SCRT+mFOLFOX6+PD-1 Antibody and Targeted Therapy for High-Risk pMMR/MSS Rectal Cancer

Patients with locally advanced rectal cancer (LARC) who have high-risk factors, such as low rectal cancer, clinical stage T4b, positive mesorectal fascia (MRF), and positive extramural vascular invasion (EMVI), are at extremely high risk of distant metastasis. For these LARC patients with high-risk factors, the pathological complete response (PCR) rate with neoadjuvant chemotherapy alone is relatively low, ranging from 4.3% to 13.3%. Therefore, the use of a more potent comprehensive neoadjuvant treatment regimen, including concurrent chemoradiotherapy combined with targeted therapy and immunotherapy, may offer greater benefits to these patients. For patients with high-risk LARC, this study aims to explore whether the combination of short-course radiotherapy, mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) can improve the pathological responce rate, and achieve better long-term survival benefits. The study will investigate the efficacy and safety of short-course radiotherapy, mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) for high-risk LARC.

This is a prospective, open-label, multicenter, single-arm, Phase II study. Patients with high-risk LARC will be eligible for enrollment.

Enrolled patients will receive neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT. If pelvic MRI indicates clinical complete response (CCR) and N0, or T1N0M0, local excision (LE) will be performed. Otherwise, total mesorectal excision (TME) will be performed. The decision regarding adjuvant chemotherapy after surgery will be made by the attending physician.

• Short-Course Radiotherapy (Radiation), also known as SCRT: Patients undergo SCRT at a dose of 5Gy × 5 fractions
• PD-1 monoclonal antibody (Drug), also known as PD-1: Patients complete immune therapy with PD-1 monoclonal antibody for 4 cycles.
• mFOLFOX6 regimen (Drug), also known as mFOLFOX6: Patients complete chemotherapy with mFOLFOX6 regimen for 4 cycles.
• Cetuximab (Drug), also known as Cetuximab Antibody: Patients with RAS/BRAF wild-type receive targeting therapy with Cetuximab for 4 cycles.
• Bevacizumab (Drug), also known as Bevacizumab Antibody: Patients with RAS/BRAF mutations receive targeting therapy with Bevacizumab for 3 cycles. (Bevacizumab is not used in the last cycle of the bevacizumab group)
• Surgical resection (Procedure), also known as Surgery: Surgery either local excition or total mesorectal excision is performed 8-10 weeks after the completion of short-course radiotherapy.

Primary outcomes

• Pathological Complete Response [1 year]: Pathological Complete Response

Secondary outcomes

• 3 Year Disease Free Survival [3 years]: 3 Year Disease Free Survival
• 3 Year Overall Survival [3 years]: 3 Year Overall Survival
• 3 Year Local Relapse Free Survival [3 years]: 3 Year Local Relapse Free Survival
• R0 resection rate [1 year]: R0 resection rate
• Objective Response Rate [1 year]: Objective Response Rate
• sever adverse events rate [1 year]: sever adverse events rate

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. Before conducting procedures related to the research protocol but not part of routine care, written informed consent, voluntarily signed and dated by the subject, must be obtained in accordance with regulations and institutional guidelines.
2. Age 18-75 years.
3. Histologically or cytologically confirmed pMMR/MSS rectal adenocarcinoma; all other histological types are excluded.
4. Distance from the lower margin of the rectal tumor to the anal verge ≤10 cm.
5. Clinical staging with high-risk factors, including cT3Nx, EMVI(+), or cT4, ±MRF(+), ±EMVI(+).
6. No evidence of distant metastasis before treatment.
7. No prior anti-cancer treatment (radiotherapy, chemotherapy, targeted therapy, or immunotherapy).
8. ECOG performance status of 0-1.
9. Peripheral blood counts and liver and kidney function within the following allowable ranges (tested within 15 days before the start of treatment):

   1. White blood cells (WBC) ≥3.0×10\^9/L or absolute neutrophil count (ANC) ≥1.5×10\^9/L;
   2. Hemoglobin (HGB) ≥80 g/L;
   3. Platelets (PLT) ≥100×10\^9/L;
   4. Liver transaminases (AST/ALT) <3.0 times the upper limit of the normal range;
   5. Total bilirubin (TBIL) <1.5 times the upper limit of the normal range;
   6. Creatinine (CREAT) <1.5 times the upper limit of the normal range.
10. No history of other malignancies; not pregnant or breastfeeding, and effective contraception must be used during the study period and for 6 months after the last dose.

Exclusion Criteria:

1. Patients with a history of severe drug allergies (including allergies to platinum agents, 5-FU, LV, and 5-HT3 receptor antagonists);
2. Patients who have participated in or are currently participating in other clinical trials within 4 weeks prior to enrollment;
3. A history of having received anti-PD-1, PD-L1, PD-L2, CTLA-4, or any other specific T-cell costimulatory or checkpoint pathway-targeted therapy;
4. Severe electrolyte abnormalities;
5. Presence of gastrointestinal diseases, such as active ulcers in the stomach or duodenum, ulcerative colitis, or tumors with active bleeding that have not been resected; or other conditions that may lead to gastrointestinal bleeding or perforation; or gastrointestinal perforation that has not healed after surgical treatment;
6. History of arterial thrombosis or deep vein thrombosis within 6 months; history of bleeding or evidence of bleeding tendency within 2 months; or patients receiving high-dose anticoagulation therapy;
7. Pregnant or breastfeeding women, or women of childbearing potential with a positive pregnancy test before the first dose; or female participants and their partners who are unwilling to strictly practice contraception during the study period;
8. Presence of other active malignancies (except for malignancies that have been treated with curative intent and have been disease-free for more than 3 years, or in situ cancers that can be cured with adequate treatment);
9. Presence of severe ECG abnormalities or active coronary artery disease, severe/unstable angina, newly diagnosed angina or myocardial infarction within 12 months prior to study entry, or New York Heart Association (NYHA) Class II or higher congestive heart failure;
10. Patients with active infections (infections causing fever above 38°C);
11. Patients with uncontrolled hypercalcemia, hypertension, or diabetes;
12. Patients with severe pulmonary diseases (interstitial pneumonia, pulmonary fibrosis, severe emphysema, etc.);
13. Patients with psychiatric disorders that may affect clinical treatment or a history of central nervous system diseases;
14. Patients with severe complications (bowel obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders, etc.);
15. Presence of any CTCAE Grade 2 or higher toxicity caused by previous treatments that has not resolved (excluding anemia, alopecia, and skin pigmentation);
16. Any unstable medical condition that may affect patient safety and compliance with the study;
17. Patients deemed by the investigator as unsuitable for participation in this clinical trial.

• Juan Huang, PhD., Principal investigator, Sun Yat-sen University