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

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

KEYWORDS:

• Denosumab
• drug repurposing
• lung cancer
• non-small cell lung cancer
• RANKL
• RANK

Article highlights

• Initially approved as antiosteoporotic agent, denosumab may be repurposed in oncology beyond the prevention of SREs of solid tumors, including lung cancer.

• Preclinical studies have demonstrated the expression of RANKL in human lung cancer tissues and have established links connecting RANKL signaling with lung carcinogenesis, rationalizing the potential therapeutic efficacy of denosumab in lung cancer.

• Preclinical data and retrospective survival clinical data indicate a direct anticancer effect of denosumab in the setting of lung cancer beyond the prevention of SREs.

• Subgroup analysis of a randomized phase 3 study in lung cancer demonstrated that denosumab was associated with significantly improved overall median survival compared to ZA.

• The SPLENDOUR trial showed that denosumab adjuvant to standard chemotherapy yielded no significant overall survival benefit for patients with stage IV NSCLC compared to chemotherapy plus best supportive care.

• The routine use of denosumab as anticancer strategy in lung cancer beyond preventing SREs cannot be embraced yet.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.