Neoadjuvant Chemoradiotherapy Followed by Chemotherapy With or Without Tislelizumab for Resectable Ultra-low Rectal Cancer: The RELIEVE-02 Study

A Multicenter, Randomized Controlled Clinical Study of Concurrent Chemoradiotherapy Followed by Chemotherapy With or Without Tislelizumab for Resectable Ultra-low Rectal Cancer: The RELIEVE-02 Study

This open-label, multicenter, randomized controlled trial involved 154 patients with pathologically confirmed, previously untreated, resectable MSI-L or MSS/pMMR ultra-low rectal adenocarcinoma. Patients were randomly assigned (1:1) to two groups to receive concurrent chemoradiotherapy followed by 4-6 cycles of chemotherapy ± tislelizumab. After treatment, patients who achieved complete clinical response (cCR), including those who reached pCR after local excision, or near cCR with pCR after local excision, were recommended to continue with 4-2 cycles of chemotherapy ± tislelizumab, followed by a watch-and-wait approach. Patients evaluated as incomplete responders were recommended for total mesorectal excision (TME) surgery. The primary endpoint is the anus preservation rate, while secondary endpoints include CR rate, 1-year/2-year/3-year organ preservation rates, 1-year/2-year/3-year EFS rates, and 1-year/2-year/3-year OS rates, etc.

Inclusion Criteria:

1. Able to provide written informed consent, understand, and comply with the requirements and evaluation schedule.
2. Age ≥18 and ≤75 years old.
3. Histologically confirmed rectal adenocarcinoma.
4. Immunohistochemistry confirmed pMMR (positive for MLH1, MSH2, MSH6, and PMS2), or PCR/NGS confirmed MSI-L or MSS.
5. Tumor distal margin confirmed to be ≤ 3 cm from the anal verge by colonoscopy, digital rectal examination, or MRI.
6. Clinical stage cT1-3N1M0 or cT3N0M0 (the 8th UICC/AJCC; T and N evaluated by MRI).
7. Resectable primary tumor assessed by the Investigator.
8. No prior anti-tumor treatment for rectal cancer.
9. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 1.
10. Adequate organ function.
11. Female subjects with the ability to become pregnant must have a serum pregnancy test with a negative result within 72 hours before the first dose and be willing to use highly effective contraceptive methods during the trial and for 120 days after the last dose. Male subjects whose partners are women of childbearing potential should be surgically sterilized or agree to use a highly effective method of contraception during the trial and for 120 days after the last dose.

Exclusion Criteria:

1. Histologically confirmed poorly differentiated/undifferentiated adenocarcinoma, mucinous adenocarcinoma, or signet ring cell carcinoma.
2. Previously received treatment for rectal cancer or have evidence of distant metastasis.
3. Presence of the following high-risk factors assessed by MRI: MRF+, EMVI+, cN2, positive lateral lymph nodes, T3d.
4. Presence of or at high risk for obstruction, perforation, or bleeding.
5. Unsuitability for long-course radiotherapy.
6. Inability to tolerate surgery.
7. ≥ 2 colorectal cancer lesions at the same time.
8. Contraindications for MRI examination.
9. Other malignant tumors in the past or currently present.
10. Active autoimmune disease requiring systemic therapy within the past 2 years.
11. HIV infection.
12. Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers (HBV DNA > 500 IU/mL) or active HCV carriers with detectable HCV RNA.
13. Hypersensitivity to any ingredient of tislelizumab, capecitabine, and oxaliplatin, or to any component of their containers.
14. Other conditions judged by the researcher as not meeting the enrollment requirements.