Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Trials. 2019 Dec 19;20(1):753. doi: 10.1186/s13063-019-3951-x.
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.
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.
The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer.
Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.
针对免疫检查点程序性死亡受体-1（PD-1）的新辅助免疫疗法正在各种肿瘤治疗领域进行研究，包括非小细胞肺癌（NSCLC）。临床前模型表明，与辅助（术后）相比，新辅助（术前）免疫疗法在消除转移性疾病和诱导持久的抗原特异性免疫方面具有更强的效果。在肿瘤学领域，广泛寻求新型有效的免疫治疗组合，针对免疫逃逸的非冗余机制。在 NSCLC 中，与抗 PD-1 联合使用的一种有前途的组合伙伴是 denosumab，一种阻断核因子-κB 配体（RANKL）受体激活剂的单克隆抗体。在临床前癌症模型和 NSCLC 的大型回顾性病例系列中，已经报道了免疫检查点抑制（ICI）和 denosumab 联合治疗的抗癌活性。此外，ICI 和 denosumab 的临床试验正在晚期黑色素瘤和透明细胞肾细胞癌中进行。然而，联合使用抗 PD-1 和抗 RANKL 的作用机制尚未明确。
本开放标签、多中心试验将通过最小化法将 30 名可切除的 IA 期（原发灶>2cm）至 IIIA 期 NSCLC 患者随机分为新辅助治疗组，每组 15 名患者，接受以下两种治疗方案之一：nivolumab（3mg/kg，每 2 周一次）两剂或 nivolumab（相同方案）加 denosumab（每 2 周一次，每次 120mg，继 nivolumab 之后）。每个治疗组的规模相等，在组织学（鳞状 vs. 非鳞状）和临床分期（I-II 期 vs. IIIA 期）方面大致平衡。所有患者在新辅助治疗最后一剂后 2 周内接受肿瘤手术。主要终点是定义与单药治疗相比联合治疗的肿瘤免疫相关性的转化研究。关键次要终点包括比较每个治疗组之间以下各项的发生率：毒性、反应（病理和影像学）和显微镜下完全切除。
POPCORN 研究为确定新型拟议联合免疫疗法治疗癌症的作用机制提供了一个独特的转化研究平台。
于 2018 年 7 月 6 日在澳大利亚和新西兰临床试验注册中心（ACTRN12618001121257）进行前瞻性注册。
