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；
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
DrugNarlumosbart is a fully humanized anti-RANKL monoclonal antibody (IgG4) with Fab arms identical to denosumab, demonstrating rapid and sustained suppression of bone resorption biomarkers in patients with bone metastases. It will be administered subcutaneously at 120 mg every 4 weeks. Calcium and vitamin D supplementation will be given concurrently to prevent hypocalcemia. Adverse events will be recorded and graded according to CTCAE v5.0. For jaw osteonecrosis, all patients will undergo a mandatory dental examination within 14 days before the first dose, with 3-monthly dental checks during treatment; suspected cases will be managed with oral surgeon consultation. Serum calcium will be monitored at baseline and prior to each dose (every 4 weeks). Corrected calcium \<2.0 mmol/L will be managed with oral calcium (500-1000 mg/day) and vitamin D (400-800 IU/day). Severe hypocalcaemia (\<1.8 mmol/L or symptomatic) will be treated with intravenous calcium gluconate.
Stereotactic Body Radiation Therapy
RadiationSBRT will be delivered within one week before the first chemo-immunotherapy cycle. All patients undergo contrast-enhanced CT simulation (1-1.5 mm slice thickness); MRI fusion (T1/T2/STIR) is mandatory for spinal metastases. Target delineation: GTV = visible tumor on CT/MRI; CTV = involved vertebral body sector(s) per ISRC guidelines for spinal lesions, or GTV + 3-5 mm margin for non-spinal lesions; PTV = CTV + 1-2 mm margin. Dose prescription: 24 Gy in 3 fractions for spinal metastases; 30-35 Gy in 5 fractions for non-spinal lesions. Treatment plans use VMAT or IMRT. Daily cone-beam CT (CBCT) is performed before each fraction for image guidance; 6-degree-of-freedom couch corrections are used for spinal lesions. Respiratory motion management (e.g., 4D-CT, gating) is applied for mobile lesions if motion exceeds 5 mm. Patient-specific quality assurance (PSQA) is performed before the first fraction, with gamma analysis (3%/2 mm criteria and ≥95% passing rate) required.
Objective response rate, ORR
Incidence of AEs, SAEs, and AE-Related Treatment Discontinuation
To assess the frequency of adverse events (AEs), severe adverse events (SAEs), and treatment discontinuation caused by AEs or SAEs over the study period.
Progression free survival, PFS
Progression-free survival (PFS) is defined as the time from randomization (or treatment initiation) to the earlier of the first documentation of objective disease progression (per RECIST v1.1) or death due to any caus
Overall survival (OS)
Overall survival (OS) is defined as the time from treatment initiation to death from any cause. Participants who are alive or lost to follow-up at the time of analysis will be censored at the date of their last known survival status.
Incidence of bone-related events (SREs)
Incidence of bone-related events (SREs) is defined as the proportion of patients experiencing at least one skeletal-related event (SRE) within the specified time intervals (3, 6, and 12 months). SREs are defined as a composite endpoint including: pathological fracture, spinal cord compression, bone-directed radiotherapy or surgery, or hypercalcaemia of malignancy, as assessed by the investigator.
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