Organ preservation strategy using dostarlimab for dMMR/MSI-H resectable solid tumors with whole-genome–based MRD monitoring (D-CURE: EPOC2401).

Abstract

TPS2697 Background: Mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) solid tumors accumulate numerous genomic alterations that generate neoantigens, which are presented on MHC molecules and activate potent Th1 and cytotoxic T-cell responses. This heightened immunogenicity simultaneously induces adaptive immune resistance through PD-1/PD-L1 upregulation, providing a strong biological rationale for the effectiveness of immune-checkpoint inhibitors in dMMR/MSI-H tumors. Neoadjuvant immune-checkpoint inhibition is particularly effective in dMMR/MSI-H tumors because it leverages the intact tumor and lymphatic microenvironment to prime robust systemic antitumor immunity before surgical removal. Standard surgery for solid tumors varies widely depending on the cancer type, but it carries risks of functional impairment and postoperative morbidity. Therefore, nonoperative management (NOM) has emerged as a clinically meaningful strategy to preserve organ function and improve patients’ quality of life. Methods: D-CURE is a multicenter phase II trial evaluating whether dostarlimab, an anti–PD-1 IgG4 humanized monoclonal antibody, can safely achieve clinical complete response (cCR) and enable NOM with organ preservation in patients with dMMR/MSI-H resectable solid tumors (excluding colorectal cancer). Patients will receive 9 cycles of dostarlimab (500 mg/body every 3 weeks). Observation with NOM will be offered to patients who achieve cCR or near-cCR. Patients undergoing NOM will be followed for up to 2 years from the date of enrollment. The primary endpoint is the 12-month cCR rate after dostarlimab. Key eligibility criteria are as follows: untreated malignancy (excluding colorectal cancer); dMMR/MSI-H confirmed in tissue or blood; age ≥18 years; ECOG PS 0–1; and clinical stage eligible for surgical resection, definitive radiotherapy, or definitive chemoradiotherapy according to the TNM 8th Edition. The target sample size of 80 was determined based on 90% power, a one-sided alpha of 5%, a threshold 12-month cCR rate of 38%, and an expected 12-month cCR rate of 56%. We also integrate personalized precise molecular residual disease (MRD) monitoring incorporating up to 1,000 tumor-specific alterations identified through whole-genome sequencing of tumor tissue, with serial ctDNA-based MRD assessment and parallel enrollment in the MONSTAR-SCREEN-3 study (UMIN000053975). Through this linkage, patients will also have access to the multi-omics platform, enabling spatial transcriptomics, bulk WES/WTS, plasma proteomics, and microbiome analyses to elucidate tumor-immune dynamics and comprehensively characterize treatment response and resistance. Enrollment of the D-CURE trial started in September 2025 and is ongoing at 12 facilities in Japan. Clinical trial information: jRCT2031250364.