The combination of nivolumab and ipilimumab generated a 100% response rate in patients with mismatch repair–deficient colon cancer and a 29% response rate in patients with MMR-proficient disease.
The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) generated a 100% response rate in patients with mismatch repair–deficient (dMMR) colon cancer and a 29% response rate in patients with MMR-proficient (pMMR) disease, according to final efficacy data from the phase 2 NICHE trial (NCT03026140) that were presented at the 2022 ASCO Annual Meeting.
In the dMMR cohort, 97% of patients (n = 31) achieved a major pathologic response (MPR), which included a 69% complete response (CR) rate (n = 22) and a 3% partial response (PR) rate (n = 1). In the pMMR cohort, 23% of patients (n = 7) achieved an MPR, including a 13% CR rate (n = 4) and a 6% PR rate (n = 2); 71% of patients were classified as nonresponders (n = 22).
NICHE was the first neoadjuvant trial to demonstrate promising pathologic responses in 100% of patients with dMMR tumors (n = 20) and 27% of those with pMMR tumors (n = 15), comparing favorably with historical findings from the phase 2/3 FOxTROT trial (NCT00647530), which showed moderate or greater pathologic regression in only 5% of patients with dMMR colon cancer (n = 115).
The open-label, exploratory NICHE study enrolled patients with nonmetastatic, treatment-naïve colon cancer with pMMR and dMMR tumors. The original cohorts included 30 patients with dMMR tumors and 30 patients with pMMR tumors. By the time of the updated analysis, 32 and 33 patients had been enrolled to the dMMR and pMMR cohorts, respectively. However, 2 patients in the pMMR cohort were excluded from the efficacy analysis due to not matching inclusion criteria.
Baseline characteristics indicated that in the dMMR cohort, the median age was 54 years (range, 22-82), most patients were women (n = 18; 56%), had T4 (n = 15; 47%) and N+ (n = 25; 78%) disease, and a right-sided primary tumor (n = 20; 62%).
In the pMMR cohort, the median age was 62 years (range, 44-77), most patients were male (n = 18; 55%), had T3 (n = 19; 58%) and N- (n = 20; 61%) disease, and a left-sided primary tumor (n = 23; 70%).
Notably, 41% of patients (n = 13) had Lynch syndrome in the dMMR cohort vs 0 in the pMMR cohort.
All patients received 3 mg/kg of nivolumab on days 1 and 15 plus 1 mg/kg of ipilimumab on day 1. pMMR patients were randomized to receive the combination with or without 200 mg of celecoxib daily from day 1 until the day prior to surgery.
Tumor and normal tissue were collected at baseline and at resection. Plasma and peripheral blood mononuclear cells were collected at baseline, during treatment, and at follow-up.
The primary end points of the trial were to establish the safety and feasibility of administration. Secondary end points included pathologic response rate, disease-free survival (DFS), and translational analysis.
The median follow-up time in the pMMR cohort was 28 months, at which point 2 patients (6%), both nonresponders, had disease recurrence; 1 patient subsequently received adjuvant chemotherapy. The median follow-up time in the dMMR cohort was 32 months, at which point no recurrences had occurred.
In the dMMR cohort, all 13 patients with Lynch syndrome achieved an MPR with treatment, including 12 who achieved a pathologic complete response (pCR). Among patients without Lynch syndrome (n = 19), 18 achieved an MPR, including 10 pCRs and 1 PR.
Notably, 4 of 9 pMMR responders received celecoxib.
Regarding subsequent therapy, 2 dMMR patients (1 MPR, 1 PR) and 8 pMMR patients (all nonresponders) received adjuvant chemotherapy.
In terms of safety, the combination was also well tolerated. Grade 3 and 4 adverse effects occurred in 11% of patients (n = 7/65) and consisted of grade 3 rash (n = 1), colitis (n = 1), myositis (n = 1); and grade 3/4 asymptomatic increases in amylase and/or lipase (n = 2).
Findings from the expanded dMMR cohort with 100 patients, which is powered for DFS, are anticipated in the third quarter of 2022. Moreover, biomarker analyses will be performed to improve patient selection and to identify potential treatment targets in nonresponders.
“Future cohorts with new combinations will follow in the adaptive-design NICHE study, and the pMMR cohort treated with nivolumab plus anti–IL-8 is currently ongoing,” the study authors concluded.