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.

Keywords: Denosumab; Immunotherapy; Lung cancer; NSCLC; Neoadjuvant; Nivolumab; PD1; RANKL.

Fig. 1

SPIRIT schedule of enrolment, interventions and assessments. ECG electrocardiogram, ECOG PS Eastern Cooperative Oncology Group Performance Status, CT computed tomography, FDG-PET fluorodeoxyglucose-position emission tomography, CBC complete blood count, U&E urea and electrolytes, LFT liver function test, TFT thyroid function test, PBMC peripheral blood mononuclear cells, AE adverse events, MPR major pathological response, Rx treatment, OS overall survival, PFS progression-free survival

Fig. 2

CONSORT diagram of the POPCORN study

Fig. 3

POPCORN study schema. NSCLC non-small cell lung cancer, i.v. intravenous, s.c. subcutaneous

Fig. 4

Translational research schedule for collection of POPCORN trial biospecimens. Figure acknowledgements: FFPE by Librepath - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=45097146; scalpel by Petit B - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=41650124