Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.
Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.
复制标题
DOI：
10.1016/s1470-2045(16)30364-3
复制
发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Nghiem P
中科院分区：
文献类型：
--
作者：
Kaufman HL;Russell J;Hamid O;Bhatia S;Terheyden P;D'Angelo SP;Shih KC;Lebbé C;Linette GP;Milella M;Brownell I;Lewis KD;Lorch JH;Chin K;Mahnke L;von Heydebreck A;Cuillerot JM;Nghiem P
默克尔细胞癌是一种罕见的侵袭性皮肤癌，晚期患者预后不良。目前的标准治疗使用各种细胞毒性化疗方案，但反应很少持久。肿瘤发生与默克尔细胞多瘤病毒整合和紫外线辐射诱导的突变有关，这为靶向PD-L1/PD-1通路的免疫治疗抗体治疗提供了依据。我们评估了avelumab（一种抗PD-L1单克隆抗体）在细胞毒性化疗后进展的IV期默克尔细胞癌患者中的治疗。在这项多中心、国际、前瞻性、单组、开放标签、II期试验中，从北美、欧洲、澳大利亚和亚洲的35家癌症治疗中心和学术医院入组了IV期化疗难治性、组织学证实的默克尔细胞癌患者（年龄≥18岁）。关键合格性标准为ECOG体力状态评分为0或1分，根据实体瘤疗效评价标准（RECIST）第1.1版确定的可测量疾病，充分的血液学、肝脏和肾脏功能，以及免疫功能状态（排除HIV、免疫抑制、血液学恶性肿瘤和既往器官移植患者）。患者选择不基于PD-L1表达或默克尔细胞多瘤病毒状态。这些评估必须采集活检材料或使用存档组织。Avelumab以每2周10 mg/kg的剂量静脉内给予。主要终点是由独立审查委员会根据RECIST第1.1版评估的经证实的客观缓解（完全缓解或部分缓解）。在所有接受至少一剂研究药物的患者（修改的意向治疗人群）中评估了安全性和临床活性。本试验在ClinicalTrials.gov注册为NCT 02155647。2014年7月25日至2015年9月3日期间，88例患者入组并接受了至少一剂avelumab。患者随访时间中位数为10.4个月（IQR 8.6 - 13.1）。在88例患者中，达到客观缓解的患者比例为28例（31.8%[95.9% CI 21.9 - 43.1]），包括8例完全缓解和20例部分缓解。在分析时，28例患者中有23例（82%）的缓解正在进行中。4例（5%）患者发生5起3级治疗相关不良事件：2例患者发生淋巴细胞减少症，1例患者发生血肌酸磷酸激酶升高，1例患者发生转氨酶升高，1例患者发生血胆固醇升高;无治疗相关4级不良事件或治疗相关死亡。5例患者（6%）报告了严重治疗相关不良事件：小肠结肠炎、输注相关反应、转氨酶升高、软骨钙质沉着症、滑膜炎和间质性肾炎（各n=1）。Avelumab与持久缓解相关，其中大部分仍在持续，并且耐受性良好;因此，avelumab代表晚期默克尔细胞癌的新治疗选择。Merck KGaA，达姆施塔特，德国。
Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Merck KGaA, Darmstadt, Germany.