Neoadjuvant CAPOX With or Without Pucotenlimab Plus Selective Radiotherapy for Locally Advanced Rectal Cancer

Neoadjuvant CAPOX Plus Pucotenlimab Combined With Selective Radiotherapy Versus CAPOX Combined With Selective Radiotherapy in Patients With Locally Advanced Rectal Cancer：A Multicenter, Phase III, Randomized Clinical Trial

This is a multicenter, phase III, randomized controlled trial. Eligible patients with pMMR/MSS locally advanced rectal cancer will be randomized in a 1:1 ratio to either the experimental group or the control group using stratified randomization, with mesorectal fascia (MRF) status as the stratification factor.

Patients in the experimental group will receive four cycles of CAPOX plus pucotenlimab. Patients in the control group will receive four cycles of CAPOX alone.

Tumor response will then be assessed. Patients with tumor shrinkage ≥20% and no persistent tumor involvement of the mesorectal fascia will proceed directly to surgery. Patients with tumor shrinkage <20% or persistent MRF-positive disease will receive short-course radiotherapy, followed by two additional cycles of CAPOX plus pucotenlimab in the experimental group or CAPOX alone in the control group. After completion of neoadjuvant treatment, efficacy will be reassessed, and the timing of surgery will be determined according to treatment response. Postoperative adjuvant therapy will be decided by the investigator.

Colorectal cancer (CRC) is the third most common malignancy worldwide. Rectal cancer accounts for more than half of CRC cases in many regions, making it a major clinical challenge. The standard treatment for locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy, total mesorectal excision (TME), and postoperative adjuvant chemotherapy. However, distant metastasis and postoperative complications remain major challenges. Total neoadjuvant therapy (TNT), by advancing adjuvant chemotherapy to the neoadjuvant phase, has significantly improved patient compliance and tumor response rates. The MSKCC study demonstrated a tumor response rate of up to 90% under the TNT regimen, with 30% of patients achieving pathological or clinical complete response (pCR or cCR). The TIMING trial further confirmed that TNT significantly increased the pCR rate without increasing side effects or surgical complications.

Immunotherapy has shown significant efficacy in dMMR/MSI-H CRC. The NICHE study demonstrated that dual immunotherapy achieved 100% pathological response in dMMR colorectal cancer patients. However, pMMR/MSS CRC is not sensitive to immunotherapy, but some patients may still benefit from combined anti-angiogenesis agents (such as regorafenib) or CTLA-4 antibodies. The REGONIVO study showed an objective response rate (ORR) of 36.0% in pMMR/MSS CRC patients, while the RIN study further increased the ORR to 27.6%. Radiotherapy combined with immunotherapy has emerged as a new treatment modality for LARC. The UNION study found that short-term radiotherapy followed by sequential PD-1 antibody and CAPOX chemotherapy increased the pCR rate to 39.8%. The TORCH study explored the effectiveness of short-term radiotherapy combined with PD-1 antibody and CAPOX chemotherapy, achieving a CR rate of over 50%. The REGINA study went further, using short-term radiotherapy combined with regorafenib and nivolumab, achieving a CR rate of 44.4%.

Although radiotherapy improves local control, it may cause significant short- and long-term toxicities, such as radiation enteritis, cystitis, and impaired anorectal, urinary, and sexual function. It may also increase surgical complexity and reduce postoperative quality of life. These concerns have driven growing interest in radiotherapy decline or even omission in selected patients. Neoadjuvant chemotherapy alone has therefore been investigated as an alternative approach. Studies such as PROSPECT, FOWARC, and the CONVERT study from our center suggest that neoadjuvant chemotherapy alone does not increase local recurrence or distant metastasis in selected patients, while substantially reducing radiation-related toxicity. In particular, the CONVERT study demonstrated that among patients with high-resolution MRI-defined negative circumferential resection margin risk, neoadjuvant chemotherapy was not inferior to conventional chemoradiotherapy. These findings provide proof of concept for a selective radiotherapy strategy.

