Effect of chemotherapy treatment on immunotherapy efficacy in colorectal cancer (CRC) patients with high microsatellite instability (MSI-H) and/or tumor mutational burden (TMB-H).

Abstract

e14561 Background: Immune checkpoint inhibitors (ICI) are more effective than chemotherapy (CT) in treating MSI-H CRC in the metastatic and neoadjuvant settings. Currently, the impact of CT on ICIs efficacy in CRC is not well characterized, especially in stage 3 CRC adjuvant therapy. Methods: Based on data from published randomized control trials in CRC, we developed a mathematical modeling of Kaplan-Meier curves for stage 3 CRC pts treated with 1) CT, 2) ICI or 3) combination CT + ICI. Our modeling generated a hypothesis on the potential interactions of CT and ICI in CRC therapy. We retrospectively analyzed 30,500 CRC pts for MSI-H and/or TMB-H (MSI/TMB-H) status from multi-institutional electronic health records on an IRB-approved protocol between January 2009 and December 2024 to obtain real-world therapeutic CT and ICI interactions. Microsatellite status and genomic testing were done in CLIA-certified, CAP-accredited labs. Pt characteristics, pathology, in-depth clinical treatment history and genomics were summarized with descriptive statistics. Treatment efficacy (overall response rate [ORR], relapse free survival [RFS], progression-free survival [PFS], and overall survival [OS]) to CT and ICIs were determined in MSI/TMB-H CRC pts. Results: The Kaplan-Meier estimate may be represented by the equation f(t) as a function of time: f(t) = ((1/(at 2 +1) + b + ((1-b) e -ct ))/2. Mathematical modeling of Kaplan-Meier curves for stage 3 MSI-H and/or TMB-H CRC pts demonstrated superior efficacy with adjuvant ICI compared to combination CT + ICI, and both regimens are better than CT. The hypothesis that CT inhibits ICI efficacy in MSI/TMB-H CRC patients is supported by our retrospective study. Stage 4 MSI/TMB-H CRC ICI-treated pts who received prior CT demonstrated significantly decreased ORR, PFS and OS. Stage 3 MSI/TMB-H CRC pts had higher RFS and OS when treated with ICI compared to CT. Conclusions: Exposure to CT decreased ICI efficacy in CRC. Mathematical modeling shows adjuvant ICI is superior to combination ICI + CT in stage 3 CRC. Clinical trial investigation with adjuvant ICI compared to CT + ICI is warranted in stage 3 CRC.