Pharmacodynamics of Pre-Operative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC): study protocol for a multicentre, open-label, phase 1B/2, translational trial (POPCORN)

• Published in: Current controlled trials in cardiovascular medicine Vol. 20; no. 1; p. 753
• Main 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19-12-2019; BMC
• Subjects: Antibodies; Antigens; Cancer therapies; Chemotherapy; Denosumab; Drug dosages; Histology; Immunotherapy; Kidney cancer; Ligands; Lung cancer; Lymphocytes; Melanoma; Metastasis; Monoclonal antibodies; NSCLC; Patients; PD1; Pharmacodynamics; RANKL; Skin cancer; Steroids; Study Protocol; Surgery; Survival analysis; Targeted cancer therapy; Tomography; RANKL; NSCLC; Immunotherapy; Lung cancer; Nivolumab; Neoadjuvant; Denosumab; PD1
• ISSN: 1745-6215; 1745-6215
• DOI: 10.1186/s13063-019-3951-x

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-κB 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.
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.
The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer.
Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.