Based on this background, we propose the CONVERT-2 study, a multicenter phase III trial designed to evaluate neoadjuvant CAPOX plus pucotenlimab with selective radiotherapy versus CAPOX with selective radiotherapy in patients with pMMR/MSS locally advanced rectal cancer. We hypothesize that the addition of pucotenlimab will further increase tumor response, reduce the proportion of patients requiring radiotherapy, and maintain favorable safety and oncologic outcomes. If successful, this study may establish a more individualized neoadjuvant strategy for pMMR/MSS LARC, balancing treatment efficacy, toxicity reduction, and organ preservation.

Inclusion Criteria:

1. Age 18 to 75 years.

2. Histologically confirmed rectal adenocarcinoma.

3. The lower edge of the tumor is ≤12 cm from the anal verge.

4. Clinical stage of cT3-4aN0M0 or cT1-4aN+M0 at initial diagnosis.

   Pre-treatment staging methods:

   Required: chest and abdominal CT and pelvic MRI. Optional: endorectal ultrasound or transrectal ultrasonography. For patients with contraindications to MRI, staging may be performed using CT combined with endorectal ultrasound or transrectal ultrasonography.

5. pMMR status confirmed by immunohistochemistry on colonoscopic biopsy specimens at the pathology department of the study center, or MSS/MSI-L status confirmed by genetic testing (PCR-based or NGS-based methods).

6. ECOG performance status 0-1.

7. Voluntary participation in the study with written informed consent provided.

8. No prior antitumor treatment for rectal adenocarcinoma, including but not limited to radiotherapy, chemotherapy, or surgery.

9. Expected survival of at least 6 months.

10. Adequate organ and bone marrow function, as defined below:

    1. Hematologic function No blood transfusion, hematopoietic growth factors, leukocyte-elevating agents, platelet-elevating agents, or anti-anemia therapy are allowed within 14 days before the first dose of study treatment.

       Absolute neutrophil count ≥1.5 × 10^9/L Platelet count ≥100 × 10^9/L Hemoglobin ≥60 g/L

    2. Biochemical function Serum albumin ≥30 g/L Total bilirubin ≤1.5 × upper limit of normal (ULN) ALT ≤2.5 × ULN AST ≤2.5 × ULN Alkaline phosphatase (ALP) ≤2.5 × ULN Serum creatinine ≤1.5 × ULN, or creatinine clearance (CrCl) ≥50 mL/min

CrCl may be calculated using the Cockcroft-Gault formula:

Male: CrCl = ((140-age)×weight)((140 - age) × weight)((140-age)×weight) / (72×serumcreatinine)(72 × serum creatinine)(72×serumcreatinine) Female: CrCl = ((140-age)×weight)((140 - age) × weight)((140-age)×weight) / (72×serumcreatinine)(72 × serum creatinine)(72×serumcreatinine) × 0.85 Weight in kg; serum creatinine in mg/mL. c. Coagulation function International normalized ratio (INR) ≤1.5 d. Urinary protein Urine protein ≤1+ by dipstick If urine protein is ≥2+, a 24-hour urine protein test is required, and patients may be enrolled only if the result is <1 g/24 h

1. For women of childbearing potential, a serum or urine pregnancy test must be performed within 72 hours before the start of study treatment, with a negative result. Such patients must agree to use effective contraception during the study and for at least 120 days after the last dose of study treatment.
2. Good compliance and willingness to cooperate with study follow-up.
3. Agreement to provide blood, urine, stool, and tumor tissue samples.

Exclusion Criteria:

Patients meeting any of the following criteria will be excluded:

1. Clinical stage T4b disease.
2. Positive lateral pelvic lymph nodes.

Positive lateral pelvic lymph nodes are defined as either:

1. a short-axis diameter ≥7 mm, or

2. a short-axis diameter <7 mm with at least two malignant imaging features, such as heterogeneous signal intensity, irregular shape, or spiculated margins.

3. Predicted inability to preserve the anus. This is defined as tumor involvement of the dentate line and assessment by two senior colorectal surgeons that sphincter preservation is not feasible.

4. Active autoimmune disease requiring systemic treatment within 2 years before enrollment, including but not limited to myasthenia gravis, systemic lupus erythematosus, interstitial pneumonitis, uveitis, ulcerative colitis, autoimmune hepatitis, hypophysitis, systemic vasculitis, nephritis, hyperthyroidism, hypothyroidism, or mixed connective tissue disease.

   Patients with vitiligo or childhood asthma that has completely resolved and requires no intervention in adulthood may be eligible.

