Low-Dose Radiotherapy to Sensitize Pucotenlimab Plus CAPEOX for pMMR Locally Advanced Rectal Cancer

Colorectal Cancer (CRC)

Colorectal cancer, Neoadjuvant therapy, Low-dose radiotherapy, Immunotherapy, Pucotenlimab, CAPEOX, Total neoadjuvant therapy, Organ preservation, Complete Response Rate, Disease-free survival, Overall survival

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. Tumor response will be assessed after two cycles using endoscopy and pelvic magnetic resonance imaging (MRI). Participants with non-progressive disease, defined as partial response (PR) or stable disease (SD), will receive no further low-dose radiotherapy and will continue pucotenlimab plus CAPEOX for cycles 3 and 4. Participants with local progressive disease, defined as enlargement of the rectal tumor, will receive salvage chemoradiotherapy according to the center's standard operating procedures. Participants who develop distant metastases will receive further treatment determined by a multidisciplinary team (MDT). After four cycles, participants who achieve a clinical complete response (cCR) may enter a watch-and-wait strategy. Participants without cCR and without progressive disease will undergo radical surgery according to total mesorectal excision (TME) principles. Participants with progressive disease will receive individualized treatment determined by the MDT.

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. An early response assessment will be performed after two cycles of neoadjuvant treatment using endoscopy and pelvic MRI. Participants with PR or SD will discontinue any further low-dose radiotherapy and will complete the remaining two cycles of pucotenlimab plus CAPEOX. Participants with local progressive disease, defined as enlargement of the rectal lesion, will receive salvage chemoradiotherapy, with the treatment regimen and implementation procedures following the center's standardized SOP. Participants with distant metastases will undergo MDT review to determine subsequent treatment based on disease status, treatment response, and tolerability. A further response assessment will be performed after four cycles. Participants achieving cCR may enter watch-and-wait surveillance. Participants who do not achieve cCR and have no progressive disease will undergo standard TME surgery. Participants with progressive disease will undergo MDT review for individualized management. 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.

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