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 the 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 immunotherapy given in the neoadjuvant (pre-operative) compared with 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 a large retrospective case series in NSCLC, anti-cancer activity of combination immune checkpoint inhibition (ICI) and denosumab has been reported. 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 > 2cm) 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 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 two 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.

Neoadjuvant immunotherapy for non–small cell lung cancer: State of the art

“…Multiple clinical studies are evaluating these results [31–33]. The pharmacodynamics of pre‐operative PD1 checkpoint blockade and receptor activator of nuclear factor‐kappa‐b ligand inhibition in NSCLC (POPCORN) trial is providing a unique platform for translational research to (1) determine the mechanism of action of novel combination immunotherapy (PD1 checkpoint blockade and receptor activator of nuclear factor kappa‐B ligand inhibition) for NSCLC and (2) define the tumor‐immune correlation of combination therapy compared with monotherapy [34]. The POPCORN trial may elucidate mechanisms that contribute to the efficacy of neoadjuvant combined immunotherapy against NSCLC.…”

Does denosumab offer survival benefits? —Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors

“…There are multiple clinical trials to investigate the anticancer property of denosumab. In the ongoing phase Ib/ II POPCORN trail, pre-operative nivolumab with and without denosumab is studied in resectable NSCLC (17). In the phase II SPLENDOUR trial in stage IV NSCLC, median OS was 8.7 months in the chemotherapy alone arm versus 8.2 months in the chemotherapy-denosumab arm (18).…”