Repurposing denosumab in lung cancer beyond counteracting the skeletal related events: an intriguing perspective

Repurposing denosumab in lung cancer therapeutics capitalizes on its well-established role in preventing the skeletal related events (SREs) and its emerging, yet elusive, bone-independent role, assigned to inhibit the contribution of RANKL to cancer initiation and progression.The present review presents the available preclinical and clinical data indicating that denosumab may provide survival benefit to lung cancer patients beyond the counteraction of SREs.Despite the preliminary data heralding the potential of denosumab to increase overall survival in lung cancer, the embracement of this strategy in clinical practice cannot be advocated until large randomized clinical trials consolidate its safety and efficacy. Given the improvement of lung cancer prognosis ascribed to revolutionary targeted treatment agents, the possibility of denosumab-related increased risk of second primary malignancies merits further evaluation. Many challenges in endorsing denosumab as a strategy to treat lung cancer beyond SREs prevention are pending counteraction, including: (i) patient selection guided by validated predictive and prognostic biomarkers; (ii) assessment of long-term outcomes; (iii) evaluation of benefit-risk ratio; (iv) translational research; (v) combination of denosumab with other targeted therapies; (vi) integration of genomic biomarkers, immune-related biomarkers, and biomarkers of active RANKL pathway to guide the decision-making process.