Neoadjuvant immunotherapy in mismatch-repair-proficient colon cancers

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Immune checkpoint blockade (ICB) revolutionized cancer treatment but shows limited efficacy in metastatic mismatch-repair-proficient (pMMR) colorectal cancer.
• Early-stage pMMR colon cancer remains a challenge for ICB therapy.

Purpose of the Study:

• To evaluate the clinical efficacy and analyze response biomarkers of neoadjuvant nivolumab plus ipilimumab in early-stage pMMR colon cancer.
• To identify predictive biomarkers for ICB response in this patient population.

Main Methods:

• Phase II NICHE study (NCT03026140) involving 31 patients with early-stage pMMR colon cancer receiving neoadjuvant nivolumab plus ipilimumab.
• Analysis included clinical response, circulating tumor DNA (ctDNA) dynamics, tumor mutational burden (TMB), chromosomal genomic instability (cGI) scores, gene expression profiling, and imaging mass cytometry.

Main Results:

• A 26% response rate was observed, with six patients achieving a major pathological response.
• ctDNA clearance before surgery was associated with response, while persistent ctDNA indicated non-response.
• Responders exhibited higher cGI scores, baseline proliferation signatures, TCF1 expression, and increased Ki-67+ cancer and CD8+ T cells compared to non-responders, despite low TMB.

Conclusions:

• Neoadjuvant nivolumab plus ipilimumab demonstrates activity in early-stage pMMR colon cancer.
• Chromosomal genomic instability, proliferation signatures, TCF1 expression, and specific immune cell infiltration are potential biomarkers for predicting response to ICB in this setting.