A Multicenter, Prospective, Phase II Clinical Trial of Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6 as Total Neoadjuvant Therapy for Patients With pMMR/MSS Locally Advanced Rectal Cancer
A Multicenter, Prospective, Phase II Clinical Trial of Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6 as Total Neoadjuvant Therapy for Patients With pMMR/MSS Locally Advanced Rectal Cancer
This is a multicenter, prospective, phase II study evaluating total neoadjuvant therapy (TNT) consisting of short-course radiotherapy (SCRT; 5×5 Gy) followed by QL1706 (a bifunctional MabPair antibody targeting PD-1 and CTLA-4, code name only) plus mFOLFOX6 chemotherapy in patients with locally advanced rectal cancer (LARC) with proficient mismatch repair/microsatellite-stable (pMMR/MSS) biology. Patients with pMMR/MSS disease derive limited benefit from immune checkpoint inhibition alone. Preclinical and clinical evidence suggests that SCRT and oxaliplatin-based chemotherapy can enhance antitumor immunity (e.g., antigen release, T-cell infiltration), providing a biological rationale for combining QL1706 with SCRT-primed TNT.
Eligible adults with cT3-4 and/or N+ mid-to-low rectal adenocarcinoma (without distant metastasis), confirmed pMMR/MSS, and ECOG 0-1 will receive: SCRT (total 25 Gy over 5 fractions), then several cycles of QL1706 plus mFOLFOX6 as neoadjuvant systemic therapy. Definitive total mesorectal excision (TME) is planned per multidisciplinary assessment; a watch-and-wait approach may be considered for patients achieving a stringent clinical complete response per institutional criteria. Standard perioperative care and postoperative follow-up will be performed.
Primary endpoint is pathologic complete response (pCR, ypT0N0) rate at surgery. Key secondary endpoints include: clinical complete response (cCR) rate, major pathologic response rate, R0 resection rate, tumor downstaging, radiologic response, disease-free survival (DFS), overall survival (OS), organ preservation rate (for patients managed non-operatively), surgical morbidity, and safety/tolerability (CTCAE v5.0). Exploratory endpoints include correlations between efficacy and baseline clinicopathologic features; optional translational analyses may investigate immune-inflammation markers related to response and resistance.
This trial aims to determine whether SCRT-primed QL1706 plus mFOLFOX6 TNT can improve tumor eradication and organ preservation while maintaining acceptable safety in pMMR/MSS LARC-a population with unmet need for effective immunotherapy-based strategies.
Inclusion Criteria:
Age 18-75 years, male or female.
Histologically confirmed rectal adenocarcinoma.
Locally advanced disease (cT3-4 and/or N+, M0) based on pelvic MRI and/or CT.
Tumor located within 12 cm from the anal verge.
Proven microsatellite stability (MSS) or proficient mismatch repair (pMMR) status.
ECOG performance status 0-1.
Adequate organ function:
Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
Platelet count ≥ 100 × 10⁹/L
Hemoglobin ≥ 90 g/L
ALT/AST ≤ 2.5 × ULN
Total bilirubin ≤ 1.5 × ULN
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min
No prior pelvic radiotherapy, chemotherapy, immunotherapy, or targeted therapy for rectal cancer.
Signed written informed consent
Exclusion Criteria:
Evidence of distant metastasis.
Previous or concurrent malignant tumor (except cured basal cell carcinoma of skin or cervical carcinoma in situ).
Active autoimmune disease requiring systemic immunosuppressive therapy.
Active infection including hepatitis B, hepatitis C, HIV, or tuberculosis.
Known allergy or hypersensitivity to study drugs or excipients.
Uncontrolled cardiovascular disease (e.g., recent myocardial infarction, unstable angina, congestive heart failure, arrhythmia).
Pregnant or breastfeeding women.
Any condition judged by investigators to make the patient unsuitable for the study.
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