根据Naiyer A.Rizvi博士在2014ASCO年会上报告的KEYNOTE-001Ib期研究结果，抗PD-1人源化抗体pembrolizumab (MK-3475) 作为晚期PD-L1阳性非小细胞肺癌（NSCLC）患者的一线治疗药物，有稳健的抗肿瘤作用。

研究方法

研究对84位进行了PD-L1筛选，其中73位患者符合可评估活检标本的标准。在这些患者中，57位（78%）患者被认为是PD-L1阳性。45位患者符合使用pembrolizumab治疗的资格标准，其中42位患者可通过RECIST v1.1标准进行评估。

肿瘤活检样本PD-L1染色应用22C3抗体和原型分析来完成。肿瘤依靠≥1%肿瘤细胞表现出PD-L1表达，或肿瘤基质应用同一试剂出现任何阳性染色来归类为阳性。对同一组织样本进行肿瘤细胞百分比分析，肿瘤细胞百分比采用PD-L1细胞膜染色并进行临床试验法，同样应用22C3。

将在之前未接受转移性NSCLC系统治疗、肿瘤表达PD-L1的患者随机接受pembrolizumab每2或3周 10 mg/kg治疗，直到疾病出现进展。前11位患者随机接受每3周2 mg/kg 和10 mg/kg 。

疗效

“80%的患者肿瘤负担有一定程度的减少，”纪念斯隆-凯特林癌症中心、胸科癌症服务部、肿瘤科医师Rizvi 说道。“在2mg/kg和10 mg/kg剂量水平和2周及3周服药日程均可观察到作用。”

在2014年3月3日数据截止日，RECIST测得总体反应率是26%，研究者评估免疫相关反应标准（irRC）测得总体反应率是47%。疾病控制率，定义为完全反应、部分反应和顽固疾病，应用RECIST标准和irRC标准分别测得64%和78%。

按照RECIST标准，中期中位无进展生存期是27周，按照irRC 标准是37周。“这些是早期数据，其中56%的患者在数据截止日仍在进行治疗，”Rizvi说道。

在中期分析中，RECIST 或 irRC标准平均反应间期均没有达到随访36周的平均反应间期。总体上，根据RECIST 标准100%的患者、根据irRC 标准90%的患者持续对治疗有反应，分别有64%和86%的患者仍在进行治疗。

在接受治疗的45位患者中，治疗时间平均为154天（平均循环数=9）。最小随访期为18周，18%的患者因为不良事件而中断研究，其中仅有2例被认为是治疗相关（1位为3级肺炎，1位为2级急性肾损伤），16%的患者因为射线性疾病进展而中断研究，11%的患者因研究者或患者选择而中断研究，剩下25位患者（56%）在数据截止日时仍在接受治疗。

安全性

发生的治疗相关性不良事件，>5%的频率均为1/2级。最常见的治疗相关性不良事件是疲劳（22%）、皮肤瘙痒（13%）、甲状腺功能减退症（9%）、痤疮样皮炎(7%)、腹泻（7%）、呼吸困难（7%）和皮疹（7%）。有集3种 3/4级治疗相关性不良事件于一身的病例：一例患者患4级血肌酸激酶增高、3级心包积液和3级肺炎。

Pembrolizumab 是一种高度选择性拮抗PD-1的人源性IgG4-κ同型性抗体，目的是通过T细胞阻断PD-1受体的负性免疫调节信号。它释放出PD-1途径的双配体(PD-L1 和PD-L2) 阻断物。将高亲和性大鼠和人PD-1抗体的多变性区域序列联合稳定Fc替代序列移植到人源性G4免疫球蛋白中。“Ig4免疫球蛋白亚型并不能结合Fc受体或活化补体，避免了锚定到本应活化T细胞抗体的细胞毒性效应，” Rizvi 说道。 

III 期KEYNOTE-024研究打算在2014年9月开始招募。本项试验将会比较pembrolizumab单一治疗与铂类双药化疗作为一线治疗PD-L1阳性转移性NSCLC患者的疗效。

编译自：Pembrolizumab Induces Robust Responses in PD-L1-positive NSCLC.OncLive,June 6,2014.

医脉通整理报道，转载请注明出处。

会议专题》》》2014年ASCO年会专题报道

阅读英文摘要

Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC).(Abstract No:8007)

Authors: Gargi Dan Basu, Anatole Ghazalpour,Barbara A.Pockaj,et al.

Session Type: Oral Abstract Session

Background: Programmed death-1 (PD-1) receptor-ligand interaction inhibits T cell activation against tumor cells. MK-3475 is a potent and highly selective humanized monoclonal antibody against PD-1 designed to directly block its interaction with its ligands, PD-L1 and PD-L2, thus removing the inhibition of T cell activation against cancer. MK-3475 led to prolonged anti-tumor activity in previously treated NSCLC patients. This Phase I study evaluated the safety, tolerability, and clinical activity of MK-3475 as initial therapy in patients with locally advanced or metastatic NSCLC. 

Methods: Patients with no prior systemic therapy for metastatic disease whose tumors expressed PD-L1 by a preliminary immunohistochemical assay were randomized to MK-3475 10 mg/kg every 2 or 3 wks (Q3W). The first 11 patients were randomized to 2 mg/kg and 10 mg/kg Q3W. At least 1 measurable tumor lesion, ECOG performance status of 0 to 1, adequate organ function and adequate tumor biopsy were required for enrollment. Prior adjuvant therapy was allowed if it preceded relapse by at least a year. Tumor response was assessed every 9 weeks until confirmed disease progression per immune related response criteria (irRC; investigator review); RECIST 1.1 by independent central review will also be performed. 

Results: 84 patients submitted tissue for PD-L1 assessment and 57 patients had tumors that expressed PD-L1. Between Feb 2013 and Oct 2013, 45 patients started treatment (n=6 2Q3W, n=23 10Q3W, n=16 10Q2W). Preliminary data indicate an ORR (confirmed and unconfirmed) of 36% (67% 2 mg/kg Q3W, 27% 10 mg/kg Q3W, 35% 10 mg/kg Q2W) by irRC. 25 patients (55%), including all but 2 responders, remain on treatment (treatment duration from 12+ to 48+ wks). 52% of patients experienced a drug-related adverse event (AE), usually grade 1-2 in severity, most commonly fatigue (14%), pruritus (8%), dermatitis acneiform (6%), diarrhea (6%) and dyspnea (6%). There was a single drug-related grade 3-5 AE, a grade 3 pericardial effusion. 

Conclusions: These data suggest that MK-3475 is generally well-tolerated and provides robust antitumor activity in a first-line setting in patients with locally advanced or metastatic NSCLC that expresses PD-L1. Clinical trial information: NCT01295827.