医学
无容量
肿瘤科
肺癌
内科学
免疫疗法
兰克尔
免疫检查点
新辅助治疗
癌症
受体
乳腺癌
激活剂(遗传学)
作者
Elizabeth Ahern,Annette Cubitt,Emma Ballard,Michele W.L. Teng,William C. Dougall,Mark J. Smyth,David Godbolt,Rishendran Naidoo,Amanda Goldrick,B Hughes
出处
期刊:Research Square - Research Square
日期:2019-12-02
标识
DOI:10.21203/rs.2.11812/v2
摘要
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.
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