avelumab 治疗既往治疗的转移性 Merkel 细胞癌患者：来自单臂 2 期 JAVELIN Merkel 200 试验的长期数据和生物标志物分析。
Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
机构信息
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
出版信息
J Immunother Cancer. 2020 May;8(1). doi: 10.1136/jitc-2020-000674.
BACKGROUND
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti-programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab.
METHODS
In a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses.
RESULTS
As of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4-49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred.
CONCLUSIONS
Avelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease.
TRIAL REGISTRATION NUMBER
NCT02155647.
背景
默克尔细胞癌（MCC）是一种罕见的侵袭性皮肤癌，转移风险高。2017 年，avelumab（抗程序性死亡配体 1（PD-L1））成为首个被批准用于转移性 MCC（mMCC）患者的治疗药物，基于部分患者出现持久缓解。在此，我们报告接受avelumab 治疗的 mMCC 患者的长期疗效和安全性数据及探索性生物标志物分析。
方法
在这项单臂、二期临床试验（JAVELIN Merkel 200）的一个队列中，既往化疗后疾病进展的 mMCC 患者接受avelumab 10mg/kg 每 2 周静脉输注。主要终点为独立审查根据实体瘤反应评价标准 1.1 版（RECIST v1.1）确认的客观缓解率（ORR）。其他评估包括缓解持续时间、无进展生存期、总生存期（OS）、安全性和生物标志物分析。
结果
截至 2018 年 9 月 14 日，88 例患者中位随访时间为 40.8 个月（范围 36.4-49.7 个月）。ORR 为 33.0%（95%CI 23.3%至 43.8%），包括 11.4%（10 例）的完全缓解，缓解持续时间中位数为 40.5 个月（95%CI 18.0 个月至不可估计）。截至 2019 年 5 月 2 日（≥44 个月随访），中位 OS 为 12.6 个月（95%CI 7.5 至 17.1 个月），42 个月 OS 率为 31%（95%CI 22%至 41%）。可评估 PD-L1 表达状态的长期生存者（OS>36 个月，n=22）中，81.8%的患者为 PD-L1+肿瘤。在探索性生物标志物分析中，高肿瘤突变负荷（每兆碱基≥2 个非同义体细胞变异）和高主要组织相容性复合体 I 表达（30%的肿瘤表达最高）与 ORR 和 OS 改善趋势相关。在长期安全性评估（≥36 个月随访）中，未报告新的或意外的不良事件，也未发生与治疗相关的死亡。
结论
avelumab 为 mMCC 患者提供了持续持久的缓解和有意义的长期生存结果，证实了 avelumab 作为该疾病的标准治疗选择。
试验注册
NCT02155647。
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