Phase II open-label trial of neoadjuvant immunotherapy in combination with CAPOX for resectable non-metastatic proficient mismatch repair (pMMR) colon cancer: NICER study.

Abstract

TPS2691 Background: Colorectal cancer (CRC) is the third most common malignancy worldwide. Immune checkpoint inhibition has transformed outcomes in deficient mismatch repair (dMMR/MSI-H) CRC but has demonstrated limited efficacy in metastatic proficient mismatch repair (pMMR) tumors, likely related to low tumor mutational burden and limited immune infiltration. Emerging neoadjuvant studies suggest that earlier exposure to immunotherapy may enhance antitumor immunity and induce pathologic responses in pMMR colon cancer. Neoadjuvant chemotherapy may further augment immunogenicity through tumor debulking, antigen release, and modulation of the tumor immune microenvironment. Combination chemo-immunotherapy has improved outcomes across multiple solid tumors and may overcome resistance to immune checkpoint blockade. Early neoadjuvant immunotherapy studies in pMMR colon cancer have demonstrated encouraging pathologic responses without compromising surgical outcomes. The NICER study evaluates the safety, feasibility, and biological activity of neoadjuvant atezolizumab plus CAPOX in resectable pMMR colon cancer. Correlative studies include longitudinal circulating tumor DNA (ctDNA) analysis and paired tissue assessment to characterize immune microenvironmental changes following treatment. Methods: This is a phase II, open-label study evaluating neoadjuvant atezolizumab in combination with capecitabine and oxaliplatin (CAPOX) in patients with resectable, non-metastatic pMMR colon adenocarcinoma. The planned accrual is 28 patients. Participants receive four 3-week cycles of neoadjuvant atezolizumab plus CAPOX, followed by standard-of-care surgical resection. Adjuvant chemotherapy is permitted per investigator discretion for high-risk patients. Key eligibility criteria include pMMR colon adenocarcinoma with tumor ≥12 cm from the anal verge and at least one high-risk feature (elevated CEA, low lymphocyte-to-monocyte ratio, poor differentiation, lymphovascular or perineural invasion, CT-defined T3–T4 disease ≥4 cm, or regional lymphadenopathy). Exclusion criteria include metastatic disease, autoimmune disorders, recent malignancy, or synchronous colorectal primaries. The primary endpoint is tumor regression grade (TRG) using the modified Ryan scoring system. The regimen will be considered promising if the post-therapy TRG 1 rate is ≥15%, compared with an expected rate of 0% with upfront surgery. Secondary endpoints include pathologic complete response, R0 resection rate, lymph node yield, safety, surgical timing, recurrence outcomes, and quality of life. As of January 2026, 7 of 28 planned patients have been enrolled since accrual began in July 2025. ClinicalTrials.gov ID NCT05870800. Clinical trial information: NCT05870800 .