Background: There is a growing body of evidence supporting neoadjuvant systemic therapy to improve outcomes for people with early-stage non-small cell lung cancer (NSCLC). However, not all patients will respond, necessitating the need to explore novel combinations and predictors of response to neoadjuvant therapies.
Patients and methods: In this open-label Phase 1B/2 signal-seeking trial, we recruited people with resectable Stage IB-IIIA NSCLC. Participants received two cycles of nivolumab with denosumab or nivolumab alone prior to surgical resection. Key clinical outcomes included the degree of pathological response, radiological overall response rate, recurrence-free survival, and overall survival. Tumor-immune correlates with pathological response were also investigated.
Results: Ten participants were recruited between August 2019 and September 2021, with five participants allocated to each treatment arm using minimization for tumor stage and histopathology. Two participants (20%) achieved a pathological complete response, with a further one patient achieving a major pathological response. Density of infiltrating CD8+ T cells correlated with the degree of pathological response to neoadjuvant therapy. With a median follow-up of 38.1 months, all patients remained alive at data cutoff. The 36-month recurrence-free survival was 80%. Treatment-related adverse events were reported in three patients (30%), all of which were Grade 1-2.
Conclusion: Our results support the feasibility of neoadjuvant systemic therapy in resectable NSCLC and explore the novel combination of nivolumab with denosumab. CD8 T-cell infiltration correlates with pathological response, warranting ongoing translational research to better understand patient selection for such novel combinations.
Keywords: RANK ligand; anti‐PD1; denosumab; immunotherapy; neoadjuvant therapy; non‐small cell lung cancer.
© 2026 The Author(s). Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.