Effect of Denosumab and Zoledronic Acid on Overall Survival in Patients with Metastatic Lung Cancer
In 30-40% of patients with non-small cell lung cancer (NSCLC), bone metastases develop during the course of the disease, causing so-called skeletal-related events (SREs). These events cause pain, increase morbidity, and reduce quality of life and mobility in patients. Antiresorptive agents, such as the bisphosphonate zoledronic acid or the osteoclast maturation and differentiation inhibitor denosumab, are used to prevent the occurrence of SREs. An exploratory analysis compared the effect of administering denosumab and zoledronic acid on the survival of patients with metastatic disease.
Study Methodology
A previously published double-blind phase III clinical study demonstrated the noninferiority of denosumab compared to zoledronic acid in delaying the first SRE in patients with metastatic solid tumors (excluding prostate and breast cancer) or multiple myeloma. In this study, similar overall survival was observed in both groups. An exploratory analysis of the data from this study focused on comparing overall survival with denosumab and zoledronic acid in a subgroup of patients with lung cancer.
Patients were randomized in a 1:1 ratio to receive either denosumab at a dose of 120 mg administered subcutaneously once a month (with intravenous placebo infusion) or zoledronic acid at a dose of 4 mg administered once a month intravenously (along with subcutaneous placebo injection). The dose of zoledronic acid was adjusted for renal insufficiency, and daily supplementation of vitamin D and calcium was recommended. The exploratory analysis included results from 811 patients with lung cancer, of whom 411 used denosumab.
Results
The basic clinical and demographic parameters were similar in both groups. Most patients (89%) had previously undergone systemic oncological treatment. More than 80% of patients in both groups had diagnosed NSCLC, with more than half having lung adenocarcinoma and about a quarter having squamous cell carcinoma.
Administration of denosumab was associated with a significant improvement in median overall survival compared to zoledronic acid in patients with any type of lung cancer (8.9 vs. 7.7 months; hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.67–0.95; p = 0.01). Longer survival was also observed when the analysis was adjusted for relevant baseline covariates (age, sex, time from diagnosis to the development of first metastases, bone metastases, and visceral metastases, ECOG status) and stratification factors (previous SRE and systemic oncological treatment).
Significantly longer overall survival with denosumab compared to zoledronic acid was also observed in patients with visceral metastases (7.7 vs. 6.4 months; HR 0.79; 95% CI 0.63–0.98; p = 0.03) and in patients with NSCLC (9.5 vs. 8.0 months; HR 0.78; 95% CI 0.65–0.94; p = 0.01). In patients with small cell lung cancer (SCLC), the difference was numerically different but did not reach statistical significance (7.6 vs. 5.1 months; HR 0.81; 95% CI 0.52–1.26; p = 0.36). Within histological subtypes of NSCLC, a significant effect of denosumab on survival was observed in patients with squamous cell carcinoma (8.6 vs. 6.4 months; HR 0.68; 95% CI 0.47–0.97; p = 0.035). In patients with lung adenocarcinoma, overall survival was similar in both groups (9.6 vs. 8.2 months).
The overall incidence of adverse events was balanced between the groups. Serious adverse events occurred in 66% of those on denosumab and 72.9% on zoledronic acid, with the cumulative incidence of osteonecrosis of the jaw being similar in both groups (0.7 vs. 0.8%). In the denosumab group, hypocalcemia was observed in 8.6% of patients compared to 3.8% on zoledronic acid.
Conclusion
The results of the exploratory analysis showed that administration of denosumab was associated with a significant extension of survival compared to zoledronic acid in most of the observed patient groups. In terms of safety, therapy with denosumab and zoledronic acid was comparable.
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Source: Scagliotti G. V., Hirsh V., Siena S. et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 2012; 7 (12): 1823–1829, doi: 10.1097/JTO.0b013e31826aec2b.
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