1. No disease recurrences were observed during the median follow-up time of 26.2 months.

2. Immune-related adverse events grade 3-4 occurred in 4% of patients.

Evidence Rating Level: 2 (Good)

Study Rundown: While adjuvant chemotherapy is standard for locally advanced DNA mismatch repair deficiency (dMMR) colon cancer, recent studies advocate for neoadjuvant immunotherapy. This study (NICHE-2) evaluated neoadjuvant nivolumab plus ipilimumab’s efficacy in this setting. The primary endpoints included 3-year disease-free survival and timely surgery (no more than 2 weeks beyond the prespecified 6 weeks after study enrollment) and secondary endpoints included pathological response and safety. No disease recurrences were observed during the median follow-up time of 26.2 months. Pathological response rates were seen in 98% of patients, including 95% with a major pathological response and 68% with a pathological complete response. Pathological complete response was seen in a higher percentage of patients with Lynch syndrome than in those without (79% vs. 61%). Whole-exome sequencing data were done in most patients and found a median tumor mutational burden of 42.5 mutations per megabase (ranging from 3.46 to 138.7). The tumor mutational burden was not associated with pathological complete response nor was it associated with Lynch vs non-Lynch syndrome–associated tumors. BRAF V600E mutation was found in 57% of non–Lynch syndrome–associated tumors, and in those tumors, the pathological complete response was higher compared with BRAF V600 wild-type tumors (75% vs 57%). With regard to safety, timely surgery was performed in 98% of patients. 2% of patients had treatment-related adverse events (myositis) that led to delay of surgery. Immune-related adverse events grade 3-4 occurred in 4% of patients and included rash, asymptomatic increase in amylase and lipase levels, myositis, hepatitis, and hyponatremia. The strengths of this study included its follow-up time, and the limitations included its single-cohort design as well as the number of participants. Overall, this study found some efficacy and safety in patients with resectable stage II-III dMMR colon adenocarcinoma who were treated with neoadjuvant immunotherapy.

Click to read the study in NEJM

Relevant Reading: Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

In-Depth [prospective cohort]: This multicenter, single-arm, phase II trial enrolled adults (n=111) with resectable stage II or III dMMR colon adenocarcinoma and administered 2 doses of nivolumab and 1 dose of ipilimumab followed by surgery within 6 weeks of study enrollment. 33% of patients had Lynch syndrome, and 67% had stage III disease. Median follow-up time was 26.2 months (9.1 to 65.3), and no disease recurrences were observed. Pathological response rates were seen in 98% (95%CI, 94-100) of patients, including 95% (95%CI, 89 to 98) with a major pathological response and 68% (95%CI, 58-76) with a pathological complete response. Pathological complete response was seen in a higher percentage of patients with Lynch syndrome than of those without (79% vs. 61%). Whole-exome sequencing data were done in most patients and found a median tumor mutational burden of 42.5 mutations per megabase (ranging from 3.46 to 138.7). The tumor mutational burden was not associated with pathological complete response nor was it associated with Lynch vs non-Lynch syndrome–associated tumors. BRAF V600E mutation was found in 57% of non–Lynch syndrome–associated tumors, and in those tumors, the pathological complete response was higher compared with BRAF V600 wild-type tumors (75% vs 57%). With regards to safety, timely surgery was performed in 98% (97.5%CI, 93-100) of patients. 2% of patients had treatment-related adverse events (myositis) that led to delay of surgery. Immune-related adverse events grade 3-4 occurred in 4% of patients and included rash, asymptomatic increase in amylase and lipase levels, myositis, hepatitis, and hyponatremia. Overall, this study found some efficacy and safety in patients with resectable stage II-III dMMR colon adenocarcinoma who were treated with neoadjuvant immunotherapy.

Image: PD

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