Efficacy and Safety of Narlumosbart in Combination With Stereotactic Body Radiation Therapy Followed by First-line Chemotherapy Combined With Immunotherapy in Advanced Driver Gene-negative Non-small Cell Lung Cancer Patients With Bone Metastases: A Phase II, Single-arm, Single-center Clinical Trial Protocol
Introduction: Immunotherapy in combination with chemotherapy have been recommended as the first-line treatment of driver-negative advanced non-small cell lung cancer (NSCLC), but the efficacy is worse in NSCLC patients with bone metastases due to the immunosuppressive microenvironment. Studies have shown that not only the nuclear factor kappa-B ligand (RANKL) inhibitors but also Stereotactic Body Radiation Therapy (SBRT) play a significant role in improving the tumor immune microenvironment. Therefore, narlumosbart，a monoclonal antibody (mAb) targeting RANKL，in combination with SBRT may have synergistic effects and improve efficacy of immunotherapy and chemotherapy in driver-negative advanced NSCLC patients with bone metastases.
Methods: This single-arm, single-center phase II clinical trial will enroll NSCLC patients with bone metastases who have not received any systemic therapy. Patients will receive narlumosbart and bone target lesion SBRT in combination with first-line treatment immunotherapy and chemotherapy after screening eligible subjects. Narlumosbart, 120mg/time, subcutaneous injection, will be administered every 4 weeks. For the treatment of SBRT for bone metastases, the dose of 24Gy/3F is used for spinal metastases, and 30Gy/5F or 35Gy/5F is used for non-spinal lesions. Chemotherapy combined with immune checkpoint inhibitor therapy will be used in accordance with the guidelines. The primary endpoint is to assess the objective response rate of NSCLC patients with bone metastases from narlumosbart combined with SBRT and first-line chemotherapy and immunotherapy. The secondary endpoints include safety and tolerability, progression-free survival, overall survival, bone-related events, pain score, and quality of life. Sample size was calculated using the Simon's Two-Stage method. 9 patients will be enrolled in the first stage. If ≥ 2 patients achieve CR/PR, the second stage of enrollment will be performed. If fewer than 2 patients achieve CR/PR, the trial will be terminated. In the second phase, 15 patients will be enrolled. 27 subjects will be enrolled in this project, considering the dropout rate of 10%. Wangjun Yan AND Zhengfei Zhu are the Co-Principal Investigators of this study.
• Signed informed consent prior to the implementation of any trial-related procedures;
• Age 18-80 years old;
• Histologically or cytologically confirmed stage IV NSCLC according to the TNM Classification of Malignant Tumours, 9th edition；
• Histologically confirmed bone metastases requiring local radiotherapy；
• Patients who have not undergone systemic drug therapy for lung cancer (including chemotherapy, targeting, immunotherapy, etc.);
• Driver genes (EGFR, ALK, ROS-1) negative in adenocarcinoma patients (genetic testing not required for squamous cell carcinoma) ;
• At least one evaluable non-bone lesion (refer to RECIST1.1);
• Bone metastases other than the lesions to be radiotherapy do not require local treatment (surgery or radiotherapy) intervention after evaluation;
• ECOG score 0-1 points;
• Expected survival time \> 3 months;
• Adequate organ function, defined as meeting all of the following laboratory criteria within 14 days prior to enrollment: 1) ANC ≥1.5×10⁹/L (no G-CSF); 2) Platelets ≥100×10⁹/L (no transfusion); 3) Haemoglobin ≥9 g/dL (no transfusion/EPO); 4) Bilirubin ≤1.5×ULN; 5) AST/ALT ≤2.5×ULN (≤5×ULN if liver metastases); 6) Creatinine ≤1.5×ULN or CrCl ≥60 mL/min; 7) INR/PT ≤1.5×ULN; 8) TSH within normal limits (or FT3/FT4 normal if TSH abnormal); 9) Cardiac enzymes (troponin I, CK-MB) ≤ ULN (isolated abnormalities not clinically significant are permitted).