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, is 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 was 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 progression-free survival, overall survival and safety. Sample size calculation used the Simon 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 only 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 written informed consent prior to the implementation of any trial-related procedures;
Age ≥ 18 years old and ≤ 80 years old;
Histologically or cytologically confirmed stage IV NSCLC (International Association for the Study of Lung Cancer and American Joint Committee on Cancer Classification 9th Edition TNM Lung Cancer Staging);
Histologically confirmed bone metastasis, which is assessed by the investigator to require local radiotherapy treatment;
The pathology is small cell lung cancer (SCLC), including lung cancer mixed with SCLC and NSCLC;
The lesion is an isolated lesion and can be treated radically;
Patients who need surgical treatment after the evaluation of the study are not allowed to enroll;
The radiotherapy lesion to be treated has been treated with radiotherapy or the lesion to be treated cannot be treated with radiotherapy after evaluation;
Single group
Narlumosbart
DrugPatients who have not received any systemic therapy 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, is 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 was 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 progression-free survival, overall survival and safety. Sample size calculation used the Simon Two-Stage method. 27 subjects will be enrolled in this project, considering the dropout rate of 10%.
Objective response rate, ORR
Overall survival，OS
The time from enrollment to death from any cause. Patients who were still alive at the time of analysis will have the date of their last contact as the cutoff date.
Progression free survival, PFS
The time from enrollment to disease progression or death from any cause. Patients who were still alive at the time of analysis will have the date of their last contact as the cutoff date.
Adverse Events, AEs
AEs are crucial for assessing the safety profile of treatments in clinical trials and medical practice. The minimum Value is 0 ,indicating no occurrence of the adverse event. The maximum varies depending on the grading system used (e.g., Common Terminology Criteria for Adverse Events, CTCAE, which ranges from 1 to 5, with 5 indicating the most severe event, such as death.Higher scores indicate more severe adverse events. For example, in the CTCAE grading system: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death.
Brief Pain Inventory - Short Form, BPI-SF
Brief Pain Inventory - Short Form, BPI-SF is a widely used, self-administered questionnaire designed to assess the severity and impact of pain. The minimum value is 0 and the maximum value is 10. Higher scores indicate more severe pain or greater.Specifically, the BPI-SF includes assessments of pain intensity (e.g., worst pain, least pain, pain right now) and pain interference (e.g., interference with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each item is rated on a scale from 0 (no pain or no interference) to 10 (worst possible pain or complete interference).
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