   Asthma requiring bronchodilator therapy is not allowed. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency, is not considered systemic treatment.

5. Use of systemic corticosteroids within 14 days before the first dose of study treatment at a dose ≥10 mg/day prednisone equivalent, or use of other immunosuppressive agents, including but not limited to cyclosporine, cyclophosphamide, azathioprine, methotrexate, or thalidomide.

   Use of immunostimulatory agents such as interferon or interleukin-2 within 4 weeks before the first dose is also excluded.

6. Receipt of a live vaccine or attenuated live vaccine within 30 days before the first dose, or planned vaccination with such vaccines during the study period.

7. Broad-spectrum antibiotic therapy by any route within 30 days before the first dose.

8. Prior antitumor therapy for rectal cancer, including radiotherapy, chemotherapy, surgery (except biopsy), PD-1/CTLA-4 dual immunotherapy, regorafenib, or any other tyrosine kinase inhibitor.

9. Presence of unresectable disease, including tumor-related unresectability, unresectability due to surgical contraindications, or refusal to undergo surgery.

10. HIV infection, other acquired or congenital immunodeficiency disorders, or a history of organ transplantation or allogeneic bone marrow transplantation (except corneal transplantation).

11. Active viral hepatitis meeting any of the following criteria:

    hepatitis B surface antigen (HBsAg) positive and/or hepatitis B core antibody (HBcAb) positive with HBV DNA >10^4 copies/mL (approximately 2000 IU/mL) anti-HCV antibody positive with HCV RNA >10^3 copies/mL concurrent HBV and HCV infection, defined as HBsAg positive and HCV RNA positive

12. History of other malignancies within the past 5 years or concurrent malignancy, except for cured basal cell carcinoma of the skin or carcinoma in situ of the cervix.

13. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage.

14. Known active tuberculosis, radiation pneumonitis, drug-induced pneumonitis, or other diseases, symptoms, or signs indicating severely impaired pulmonary function.

15. Renal failure requiring hemodialysis or peritoneal dialysis.

16. Active infection, unexplained fever ≥38.5°C within 7 days before treatment, or baseline white blood cell count >15 × 10^9/L.

17. Uncontrolled clinically significant cardiac disease, including but not limited to:

    New York Heart Association (NYHA) class II or above heart failure left ventricular ejection fraction (LVEF) <50% unstable angina myocardial infarction within 1 year before randomization clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention corrected QT interval (QTc) >450 ms in males or >470 ms in females

18. Hypertension not adequately controlled with antihypertensive treatment, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg.

    Patients whose blood pressure can be controlled to below these thresholds with treatment are eligible.

    A history of hypertensive crisis or hypertensive encephalopathy is excluded.

19. Arterial or venous thrombotic events within 6 months before enrollment, including cerebrovascular accident, transient ischemic attack, cerebral hemorrhage, cerebral infarction, deep venous thrombosis, or pulmonary embolism.

20. Known hereditary or acquired bleeding or thrombotic disorders, such as hemophilia or coagulation dysfunction.

21. Tumor invasion of major blood vessels, or imaging findings suggesting a high likelihood of major vascular invasion during the study period that may result in fatal hemorrhage, as judged by the investigator.

22. Major surgery (excluding diagnostic procedures) within 4 weeks before the start of study treatment, or an anticipated need for major surgery during the study period other than protocol-specified surgery.

23. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months before the start of study treatment.

24. Need for long-term or high-dose nonsteroidal anti-inflammatory drugs (for example, aspirin ≥325 mg/day) or anticoagulant therapy.

25. Known or suspected allergy to the study drugs or to any medications administered in relation to this trial.

26. History of severe hypersensitivity reactions to other monoclonal antibodies, or known allergy or hypersensitivity to PD-1 antibodies, oxaliplatin, capecitabine, or any of their components.

27. Difficulty swallowing or inability to take oral study medication.

28. Pregnant or breastfeeding women.

29. Any other condition that, in the investigator's judgment, may interfere with study participation, affect study results, increase patient risk, or lead to premature termination of the study, including but not limited to alcohol abuse, drug abuse, severe comorbidities (including psychiatric disorders), significant laboratory abnormalities, or family/social factors affecting patient safety or compliance.