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

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

Neoadjuvant immunotherapy for non-small cell lung cancer: right drugs, right patient, right time?

“…[55][56][57][58][59] Two trials are assessing novel immunotherapy combinations in stage I-IIIA NSCLC patients (combining anti-PD1 with anti-Lag3 or anti-RANKL). 60 61 Three studies are assessing neoadjuvant chemoimmunotherapy in stage III NSCLC patients, and these all include adjuvant ICI treatment postsurgery. [62][63][64] Finally, two trials are assessing a potential role for neoadjuvant immunoradiotherapy in patients with stage III NSCLC, with one of these involving neoadjuvant chemoimmunoradiotherapy and adjuvant ICI.…”

Development of an Immune-Related Risk Signature for Predicting Prognosis in Lung Squamous Cell Carcinoma

“…Some immunotherapies have been utilized to leverage the immune system to fight tumors ( Kobold et al, 2018 ; Popovic et al, 2018 ). Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1, have emerged as an effective therapeutic selection for advanced breast cancer, metastatic melanoma and NSCLC ( Wang et al, 2018 ; Ahern et al, 2019 ; Liu D. et al, 2019 ). NSCLC is characterized by several mutations in the immune system, making it possible that these patients may benefit from immunotherapy.…”

Association of Genetic Polymorphisms in TNFRSF11 with the Progression of Genetic Susceptibility to Gastric Cancer

“…Recently, the RANK/RANKL/OPG system has been observed to play a key role in tumor cell migration and invasion [7][8][9]. Studies have shown that TNFRSF11(RANK) is expressed in a variety of tumor tissues, such as osteosarcoma [10,11], chondrosarcoma [12], breast cancer [13], prostate cancer [14,15], renal cancer [16], oral squamous cell carcinoma [17], lung cancer [18], thyroid cancer [19], and melanoma [20]. However, the expression of TNFRSF11 in gastric cancer cells is rarely reported, and there is no report on the relationship between TNFRSF11 gene polymorphism and gastric cancer.…”