Short-course Radiotherapy Combined With Retlirafusp Alfa and CAPOX Chemotherapy as Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Prospective, Single-arm, Phase II Clinical Study

Short-course Radiotherapy Combined With Retlirafusp Alfa and CAPOX Chemotherapy as Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Prospective, Single-arm, Phase II Clinical Study

This study aims to evaluate the efficacy and safety of neoadjuvant short-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy in the treatment of locally advanced rectal cancer. This is a prospective, single-arm, phase II clinical trial planned to enroll 44 patients with locally advanced rectal cancer. The primary endpoint is the complete response rate, and secondary endpoints include objective response rate, pathological complete response rate, event-free survival, and overall survival, with the goal of providing evidence to optimize clinical treatment decisions.

The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy followed by total mesorectal excision. However, the pathological complete response rate of the traditional regimen is only 10%-15%, and the distant metastasis rate remains high, which falls short of clinical needs. In recent years, immune checkpoint inhibitors have demonstrated significant efficacy in various malignancies. However, microsatellite-stable (MSS) colorectal cancer responds poorly to immunotherapy monotherapy and is therefore considered a "cold tumor." Preclinical and clinical studies suggest that radiotherapy can enhance immune responses by remodeling the tumor microenvironment and promoting tumor antigen release, thereby exerting synergistic antitumor effects when combined with immunotherapy. In addition, the TGF-β signaling pathway plays an important role in immune evasion in colorectal cancer, and bifunctional fusion proteins that simultaneously target PD-L1 and TGF-β are expected to more effectively restore T-cell activity. Based on these findings, this study innovatively combines short-course radiotherapy, Retlirafusp alfa (an anti-PD-L1/TGF-βRII bifunctional fusion protein), and the CAPOX chemotherapy regimen as neoadjuvant therapy for locally advanced rectal cancer.This study plans to enroll 44 patients with previously untreated locally advanced rectal cancer (T3N+M0 or T4NanyM0, AJCC 8th edition). The treatment regimen consists of short-course radiotherapy (25 Gy/5 fractions, D2-D6) combined with Retlirafusp alfa and CAPOX chemotherapy in the first cycle, followed by Retlirafusp alfa plus CAPOX chemotherapy in cycles 2 through 4. Efficacy evaluations will be performed after cycles 2 and 4, respectively. Patients who achieve clinical complete response may opt for a watch-and-wait strategy, while those who do not are recommended to undergo total mesorectal excision. The primary endpoint is the complete response rate (cCR + pCR). Secondary endpoints include objective response rate, pathological complete response rate, major pathological response, tumor regression grade,event-free survival, overall survival, safety, and changes in patient quality of life and anal function. The conduct of this study will provide important evidence on the efficacy and safety of the "short-course radiotherapy + immunotherapy + chemotherapy" neoadjuvant treatment model for locally advanced rectal cancer, with the potential to offer patients greater opportunities for organ preservation and improved long term survival.

Inclusion Criteria:

1. Age 18-70 years, male or female.

2. Histologically or cytologically confirmed rectal adenocarcinoma, stage T3N+M0 or T4NanyM0 (AJCC/UICC TNM 8th edition), with measurable lesion(s) per RECIST 1.1.

3. Tumor lower border 5-10 cm from the anal verge.

4. Expected to achieve R0 resection after neoadjuvant therapy, and planned for surgery thereafter.

5. ECOG PS 0-1.

6. No prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immune checkpoint inhibitors, or surgery.

7. Adequate organ function (without blood product or growth factor support during screening):

   ANC ≥1.5×10⁹/L; platelets ≥100×10⁹/L; hemoglobin ≥8.5 g/dL.

   TSH ≤1×ULN (if abnormal, T3/T4 must be within normal limits for enrollment).

   Bilirubin ≤1.5×ULN; ALT and AST ≤2.5×ULN.

   Serum creatinine ≤1.5×ULN or CrCl ≥50 mL/min (Cockcroft-Gault formula).

   INR ≤1.5×ULN; APTT ≤1.5×ULN.

8. Negative pregnancy test (β-hCG) for women of childbearing potential before treatment initiation.Women of childbearing potential and men (who are sexually active with women of childbearing potential) must agree to use effective contraception continuously during treatment and for 6 months after the last dose.

9. Voluntary participation with written informed consent.

Exclusion Criteria:

1. History of other malignancies within the past 5 years, except adequately treated cervical carcinoma in situ, cutaneous squamous cell carcinoma, or basal cell carcinoma.
2. Major surgery or severe trauma within 4 weeks prior to first study drug administration.
3. Systemic corticosteroids (equivalent to prednisone >10 mg/day) or other immunosuppressive therapy within 2 weeks prior to study drug administration.
4. Active, known, or suspected autoimmune disease. Patients with stable conditions not requiring systemic immunosuppression (e.g., type 1 diabetes, hypothyroidism on hormone replacement, or skin disorders without systemic treatment) are eligible.
5. Immunodeficiency, including HIV positivity, other acquired/congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation.
6. Congestive heart failure, uncontrolled arrhythmia, myocardial infarction within 6 months, unstable angina, stroke, or other conditions precluding surgery.
7. Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired pulmonary function.
8. Uncontrolled symptomatic brain metastases, poorly controlled psychiatric disorders, or severe intellectual/cognitive impairment.
9. Known substance abuse or drug addiction.
10. Clinically significant bleeding symptoms or clear bleeding tendency within 3 months prior to enrollment.
11. Severe active infection requiring IV antibiotics during screening.
12. Known hypersensitivity to Retlirafusp alfa or any excipients (polysorbate 80 (II), sucrose, citric acid, sodium citrate, water for injection, etc.), or severe allergic reactions to other monoclonal antibodies.
13. Active hepatitis B (HBV DNA >2000 IU/mL or 10⁴ copies/mL), or hepatitis C antibody-positive with HCV RNA above the lower limit of detection.
14. Receipt or planned receipt of live vaccine within 30 days prior to immunotherapy administration.
15. Intolerance to chemotherapy.
16. Inability to comply with the protocol or follow-up.
17. Other conditions deemed unsuitable for participation by the investigator.