Overview
This is a prospective, open-label, randomized, parallel-group phase II trial evaluating the efficacy and safety of a low-dose radiotherapy sensitization strategy combined with a PD-1 antibody (pucotenlimab) and CAPEOX as neoadjuvant therapy in patients with pMMR/MSS locally advanced rectal adenocarcinoma. Participants will be randomized 1:1 to receive either 2 Gy or 5 Gy low-dose radiotherapy. Low-dose radiotherapy is delivered as a single fraction of 2 Gy (Arm A) or 5 Gy (Arm B). On the day after radiotherapy, participants will start pucotenlimab 200 mg IV Q3W (administered on Day 2 of each 21-day cycle) plus CAPEOX chemotherapy. Early response will be assessed after 2 cycles using endoscopy and pelvic MRI to guide subsequent treatment: participants with partial response may discontinue radiotherapy and continue neoadjuvant systemic therapy; participants with stable disease may switch to standard chemoradiotherapy; participants with progressive disease will receive multidisciplinary-team-guided salvage therapy. After 4 cycles, participants with clinical complete response may adopt a watch-and-wait strategy; otherwise, they will undergo radical surgery 2-4 weeks after completion of neoadjuvant therapy. Long-term follow-up will include recurrence and survival outcomes and quality of life.
Description
Rectal cancer remains a major global health burden, with a higher risk of local recurrence and worse prognosis compared with colon cancer. The introduction of total mesorectal excision (TME) has substantially reduced local recurrence rates, and the incorporation of peri-operative radiotherapy and chemotherapy has further improved oncologic outcomes. Current National Comprehensive Cancer Network (NCCN) guidelines recommend pre-operative chemoradiotherapy followed by radical surgery for patients with stage II-III locally advanced rectal cancer.In recent years, total neoadjuvant therapy (TNT) has emerged as an optimized treatment paradigm, increasing pathologic complete response (pCR) rates to approximately 20-40%, and even higher when combined with immunotherapy. For patients achieving a clinical complete response (cCR) after neoadjuvant therapy, a non-operative "watch-and-wait" strategy has been shown to be safe and effective, allowing organ preservation without compromising long-term oncologic outcomes.However, most patients with proficient mismatch repair (pMMR) or microsatellite-stable (MSS) rectal cancer derive limited benefit from immune checkpoint blockade alone. Preclinical and clinical evidence suggests that radiotherapy, particularly low-dose radiotherapy (LDRT), may enhance antitumor immune responses by modulating the tumor microenvironment and promoting immune sensitization. Whether different low-dose radiotherapy regimens can differentially enhance the efficacy of immunotherapy combined with chemotherapy in pMMR/MSS locally advanced rectal cancer remains unknown.To address this question, the present study is designed as a prospective, open-label, randomized, parallel-group phase II clinical trial evaluating a low-dose radiotherapy sensitization strategy combined with a PD-1 antibody (pucotenlimab) and CAPEOX chemotherapy as neoadjuvant treatment.Eligible participants with pMMR/MSS locally advanced rectal adenocarcinoma will be randomized in a 1:1 ratio to receive either 2 Gy or 5 Gy low-dose radiotherapy. On the day following radiotherapy, all participants will initiate systemic treatment with pucotenlimab 200 mg administered intravenously every 3 weeks (Q3W) on Day 2, in combination with CAPEOX chemotherapy in 21-day cycles.Treatment response will be assessed early after 2 cycles of neoadjuvant therapy using endoscopy and pelvic magnetic resonance imaging (MRI). Based on response evaluation, subsequent treatment will be adapted: participants demonstrating partial response may discontinue radiotherapy and continue systemic neoadjuvant therapy; those with stable disease may transition to standard chemoradiotherapy; and those with progressive disease will receive multidisciplinary team-guided salvage treatment.After completion of 4 cycles of neoadjuvant therapy, response will be reassessed. Participants achieving a clinical complete response may adopt a watch-and-wait strategy with close surveillance, whereas those without cCR will proceed to radical surgery, typically performed 2-4 weeks after completion of neoadjuvant treatment.The primary objective of this study is to compare the complete response rate, defined as the sum of clinical complete response and pathological complete response, between the two low-dose radiotherapy regimens. Secondary objectives include long-term disease control, survival outcomes, surgical quality metrics, postoperative morbidity, stoma rates, and patient-reported quality of life. This study aims to determine whether optimization of low-dose radiotherapy can enhance immune-chemotherapy efficacy and increase organ preservation opportunities in patients with pMMR/MSS locally advanced rectal cancer.
Eligibility
Inclusion Criteria
- Written informed consent provided prior to any study-specific procedures.
- Age 18 to 75 years at the time of enrollment.
- Histologically confirmed rectal adenocarcinoma.
- Tumor located within 10 cm from the anal verge, as assessed by endoscopy or imaging.
- Locally advanced disease, defined as clinical stage T2N+ or T3-T4a (any N) based on pelvic magnetic resonance imaging (MRI).
- Proficient mismatch repair (pMMR) or microsatellite-stable (MSS) tumor status confirmed by immunohistochemistry or molecular testing.
- No evidence of distant metastasis on preoperative imaging, including chest, abdominal, and pelvic computed tomography (CT).
- Circumferential resection margin (CRM) ≥2 mm and no involvement of the mesorectal fascia on baseline MRI.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Adequate organ function as defined by:
- Absolute neutrophil count ≥1.5 × 10⁹/L
- Platelet count ≥100 × 10⁹/L
- Hemoglobin ≥90 g/L
- Total bilirubin ≤1.5 × upper limit of normal (ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN
- Creatinine clearance ≥50 mL/min
- Thyroid-stimulating hormone (TSH) within normal limits
- Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for a protocol-defined period after the last dose.
- Men with partners of childbearing potential must agree to use effective contraception during the study and for a protocol-defined period after the last dose.
Exclusion Criteria
- Clinical T4b disease, defined as tumor invasion into adjacent organs or structures on baseline imaging.
- Circumferential resection margin (CRM) \<2 mm or definite involvement of the mesorectal fascia on baseline MRI.
- Evidence of distant metastasis outside the pelvis.
- Prior pelvic or abdominal radiotherapy.
- Prior treatment with immune checkpoint inhibitors or other systemic anticancer therapy for rectal cancer.
- Active or history of autoimmune disease requiring systemic treatment, except for conditions considered low risk for recurrence (e.g., vitiligo, resolved childhood asthma).
- Ongoing use of systemic immunosuppressive therapy, including corticosteroids equivalent to \>10 mg/day of prednisone, within 2 weeks prior to enrollment.
- Known human immunodeficiency virus (HIV) infection.
- Active hepatitis B virus infection with positive hepatitis B surface antigen and high viral load, or hepatitis C virus infection requiring treatment.
- Uncontrolled active infection or other serious medical condition that, in the investigator's judgment, would compromise patient safety or study compliance.
- History of another malignancy within 5 years, except for adequately treated basal cell carcinoma of the skin, cervical carcinoma in situ, or other malignancies with negligible risk of recurrence.
- Known hypersensitivity or allergy to pucotenlimab, oxaliplatin, capecitabine, or any of their excipients.
- Pregnant or breastfeeding women.
- Any condition that, in the investigator's opinion, makes the participant unsuitable for study participation.
