National clinical study

Comparison of tumor-agnostic and tumor-informed ctDNA analysis methods to predict response in patients with dMMR CRC treated with neoadjuvant pembrolizumab

Colorectal cancer (CRC) treatment has improved significantly, with reduced 30-day mortality rates. However, postoperative complications and cancer recurrence remain challenges. Neoadjuvant immunotherapy has shown promise in deficient mismatch repair (dMMR) colon cancer (CC), with recent studies demonstrating high pathological complete response (pCR) rates. Circulating tumor DNA (ctDNA) analysis may help identify patients achieving pCR, but the optimal approach (tumor-agnostic or tumor-informed) is unclear. This study aims to compare these ctDNA analysis methods as efficacy biomarkers in patients with localized dMMR CRC receiving neoadjuvant pembrolizumab included in the RESET-C trial.

Abstract

Introduction: Colorectal cancer (CRC) treatment has improved significantly, with reduced 30-day mortality rates. However, postoperative complications and cancer recurrence remain challenges. Neoadjuvant immunotherapy has shown promise in deficient mismatch repair (dMMR) colon cancer (CC), with recent studies demonstrating high pathological complete response (pCR) rates. Circulating tumor DNA (ctDNA) analysis may help identify patients achieving pCR, but the optimal approach (tumor-agnostic or tumor-informed) is unclear. This study aims to compare these ctDNA analysis methods as efficacy biomarkers in patients with localized dMMR CRC receiving neoadjuvant pembrolizumab included in the RESET-C trial.

Methods: The RESET-C trial, a multicenter, prospective, single-arm phase II study, enrolled 85 patients with stage I-III dMMR CC. Patients received one dose of pembrolizumab (4mg/kg, maximum 400mg) followed by surgery 3-5 weeks later. Blood and tumor samples were collected pre-treatment, post-treatment, and 4 weeks post-surgery. The tumor-agnostic TriMeth test, targeting hypermethylation of C9orf50, KCNQ5, and CLIP4 genes in blood, will be compared with a tumor-informed ctDNA analysis. The tumor-informed approach utilizes a focused 40-gene panel on tumor samples, expected to identify potential mutations for ctDNA analysis in >98% of cases. Performance metrics, concordance analysis, and cost-effectiveness analysis will be conducted to comparethe two approaches.

Perspectives: This study aims to identify a reliable method for predicting patient response to neoadjuvant immunotherapy in dMMR CC. The tumor-agnostic TriMeth approach may offer clinical utility due to its rapid turnaround time, potentially supporting treatment decisions, but it may lack in sensitivity compared with a tumor-informed approach. Identifying patients likely to benefit from immunotherapy is crucial to avoid unnecessary exposure and associated adverse events with immunotherapy and surgery. This project has the potential to improve patient selection for neoadjuvant immunotherapy and optimize treatment strategies for dMMR CC.

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