派姆单抗治疗铂类耐药生殖细胞肿瘤患者的 II 期临床试验：Hoosier Cancer Research Network 研究 GU14-206。

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206.

机构信息

Melvin & Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, USA.

Department of Biostatistics, Indiana University School of Medicine, Indianapolis, USA.

出版信息

Ann Oncol. 2018 Jan 1;29(1):209-214. doi: 10.1093/annonc/mdx680.

DOI:10.1093/annonc/mdx680

PMID:29045540

Abstract

BACKGROUND

Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT.

PATIENTS AND METHODS

Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized.

RESULTS

Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining.

CONCLUSION

This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT.

CLINICAL TRIAL INFORMATION

NCT02499952.

摘要

背景

尽管挽救性标准剂量或高剂量化疗的效果显著，但仍有 15%左右的复发性生殖细胞肿瘤（GCT）患者无法治愈。免疫检查点抑制剂在多种肿瘤类型中产生了显著的缓解作用。我们报告了首例 GCT 患者免疫治疗的研究。

患者和方法

这是一项单臂 II 期试验，研究了帕博利珠单抗 200mg 静脉注射，每 3 周一次，用于治疗复发的 GCT 且无治愈选择的患者。符合条件的患者为年龄≥18 岁，GCT 患者在一线顺铂为基础的化疗后和至少一种挽救方案（高剂量或标准剂量化疗）后进展。对肿瘤和浸润免疫细胞的程序性死亡配体 1（PD-L1）进行中心评估。使用免疫相关反应标准评估总缓解率作为主要终点。采用 I 型错误率为 20%、效能为 80%的西蒙两阶段设计。

结果

共纳入 12 名男性患者。中位年龄为 38 岁。所有患者均为非精原细胞瘤。原发部位为睾丸（11 例）或纵隔（1 例）。中位 AFP 为 615（范围 1-32，760）和 hCG 为 4（范围 0.6-37，096）。6 例患者为晚期复发（＞2 年）。中位化疗方案数为 3 种。6 例患者接受过高剂量化疗。2 例患者 PD-L1 染色阳性（H 评分 90 和 170）。中位帕博利珠单抗剂量为 2（范围 1-8）。发生 6 例 3 级不良事件。未报告免疫相关不良事件。未观察到部分或完全缓解。2 例患者分别获得 28 周和 19 周的影像学稳定疾病，尽管影像学稳定，但 AFP 水平持续升高，且 PD-L1 染色阴性。