adjuvant pd-1 blockade for high-risk stage-ii dmmr/msi-h colorectal cancer

Conditions: Colorectal Cancer; Microsatellite Instability High

Summary: this open-label phase iii trial investigates the efficacy of two cycles of pd-1 blockade (tislelizumab) as adjuvant therapy to see how it works compared with standard of care (soc) in treating patients with stage ii dmmr/msi-h colorectal cancer. the rational of giving pd-1 blockade as adjuvant therapy is based on the fact that tumor recurrence is extremely low among patients receiving neoadjuvant immunotherapy, which suggests that pd-1 blockade may likely improve patients' long-term survival. as for the short course (two cycles), we have the following considerations: firstly, the niche-2 trial, which adopted a two-cycle regimen, reported no recurrences during follow-up, suggesting that short-course anti-pd-1 therapy may be sufficient to improve the survival of patients with localized dmmr/msi-h colorectal cancer. secondly, the potential benefits of pd-1 blockade should be balanced against its toxicities, because patients with stage-ii dmmr colorectal cancer generally have a good prognosis. two cycles of pd-1 blockade have been shown to have a good safety profile, with low incidence of grade 3-4 and immune-related adverse events.

this is an open-label, multi-centre, randomised, phase iii trial comparing the combination of pd-1 blockade + soc versus soc alone as adjuvant therapy for patients with high-risk stage-ii dmmr/msi-h colorectal cancer. primary objective: to determine whether the addition of tislelizumab can significantly improve disease-free survival (dfs) compared to standard of care in patients with high-risk stage-ii colorectal cancer. secondary objectives: * to determine whether the addition of tislelizumab can significantly improve overall survival (os) compared to standard of care * to assess the adverse events (ae) profile (including immune-related adverse events, ir-aes). outline: patients are randomized to 1 of 2 arms, stratified by ct4 status. arm 1 (experimental group): patients receive tislelizumab 200mg intravenously on day 1, with or without adjuvant chemotherapy, and repeat the treatment on day 22. patients undergo routine follow-up every 3 months for the first 3 years, and then every 6 months for the year 4-5. arm 2 (control group): patients receive standard of care (soc), whether with surveillance alone, single-agent capecitabine, or capeox/folfox, at the discretion of the doctor in charge. patients undergo routine follow-up every 3 months for the first 3 years, and then every 6 months for the year 4-5. statistics according to the statistical design, 180 patients (90 per arm) are to be randomized. the study is expected to take up to 36 months to complete accrual.

Eligibility criteria:
inclusion criteria: * dmmr and/or msi-h colorectal carcinoma that undergo surgical resection * pathologically confirmed as stage ii (t3-4,n0), with at least one of the following risk factors: 1) t4 (including t4a and t4b); 2) vascular invasion; 3) perineural invasion; 4) poor differentiation (including mucinous and signet-ring carcinoma); 5) obstruction and/or perforation before surgery. * perioperative ct/mr/pet-ct find no signs of metastases * eastern cooperative oncology group (ecog) performance status of 0 or 1 within 10 days prior to study start * aged 18-80 * no prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current cancer * adequate organ function exclusion criteria: * active autoimmune disease that has required systemic treatment in past 2 years * positive surgical margin (r1/r2 resection) * presence of post-operative complications that may preclude treatment * active infection requiring systemic therapy * any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with a recurrence risk \<5%.

Keywords: adjuvant therapy stage ii crc dmmr/msi-h pd-1 blockade