A randomised phase III trial evaluating the addition of denosumab to standard first-line treatment in advanced NSCLC: The ETOP and EORTC SPLENDOUR trial

Abstract

Background: RANKL stimulates NF‐kB‐dependent cell signalling and is known to act as primary signal for bone resorption. In a large trial comparing denosumab vs zoledronic acid in bone metastatic solid tumours, retrospective analysis suggested a significant overall survival (OS) advantage in lung cancer patients who were receiving denosumab. SPLENDOUR is a randomised phase III trial, evaluating whether the addition of denosumab to standard first‐line platinum‐based doublet chemotherapy improves OS in advanced NSCLC. Methods: Stage IV NSCLC patients randomised to the control arm received 4‐6 cycles of standard chemotherapy plus best supportive care, if there were no bone metastases, or zoledronic acid in case of skeletal involvement. Patients in the denosumab arm were given standard chemotherapy plus denosumab, 120 mg every 3‐4 weeks. Randomisation was stratified by bone metastases, PS, histology and region. 847 OS events were required to detect an OS increase from 9 to 11.25 months (HR=0.80). The trial closed early due to a decrease in accrual rate. Results: Total of 514 patients were randomised, with 509 (252 vs 257) patients receiving at least one dose of assigned treatment. Median age was 65.4 vs 66.5 years, the majority were male (73 vs 69%) and former smokers (58 vs 60%). 275 (54 vs 53%) patients had bone metastasis. Median follow‐up time with respect to OS was 18.8 vs 25.3 months. Grade 3/4/5 adverse events were observed in 40.9%/5.2%/8.7% vs 45.5%/ 10.9%/10.5% of patients. Median OS (95% CI) was 8.8 (7.6, 11.0) months in the control vs 8.2 (7.4, 10.4) months in the denosumab arm, HR=0.96 (95%CI: 0.78‐1.19; p=0.71). Conditional power calculations indicated that if the trial had proceeded to completion, the power of detecting a significant OS benefit would still be less than 10%. Conclusions: Denosumab was well tolerated without major safety concerns. The final analysis of SPLENDOUR did not show an improvement of OS for denosumab when added to standard first‐line platinum‐based chemotherapy. These results are at variance with our trial assumption and previous studies. In addition to the primary OS analysis, outcome by subgroups with or without bone metastases will be presented.