Abstract

BACKGROUND: Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-?B ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. METHODS: This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary >?2?cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3?mg/kg every 2?weeks) or two doses of nivolumab (same regimen) plus denosumab (120?mg every 2?weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. DISCUSSION: The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. TRIAL REGISTRATION: Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.

Authors	Ahern, Elizabeth; Cubitt, Annette; Ballard, Emma; Teng, Michele W L; Dougall, William C; Smyth, Mark J; Godbolt, David; Naidoo, Rishendran; Goldrick, Amanda; Hughes, Brett G M
Journal	Trials
Pages	753
Volume	20
Date	1/12/2019
Grant ID
Funding Body	Metro North Hospital and Health Service (Queensland, Australia)
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1186/s13063-019-3951-x
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