made up 68%, those with left colon tumors 17%, and those with transverse colon tumors 15%.

The 3-year DFS data are expected in 2023. Future studies may look at organ-sparing approaches for patients with dMMR colon cancers. According to Chalabi, assessment of radiologic response, or any response, in patients with colon cancer is much more difficult than in rectal cancer so circulating tumor DNA dynamics and novel imaging techniques should be explored and may aid in achieving organ preservation.

“I believe that neoadjuvant immunotherapy has a very strong potential to become standard of care for patients with dMMR colon cancer. The future has never been brighter for this patient population, and for that, I urge the pharmaceutical companies to please strive for registration of neoadjuvant immunotherapy,” Chalabi concluded.

Reference

Chalabi M, Verschoor YL, van den Berg J, et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089