Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
复制标题
DOI：
10.1056/nejmoa1200690
复制
发表时间：
2012-06-28
期刊：
影响因子：
--
通讯作者：
Sznol M
中科院分区：
文献类型：
--
作者：
Topalian SL;Hodi FS;Brahmer JR;Gettinger SN;Smith DC;McDermott DF;Powderly JD;Carvajal RD;Sosman JA;Atkins MB;Leming PD;Spigel DR;Antonia SJ;Horn L;Drake CG;Pardoll DM;Chen L;Sharfman WH;Anders RA;Taube JM;McMiller TL;Xu H;Korman AJ;Jure-Kunkel M;Agrawal S;McDonald D;Kollia GD;Gupta A;Wigginton JM;Sznol M
阻断T细胞表达的抑制性受体PD-1可以克服免疫抵抗。我们评估了BMS-936558的抗肿瘤活性和安全性，该抗体是一种特异性阻断PD-1的抗体。我们招募了晚期黑色素瘤、非小细胞肺癌、去势耐受前列腺癌、肾细胞癌或结直肠癌的患者接受抗PD-1抗体，剂量为每公斤体重0.1至10.0毫克，每两周一次。在每个8周的治疗周期后评估疗效。患者接受最多12个周期，直到疾病进展或完全缓解。截至2012年2月24日，共有296名患者接受治疗。14%的患者发生了与药物有关的3级或4级不良事件；有3人死于肺部毒性。没有定义最大耐受剂量。观察到与免疫相关原因一致的不良事件。在236例可以评估疗效的患者中，非小细胞肺癌、黑色素瘤或肾癌患者的客观反应(完全或部分反应)被观察到。非小细胞肺癌患者(76名患者中的14名)、黑色素瘤患者(94名患者中的26名)和肾细胞癌患者(33名患者中的9名)的累积有效率(所有剂量)分别为18%、28%和27%。反应是持久的；在31个反应中，有20个持续了1年或1年以上的随访。为探讨肿瘤内PD-1配体(PD-L1)的表达在PD-1-PD-L1途径调控中的作用，对42例患者的肿瘤标本进行免疫组织化学分析。PD-L1阴性的17例患者中，无一例有客观反应；PD-L1阳性的25例患者中有9例(36%)有客观反应(P=0.006)。抗PD-1抗体在大约四分之一至五分之一的非小细胞肺癌、黑色素瘤或肾癌患者中产生了客观反应；不良事件情况似乎并不妨碍其使用。初步数据表明，肿瘤细胞上PD-L1的表达与客观反应有关。(由百时美施贵宝和其他公司资助；ClinicalTrials.gov编号，NCT00730639。)
Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. We enrolled patients with advanced melanoma, non–small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)