Phase II trial of adjuvant toripalimab in stage IIb, IIc, or III colon cancer with mismatch repair deficiency.

TPS269 Background: Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer-related mortality in the USA with approximately 15% of CRCs characterized by DNA mismatch repair deficiency (dMMR). Mismatch repair deficiency is a predictive biomarker for response to immune checkpoint inhibitors (ICI) in metastatic CRC and is superior to chemotherapy. Prospective phase II clinical trials have evaluated the efficacy of neoadjuvant ICIs in localized dMMR CRC and have shown high rates of complete response with an ongoing study in dMMR colon cancer (AZUR-2 trial, NCT05855200 - perioperative dostarlimab vs adjuvant chemotherapy in stage II and III dMMR colon cancer). Significant limitations of the neoadjuvant approach in colon cancer however exist, including the challenges of radiologic staging of dMMR colon cancer, and the risk of progression in non-responders when upfront surgery is deferred. For patients who undergo upfront surgical resection, cytotoxic chemotherapy remains a standard adjuvant therapy whereby adjuvant chemotherapy + ICI demonstrated superior disease-free survival (DFS) vs adjuvant chemotherapy alone in stage III dMMR colon cancer in the ATOMIC trial. Evidence shows that dMMR CRC demonstrates resistance to cytotoxic chemotherapy, indicating an unmet need for a chemotherapy -free adjuvant therapy with ICI only in dMMR colon cancer. Methods: This single arm phase 2 study evaluates the efficacy of adjuvant toripalimab monotherapy in patients with resected stage IIB, IIC, and III dMMR colon cancer. Toripalimab is an anti-PD-1 antibody that is FDA -approved for advanced nasopharyngeal carcinoma either as monotherapy or in combination with chemotherapy. It has previously demonstrated efficacy in dMMR CRC. Key inclusion criteria will include completely resected stage IIB, IIC, III dMMR colon cancer with ECOG performance status of 0, 1, or 2 and adequate organ function, while key exclusion criteria include receipt of neoadjuvant therapy and active autoimmune disease. Participants will be enrolled at Emory Winship Cancer Institute sites and will receive 8 cycles of adjuvant toripalimab every 3 weeks. The primary endpoint is 3-year DFS. With a sample size of 35 patients, we have 80% power to detect a 3-year DFS of 80% vs. a null value of 65% assuming a one-sided type I error of 0.05, 24 months of accrual, and 60 months of follow-up time: 40 patients will be enrolled. Secondary endpoints will include 5-year DFS, 3-year recurrence free survival (RFS), 5-year OS, colon cancer specific survival, and safety. After completion of study treatment, colon cancer surveillance with history and physical examination, CEA, ctDNA, CT scans, and colonoscopy will be performed until 5 years from registration. Correlative studies will include immune, genomic and transcriptomic markers; patient reported outcomes and quality of life. Clinical trial information NCT07140679. Clinical trial information: NCT07140679 .