Department of Surgery and Cardiothoracic Surgery, Amsterdam University Medical Center, location VUmc, Cancer Center Amsterdam, de Boelelaan 1117, 1081HV, Amsterdam, the Netherlands.
Department of Radiation Oncology, Amsterdam University Medical Center, location VUmc, Cancer Center Amsterdam, de Boelelaan 1117, 1081HV, Amsterdam, the Netherlands.
BMC Cancer. 2020 Aug 14;20(1):764. doi: 10.1186/s12885-020-07263-9.
The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28-38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019-003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence.
METHODS/DESIGN: This single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0-1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020. On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets.
The INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0-1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events.
Netherlands Trial Registration (NTR): NL8435 , Registered 03 March 2020.
接受多模态治疗的 T3-4N0-1 期非小细胞肺癌患者肿瘤复发的可能性仍然很大，主要是远处转移。由于在接受放化疗后，仅少数（28-38%）患者的切除标本中出现病理完全缓解（pCR），因此我们设计了 INCREASE 试验（EudraCT-编号：2019-003454-83；荷兰试验登记号：NL8435），以评估在诱导放化疗中加入短程免疫疗法是否可以进一步提高 pCR 率。转化研究将相关性局部和全身免疫状态的变化与复发模式。
方法/设计：这项单臂、前瞻性 II 期试验将纳入 29 例可切除或边缘可切除的 T3-4N0-1 期非小细胞肺癌患者。该方案已获得机构伦理委员会批准。研究招募于 2020 年 2 月开始。在推荐的指南同步放化疗（CRT）的第 1 天，将给予 ipilimumab（IPI，1mg/kg IV）和 nivolumab（NIVO，360mg 平剂量 IV），然后在 3 周后给予 nivolumab（360mg 平剂量 IV）。放射治疗包括每天一次 2Gy，总量 50Gy，化疗将包括铂类双药。在放疗最后一天后 6 周计划进行解剖性肺切除术。主要研究目的是确定在术前 CRT 中添加 IPI/NIVO 的安全性及其对病理肿瘤反应的影响。次要目标是评估在 CRT 中添加 IPI/NIVO 对无病和总生存的影响。探索性目标是描述肿瘤炎症和肿瘤引流淋巴结（TDLN）中的免疫结构，并探索 IPI/NIVO 和 CRT 及手术对周围血免疫亚群分布和表型的影响。
INCREASE 试验将评估在可切除的 T3-4N0-1 期非小细胞肺癌患者中，4 种联合治疗模式的安全性和局部疗效。转化研究将研究作用机制和与药物相关的不良事件。
荷兰试验注册（NTR）：NL8435，于 2020 年 3 月 3 日注册。
