New Treatment Approaches in Metastatic Bone Disease from Lung Cancer.

   Bone metastases occur in 30-40% of patients with lung cancer. They have debilitating consequences=skeletal related events (SRES) such as fractures, radiation and surgery to bone, spinal cord compression and hypocalcemia. The consequences are significant morbidity, loss of autonomy, bone pains, reduced quality of life (QOL) and decreased survival. In phase 3 study 257 patients (pts) on Zoledronic acid (ZA) 4 mg every 3 weeks iv were compared to placebo (250 pts), 49 % of pts (244) had NSCLC and 7 % SCLC. In NSCLC ZA reduced the risk of SREs by 32 %, p=0.01; if pts had prior SRE, the risk reduction was by 31%, p=0.0009. RANK Ligand plays a destructive role in pts with bone metastases. It is produced by osteoblasts and it stimulates osteoclast activity which then resorb bone. Tumor cells stimulate osteoblasts to secrete RANK legand. XGEVA (denozenumab) is a fully human monoclonal antibody with high affinity and specificity for human RANK ligand (RANKL), It targets and inhibits RANKL to break the vicious cycle of bone destruction. In randomized phase 3 trial of denosumab 120 mg s.c. every 4 weeks (886 pts) vs ZA (890 pts) 4 mg i.v. every 4 weeks denosumab was non-inferior to ZA in time to first on-study SRE and also by multiple event analysis.

   Disease progression and overall survival were equal. When solid tumors only (without multiple myeloma) were analysed, denosumab was superior to ZA for both endpoints, HR=0.81, p=0.017 and HR=0.85, p= 0.048 respectively. There were more acute phase reactions on ZA and more hypocalcemia on denosumab. ONJ incidence was about 1% in both arms. No renal toxicity is caused by denosumab. Denosumab delayed the time to moderate/severe pain and fewer patients required increased analgesic use compared to ZA. When only lung cancer patients were analysed for overall survival, pts on denosumab had median OS=8.9 months vs 7.7 months on ZA, HR=0.80, p=0.01. Preclincial investigations are underway to evaluate if RANKL inhibition has direct anti-tumor effects on lung cancer cells.

   Conclusion

   Results from phase 3 trial in pts with solid tumors (excluding breast and prostate ca and multiple myeloma) and bone metastases showed denosumab was superior to ZA in delaying time to first and subsequent on study SREs, in better pain control and superior survival.