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).

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-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.

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: Elizabeth Ahern, Annette Cubitt, Emma Ballard, Michele W L Teng, William C Dougall, Mark J Smyth, David Godbolt, Rishendran Naidoo, Amanda Goldrick, Brett G M Hughes
• Journal: Trials (Trials) Vol. 20 Issue 1 Pg. 753 (Dec 19 2019) ISSN: 1745-6215 [Electronic] England
• PMID: 31856909 (Publication Type: Clinical Trial Protocol, Journal Article)

Chemical References

• Antineoplastic Agents, Immunological
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• RANK Ligand
• TNFSF11 protein, human
• Nivolumab
• Denosumab

Topics

• Adult
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (immunology, mortality, pathology, therapy)
• Chemotherapy, Adjuvant
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Denosumab (pharmacology, therapeutic use)
• Female
• Humans
• Lung (drug effects, pathology, surgery)
• Lung Neoplasms (immunology, mortality, pathology, therapy)
• Male
• Margins of Excision
• Multicenter Studies as Topic
• Neoadjuvant Therapy (methods)
• Neoplasm Staging
• Nivolumab (pharmacology, therapeutic use)
• Pneumonectomy
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Progression-Free Survival
• RANK Ligand (antagonists & inhibitors)