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-centre clinical trial protocol.

introductionImmunotherapy in combination with chemotherapy has been recommended as the first-line treatment of driver gene-negative advanced non-small cell lung cancer (NSCLC), but the efficacy is reduced in NSCLC patients with bone metastases due to the immunosuppressive microenvironment. Both nuclear factor kappa-B ligand (RANKL) inhibitors and stereotactic body radiation therapy (SBRT) have been shown to modulate the tumour immune microenvironment. Therefore, narlumosbart, a monoclonal antibody targeting RANKL, in combination with SBRT, may exert synergistic effects and improve efficacy of first-line chemoimmunotherapy in this population. METHODS AND ANALYSIS: This single-arm, single-centre phase II clinical trial will enrol driver gene-negative advanced NSCLC patients with bone metastases who have not received any systemic therapy. Eligible patients will receive narlumosbart (120 mg subcutaneously every 4 weeks) and SBRT to bone target lesions (24 Gy/3 fractions for spinal metastases and 30-35 Gy/5 fractions for non-spinal lesions), followed by standard first-line chemoimmunotherapy. The primary endpoint is the objective response rate of non-radiotherapy lesions. 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 (α=0.05, power=0.8, H₀=25%, H₁=50%). Nine patients will be enrolled in stage 1. If ≥2 patients achieve complete response (CR)/partial response (PR), an additional 15 patients will be enrolled in stage 2. If fewer than two patients achieve CR/PR, the trial will be terminated. 27 subjects will be enrolled in this project, considering the dropout rate of 10%. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of Fudan University Shanghai Cancer Center (approval number 2411308-15) on 6 December 2024. The trial registration number is NCT06738160 at clinicaltrials.gov, sponsored by Fudan University, and registered in December 2024 before the enrolment of the first participant in February 2025. The trial will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent will be obtained from all participants prior to enrolment. Results will be published in a peer-reviewed journal.