Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
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DOI：
10.1056/nejmoa1200694
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发表时间：
2012-06-28
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影响因子：
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通讯作者：
Wigginton JM
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作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
程序性死亡1(PD-1)蛋白是一种T细胞共抑制受体，其配体PD-L1在肿瘤细胞逃避宿主免疫系统的能力中起着关键作用。阻断PD-1和PD-L1之间的相互作用在体外增强免疫功能，并在临床前模型中介导抗肿瘤活性。在这项多中心的第一阶段试验中，我们给选定的晚期癌症患者静脉注射抗PD-L1抗体(递增剂量从每公斤体重0.3毫克到10毫克)。抗PD-L1抗体在6周周期中每14天注射一次，最多16个周期，或直到患者完全应答或确认疾病进展。截至2012年2月24日，共有207例患者--75例非小细胞肺癌、55例黑色素瘤、18例结直肠癌、17例肾细胞癌、17例卵巢癌、14例胰腺癌、7例胃癌和4例乳腺癌--接受了抗PD-L1抗体治疗。中位疗程为12周(范围2-111周)。研究人员认为与治疗有关的3级或4级毒性反应发生在9%的患者中。在可评估疗效的患者中，52例黑色素瘤患者中有9例客观有效(完全或部分有效)，17例肾细胞癌患者中有2例客观有效，49例非小细胞肺癌患者中有5例客观有效，17例卵巢癌患者中有1例客观有效。在16名患者中，有8名患者的反应持续了一年或更长时间，并获得了至少一年的随访。在包括非小细胞肺癌、黑色素瘤和肾癌在内的晚期癌症患者中，抗体介导的PD-L1阻断可导致持久的肿瘤消退(客观缓解率为6%至17%)和疾病的长期稳定(24周时的缓解率为12%至41%)。(由百时美施贵宝和其他公司资助；ClinicalTrials.gov编号，NCT00729664。)
Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host’s immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non–small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non–small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.)