This study is a multicenter, prospective, randomized, double-arm, Phase II clinical trial designed to evaluate the efficacy of short-term radiotherapy combined with Iparomlimab and Tuvonralimab (QL1706), Regorafenib, and CAPOX as neoadjuvant therapy for locally advanced rectal cancer. Additionally, the study seeks to explore the relationship between biomarkers in blood, urine, feces, and tumor tissue and treatment efficacy.
Eligible participants (pMMR/MSS locally advanced rectal cancer) were randomly assigned in a 1:1 ratio to two groups, with randomization stratified by MRF (+ vs. -).
Participants will:
* Group A patients received two cycles of QL1706, regorafenib, and CAPOX induction therapy, followed by sequential short-course radiotherapy, and then continued with four cycles of QL1706, regorafenib, and CAPOX consolidation therapy. * Group B patients received short-course radiotherapy followed by six cycles of QL1706, regorafenib, and CAPOX consolidation therapy.
After two cycles of neoadjuvant therapy in Group A and six cycles in Group B, efficacy was evaluated and decisions regarding surgery or watchful waiting were made based on efficacy.
Age: 18-75 years.
Pathology: Histologically confirmed rectal adenocarcinoma, with the lower tumor edge ≤12 cm from the anal verge.
Initial Clinical Stage: cT3-4aN0M0 or cT1-4aN+M0, regardless of MRF, EMVI, or LLNM status.
pMMR/MSS Status: pMMR confirmed by immunohistochemistry (IHC) at the study center's pathology department, or MSS/MSI-L confirmed by PCR or NGS.
Active Autoimmune Disease: Any active autoimmune disease requiring systemic treatment (i.e., disease-modifying medications, corticosteroids, or immunosuppressive agents) within 2 years prior to enrollment (e.g., myasthenia gravis, systemic lupus erythematosus, interstitial pneumonitis, uveitis, ulcerative colitis, autoimmune hepatitis, hypophysitis, systemic vasculitis, nephritis, hyperthyroidism, hypothyroidism, mixed connective tissue disease).
Concurrent Systemic Therapy: Use of systemic corticosteroids (≥10 mg/day of prednisone or equivalent) or other immunosuppressants (e.g., cyclosporine, cyclophosphamide, azathioprine, methotrexate, thalidomide) within 14 days before the first dose, or use of immunostimulants (e.g., interferon, interleukin-2) within 4 weeks before the first dose.
Live Vaccines: Receipt of a live or attenuated live vaccine within 30 days before the first dose or potentially during the study period.
Antibiotic Use: Administration of broad-spectrum antibiotics by any route within 30 days prior to the first dose.
Parallel
lparomlimab and Tuvonralimab Injection and regorafenib and CPAOX and short-course radiotherapy
Combination productGroup A patients received two cycles of QL1706, regorafenib, and CAPOX induction therapy, followed by sequential short-course radiotherapy, and then continued with four cycles of QL1706, regorafenib, and CAPOX consolidation therapy. lparomlimab and Tuvonralimab Injection(QL1706): 5 mg/kg, intravenous (IV), on Day 1, every 3 weeks (q3w) during the neoadjuvant treatment phase. Regorafenib:80 mg, oral (PO), once daily (qd), Days 1-14, every 3 weeks (q3w) during the neoadjuvant treatment phase. CAPOX: Oxaliplatin( 130 mg/m², IV over 2 hours, Day 1, every 3 weeks (q3w))+ Capecitabine( 1000 mg/m², PO, twice daily (bid), Days 1-14, every 3 weeks (q3w)). Short-course radiotherapy:The total dosage was 25Gy consisted of 5 fractions of 5 Gy to clinical target volume without a boost dose.
lparomlimab and Tuvonralimab Injection and regorafenib and CPAOX and short-course radiotherapy
Combination productGroup B patients received short-course radiotherapy followed by six cycles of QL1706, regorafenib, and CAPOX consolidation therapy. lparomlimab and Tuvonralimab Injection(QL1706): 5 mg/kg, intravenous (IV), on Day 1, every 3 weeks (q3w) during the neoadjuvant treatment phase. Regorafenib:80 mg, oral (PO), once daily (qd), Days 1-14, every 3 weeks (q3w) during the neoadjuvant treatment phase. CAPOX: Oxaliplatin( 130 mg/m², IV over 2 hours, Day 1, every 3 weeks (q3w))+ Capecitabine( 1000 mg/m², PO, twice daily (bid), Days 1-14, every 3 weeks (q3w)). Short-course radiotherapy:The total dosage was 25Gy consisted of 5 fractions of 5 Gy to clinical target volume without a boost dose.
Complete response (CR)
Complete response: Pathological complete response and clinical complete response
Objective response rate (ORR)
The proportion of patients achieving a complete response (CR) or partial response (PR), evaluated according to RECIST v1.1.
Major Pathological Response (MPR)
The proportion of patients whose primary tumor shows ≤10% residual tumor cells on pathology.
Tumor Regression Grade (TRG)
Assessed based on the 8th edition of the AJCC staging system to grade the extent of tumor regression
R0 Resection Rate
The proportion of surgical patients who achieve an R0 resection. R0 resection: All gross disease has been removed, and microscopic examination reveals all surgical margins free of tumor.
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