Long-course versus short-course radiotherapy before immunotherapy and total neoadjuvant therapy for locally advanced rectal cancer

A National Multicenter, Randomized, Placebo-Controlled Phase III Clinical Trial Comparing Long-Course Versus Short-Course Radiotherapy Followed by Immunotherapy Combined With Total Neoadjuvant Therapy (TNT) to Long-Course Radiotherapy Followed by TNT in Locally Advanced Rectal Cancer

This trial tests whether adding immunotherapy to total neoadjuvant therapy and using short-course versus long-course radiotherapy improves outcomes for adults with locally advanced rectal cancer.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 444 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 1 site (Wuhan, Hubei)
• Trial ID: NCT07113275 on ClinicalTrials.gov

What this trial studies

This is a national, multicenter, randomized, placebo-controlled Phase III trial comparing TNT combined with immunotherapy to a conventional long-course radiotherapy followed by TNT approach, and also comparing short-course versus long-course radiotherapy within the TNT-plus-immunotherapy strategy. Eligible patients with pMMR/MSS locally advanced rectal adenocarcinoma are randomized to receive radiotherapy (short- or long-course) plus standard chemotherapy (capecitabine and oxaliplatin) with or without the investigational immunotherapy agent HLX10. The trial incorporates dynamic minimal residual disease (MRD) monitoring for precision management of patients with clinical complete response, including baseline and follow-up testing for tumors ≤5 cm from the anal verge. Primary comparisons focus on efficacy and toxicity between the radiotherapy schedules and on whether adding immunotherapy to TNT improves outcomes compared with historical long-course RT followed by TNT.

Who should consider this trial

Good fit: Adults 18–75 with histologically confirmed locally advanced rectal adenocarcinoma, pMMR/MSS status, ECOG 0–1, tumor margin ≤10 cm from the anal verge, no prior anti-tumor therapy, and adequate organ function are ideal candidates.

Not a fit: Patients with dMMR/MSI-H tumors, prior rectal cancer treatment, poor performance status, significant organ dysfunction, or other operative contraindications are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could increase tumor response rates and organ-preservation opportunities while reducing recurrence for some patients with locally advanced rectal cancer.

How similar studies have performed: Previous trials have shown clear immunotherapy benefit in MSI-H rectal cancer and have examined TNT and different radiotherapy schedules, but combining immunotherapy with TNT in pMMR/MSS rectal cancer and directly comparing short- versus long-course RT in this context remains largely unproven.

Eligibility criteria

Inclusion Criteria:

1. Patients or their family members agree to participate in the study and sign the informed consent form;
2. Age 18-75 years, male or female;
3. Histologically confirmed Locally Advanced rectal adenocarcinoma;
4. Immunohistochemistry and/or genetic testing confirmed pMMR/MSS;
5. inferior margin ≤ 10 cm from the anal verge;
6. ECOG performance status score is 0-1;
7. Untreated with anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, surgery, etc;
8. There was no operative contraindication;
9. Laboratory tests were required to meet the following requirements: white blood cell (WBC) ≥ 4×109/L; Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet count ≥ 100×109/L; Hemoglobin ≥90 g/L; Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN); Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; Serum creatinine ≤1.5 times the upper limit of normal value or creatinine clearance rate ≥50 mL/min; International normalized ratio (INR) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
10. Urinary protein \< 2+ or 24-hour urinary protein excretion \< 1 g at baseline.

Exclusion Criteria:

1. Patients with MSI-H/dMMR LARC；
2. Subjects who have previously received any form of immunotherapy, including but not limited to immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy, or any other treatment targeting tumor immunomodulatory mechanisms;
3. Presence of any concurrent disease, condition (including laboratory abnormality), history of substance abuse, or current evidence thereof, which, in the judgment of the Investigator, may compromise subject safety, interfere with the process of obtaining informed consent, affect subject compliance, or confound the safety assessment of the investigational product(s).

Where this trial is running

Wuhan, Hubei

• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan, Hubei, China (Recruiting)

Study contacts

• Principal investigator: Zhenyu Lin, MD — Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
• Study coordinator: Zhenyu Lin, MD

Conditions Rectal Cancer; Total Neoadjuvant Therapy; Radiotherapy; Immunotherapy