Introduction: RANKL stimulates NF-kB-dependent cell-signalling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumours suggested significant overall survival (OS) advantage for lung cancer patients with denosumab. The randomised open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improves OS in advanced NSCLC. Methods:Stage IV NSCLC patients were randomised 1:1 to either chemotherapy with or without denosumab (120mg every 3-4 weeks), stratified by presence of bone metastases (at diagnosis), ECOG performance status, histology and region. To detect an OS increase from 9-11.25 months (HR=0.80), 847 OS events were required. The trial closed prematurely due to decreasing accrual rate.Results: 514 patients were randomised, 509 receiving ≥1 dose of assigned treatment (chemotherapy:252, chemotherapy-denosumab:257). Median age was 66.1 years, 71% male, 59% former smokers. Bone metastases were identified in 275(53%) patients. Median OS(95%CI) was 8.7(7.6-11.0) in the control versus 8.2(7.5-10.4) months in the chemotherapy-denosumab-arm, Addition of denosumab to first-line platinum-based doublet chemotherapy in advanced NSCLC 4 (HR=0.96;95%CI:[0.78-1.19]; 1-sided P=0.36). For patients with bone metastasis HR=1.02(95%CI:[0.77-1.35]), while for those without HR=0.90(95%CI:[0.66-1.23]). Grade≥3 adverse events were observed in 40.9%/5.2%/8.7% versus 45.5%/10.9%/10.5% of patients.Conditional power for OS benefit was ≤10%.Conclusions: Denosumab was well tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the ITT, and in the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in NSCLC patients without bone metastases.

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