Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab

Abstract

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34–0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37–0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41–0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19–0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Assessing EGFR‐mutated NSCLC with bone metastasis: Clinical features and optimal treatment strategy

“…In a retrospective study of 190 NSCLC patients with BoM, combining denosumab with first-or second-generation EGFR-TKI was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). 20 However, another real-world study reported that denosumab had no significant prognostic effects in lung adenocarcinoma patients with BoM treated with first-line EGFR-TKIs. 21 In our study, combining EGFR-TKI with denosumab showed a nonsignificant trend toward improving the OS of EGFRmutated NSCLC patients with BoM.…”

“…Third, our study does not report on SREs, which previous studies have identified as a poor prognostic factor. 20,21 Fourth, we used different dosages of bevacizumab (7.5 mg/kg every 3 weeks) and intravenous ramucirumab (5-10 mg/kg every 3 weeks) compared to prior trials, 22,23 due to these drugs not being covered for lung cancer treatment under Taiwan's National Health Insurance, leading to the use of reduced dosages. Previous research showed that combining chemotherapy with 7.5 mg/kg of bevacizumab was as effective as using 15 mg/kg.…”

“…Despite denosumab being commonly used in Taiwan following a reimbursement program initiated by National Health Insurance on December 1, 2015, not all physicians prescribe it for managing bone diseases or skeletal-related events (SREs) in NSCLC patients. 6,20,21 Additionally, anti-VEGF medicine is not covered by Taiwan Health Insurance. Therefore, large-scale clinical trials are necessary to conclusively demonstrate the benefits of combining denosumab and anti-VEGF with EGFR-TKIs.…”

“…19 A retrospective study of patients with metastatic NSCLC and EGFR mutations receiving first-line EGFR-TKI treatment revealed that combining denosumab with EGFR-TKI leads to longer OS than EGFR-TKI monotherapy. 20 However, another study found that denosumab did not impact progressionfree survival (PFS) or OS. 21 Recent research has explored combining EGFR-TKIs with vascular endothelial growth factor (VEGF) inhibitors in treating NSCLC patients with EGFR mutations.…”

“…An in vitro study showed that osimertinib can regress tumors, improve bone remodeling, and increase survival rates in mice with BoM models, suggesting its potential as a treatment for EGFR‐mutated NSCLC patients with BoM 19 . A retrospective study of patients with metastatic NSCLC and EGFR mutations receiving first‐line EGFR–TKI treatment revealed that combining denosumab with EGFR–TKI leads to longer OS than EGFR–TKI monotherapy 20 . However, another study found that denosumab did not impact progression‐free survival (PFS) or OS 21 .…”