Neoadjuvant Chemoimmunotherapy Versus Concurrent Chemoradiotherapy for LACC

Neoadjuvant Chemoimmunotherapy Combined With Surgery Versus Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer: a Multicenter Randomized Controlled Clinical Trial

It is a prospective, open-label, randomized, controlled phase II/III clinical trial in which patients with PD-L1-positive FIGO stage IB3, IIA2 and IIB（tumors >4 cm in diameter）will be enrolled and randomly divided into the neoadjuvant chemoimmunotherapy plus surgery group and the CCRT group.

Cervical cancer is the most common gynecological malignancy in China, with locally advanced cervical cancer (LACC) accounting for approximately 37% of cases. Currently, the recommended standard of care for LACC according to international guidelines is concurrent chemoradiotherapy (CCRT). However, the impacts of radiation therapy on patients' quality of life are increasingly being recognized. Additionally, 23.3% to 34.4% of patients still face recurrence or metastasis after treatment, and the 5-year overall survival rate remains around 75%.

Neoadjuvant chemotherapy (NACT) is a chemotherapy regimen used prior to surgery for LACC. NACT followed by radical surgery has a similar overall survival compared to CCRT, but the disease-free survival is relatively lower with NACT. Moreover, 9.8% to 30.6% of patients show poor response to NACT, and over 30% of patients require postoperative adjuvant therapy. These issues significantly limit the application of NACT in LACC.

In recent years, immunotherapy has made significant progress in advanced or recurrent cervical cancer. A phase II clinical trial of combination of PD-1 inhibitors and neoadjuvant chemotherapy showed significant anti-tumor activity and safety. Therefore, based on the preliminary results, this project aims to conduct a multicenter, prospective, randomized controlled clinical trial to further confirm the value of neoadjuvant immunotherapy combined with surgery in LACC. It will be compared with the standard CCRT regimen to explore the differences in clinical efficacy and adverse events between the two groups, providing high-level evidence for the application of neoadjuvant immunotherapy in cervical cancer.

Inclusion Criteria:

1. Locally advanced (2018 FIGO staged IB3, IIA2 and IIB（tumor size> 4cm) ) cervical cancer，staging determined by two physicians of associate seniority or higher after gynecologic examination and imaging evaluation);
2. At least one measurable lesion at baseline according to RECIST 1.1 criteria, with lesion size based primarily on magnetic resonance imaging;
3. Pathologically confirmed diagnosis of cervical cancer, including cervical squamous cell carcinoma, adenocarcinoma (common type), and adenosquamous carcinoma;
4. Positive PD-L1 expression, Combined Positive Score (CPS) ≥1;
5. Patient age ≥18 years and ≤70 years;
6. ECOG score ≤1;
7. Laboratory tests: WBC (white blood cell count) ≥ 3.5×109/L, NEU (neutrophil count) ≥ 1.5×109/L, PLT (platelet count) ≥ 100×109/L, total bilirubin ≤ 1.5 times the upper limit of normal, ALT (alanine aminotransferase) and AST (aspartate aminotransferase) ≤ 1.5 times the upper limit of normal, serum creatinine (BUN) ≤ 1.5 times the upper limit of normal or creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula, the Chronic Kidney Disease Epidemiology Collaboration equation, or the Modification of Diet in Renal Disease equation);
8. Be willing to follow up and good compliance;
9. Be willing to sign the informed consent, including compliance with the requirements and restrictions listed in the informed consent and program；
10. Agree to use effective contraception measures during the trial period and for 5 months after the last dose of pembrolizumab or 6 months after chemotherapy (whichever is longer).

Exclusion Criteria:

1. Any active autoimmune disease or history of autoimmune disease requiring systemic treatment, including but not limited to autoimmune hepatitis, interstitial pneumonitis, uveitis, enterocolitis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, thyroid dysfunction, asthma requiring bronchodilator intervention;
2. Prior treatment with immune checkpoint inhibitors, including but not limited to other anti-PD-1 and anti-PD-L1 antibodies; known hypersensitivity to any component of the study medication or other monoclonal antibodies;
3. Has a history of human immunodeficiency virus (HIV) infection, active hepatitis B (HBV-DNA ≥ 2000 IU/mL or 104 copies/mL), and hepatitis C (HCV antibody positive, and HCV-RNA above the lower limit of detection of the assay);
4. Receipt of immunosuppressive medications or systemic corticosteroid therapy for immunosuppression (>10 mg/day prednisone or equivalent) within 2 weeks prior to study dosing;
5. Diagnosed with another primary malignancy within 5 years prior to the first use of the investigational drug;
6. Received other investigational drugs/treatments or participated in another clinical trial within 4 weeks prior to randomization. Participation in observational and non-interventional clinical trials is allowed;
7. Pregnant or breastfeeding female patients;
8. Uncontrolled co-morbidities, including but not limited to New York Heart Association (NYHA) class 2 or higher, severe/unstable angina pectoris, myocardial infarction within ≤ 6 months prior to study drug administration, severe arrhythmias requiring medication or intervention; difficult-to-control hypertension; cerebral vascular accidents or brain disorders within ≤ 6 months prior to study drug administration, or individuals with adjudicated abnormal behavioral skills; hematologic disorders: coagulation abnormalities (INR >2. 0, PT>16s), bleeding tendency, or undergoing thrombolytic or anticoagulant therapy; abnormalities in hepatic or renal development or a history of surgery; and development of an active infection requiring systemic anti-infective therapy within 14 days prior to the first dose of study drug;
9. Treatment with a live or attenuated vaccine administered within 4 weeks prior to the first dose of study drug; inactivated seasonal influenza virus vaccine is permitted;
10. Patients with a prior allogeneic bone marrow or solid organ transplant;
11. Drug and/or alcohol abuse;
12. Patients who, in the opinion of the investigator, are unlikely to comply with the procedures, restrictions, and requirements of the study may not be enrolled in the study.