Denosumab: The Better Option for Bone Metastases in NSCLC?

H. Jack West, MD


January 23, 2013

Overall Survival Improvement in Patients With Lung Cancer and Bone Metastases Treated With Denosumab versus Zoledronic Acid

Scagliotti GV, Hirsh V, Siena S, et al
J Thorac Oncol. 2012;7:1823-1829


Patients with bone metastases from solid tumors typically are treated with either zoledronic acid or denosumab to reduce the risk for future skeletal metastases. However, therapy for bone metastases is usually a secondary focus, with greater emphasis placed on systemic therapies to improve survival and/or directly reduce a patient's cancer-related symptoms.

Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), is administered subcutaneously once every 28 days. The treatment became a feasible and arguably superior option in the wake of several trials demonstrating a significantly superior reduction in the rate of skeletal complications as compared with zoledronic acid.[1,2,3] In the absence of a difference in overall survival (OS) or any major differences in adverse events, combined with the notably greater cost for denosumab, I concluded in the editorial[4]that accompanied the publication of one of the studies[1] that denosumab was an appealing option but there was no mandate to consider it the standard of care.

Oncologists and patients have historically been most motivated by improvements in OS. Consequently, when a subset analysis of patients with lung cancer from the trial of denosumab vs zoledronic acid reveals a significant improvement in OS, as published by Scagliotti and colleagues, I view this as a very relevant factor to consider in our clinical management decisions.

Study Summary

Specifically, the broader trial enrolled 1776 patients, and the leading subtype was lung cancer, including both non-small cell lung cancer (NSCLC) (n = 702) and small cell lung cancer (SCLC) (n = 109). Denosumab when compared with zoledronic acid was associated with a statistically significant improvement in skeletal-related complications of new or progressive bone lesions that required palliative radiation, opioid pain medication, or caused a pathologic fracture. More important, denosumab was associated with a significantly superior OS by 1.2 months (8.9 vs 7.7 months; HR = 0.80). Also, an improvement in survival was seen across tumor histologies, including adenocarcinoma and squamous NSCLC, as well as SCLC, in which denosumab was associated with a difference in survival of 2.5 months (7.6 vs 5.1 months; HR = 0.81).


The oncology community is typically somewhat skeptical about exploratory subset analyses, which are often viewed as "fishing expeditions" for positive results that might not be borne out in prospective testing. I think it is quite fair to view the results of this subset analysis with some skepticism, but I consider these results to be more robust than many post-hoc subset analyses because of the large size of the study (having a total of 811 patients), the hard endpoint of OS, and the consistency of the results across multiple histologically defined groups of lung cancer patients.

Overall, my view is that even without the difference in OS, denosumab offered some compelling arguments to favor it over zoledronic acid, but with evidence supporting a 1.2-month improvement in OS -- seen in SCLC and squamous cell NSCLC patients, 2 groups for which we have had great difficulty offering any interventions with a survival difference -- the cost of denosumab over zoledronic acid seems to be a relative bargain. I'm inclined to accept the shortcomings of a retrospective subset analysis because I would argue that these data only move denosumab from a justifiable, compelling option to a very strong leading consideration for my patients with bone metastases from lung cancer. If denosumab can improve survival at a relatively low cost compared with so many of our other interventions, the oncology community should be more proactive about providing denosumab to appropriate patients and not relegating it to the status of an afterthought compared with other systemic interventions.