派姆单抗降低三期黑色素瘤的复发_黑色素瘤

本文于2018年4月15日发表于AACR网站，翻译仅供参考！

芝加哥---4月14-18日的AACR年会上，KEYNOTE-054/EORTC 1325-MG三期临床试验研究表明，经过一整年的共18剂派姆单抗给药治疗后，三期黑色素瘤病人术后复发率大幅度下降。

该研究同时发布在了新英格兰医学杂志上。

法国维勒瑞夫大巴黎Gustave Roussy癌症中心主任Alexander M. M. Eggermont医学博士告诉我们：“三期黑色素瘤病人在一个或多个局部淋巴结处患有转移性疾病。病人的复发风险决定于患病的淋巴结数量和肿瘤负荷。复发风险高的病人，其一个或多个区域淋巴结呈黑色素转移状态。单个阳性淋巴结，其直径远大于1毫米。”

Eggermont博士表示：“我们很高兴，佐剂派姆单抗可以起到成效。术后一年内，每三周给药一次，每次200毫克，一年18次给药后，肿瘤全切的三期黑色素瘤病人的复发率大大降低。希望美国和欧洲国家的相关政府管理人员能看到这一研究发现，并批准使用派姆单抗作为这类病人的新疗法。

随机分配到派姆单抗组的病人，其术后12个月无复发存活率为75.4%，而随机分配到安慰剂组的病人，这一数字为61.0%。整体来看，派姆单抗组的病人的复发率下降了43%。

FDA分别于2015年10月和2017年12月批准使用ipilumumab (Yervoy)和nivolumab (Opdivo)用于全切高风险三期黑色素瘤病人的术后治疗佐剂。

Eggermont博士和同事们在KEYNOTE-054/EORTC 1325-MG三期临床试验中，对1019名肿瘤全切高复发风险三期黑色素瘤病人进行试验，1:1将他们随机分配至派姆单抗组和安慰剂组，每三周进行一次200毫克的给药，共18次给药（中途如发生复发或产生不可耐受的毒性反应，则立即停止给药）。

取中值1.25年的跟踪观察后，随机派姆单抗组的全部514名病人中有135名病人复发或死亡，随机安慰剂组的全部505名病人中有216名病人复发或死亡。

PD-L1阳性和PD-L1阴性的肿瘤单独分析时，派姆单抗产生的效力相似。在852名带有PD-L1阳性肿瘤的病人中，随机派姆单抗组的病人，其复发率或死亡率相较于随机安慰剂组下降46%。在116名带有PD-L1阴性肿瘤的病人中，随机派姆单抗组的病人，其复发率或死亡率相较于随机安慰剂组下降53%。

Eggermont 博士说：“这次试验的重要点在于随机安慰剂组的病人复发后可获得派姆单抗的治疗。这种跨界的试验设计在黑色素瘤的佐剂试验中是的，我们从中可以分析出派姆单抗的应用是在术后立刻开始比较好，还是在复发发生时开始比较好。”

从Eggermont博士那里还了解到，这项研究的主要不足之处是，目前我们尚需更多时间来判断现阶段得到的防复发的良好效果可以从整体上提高病人的存活率。

这项研究由欧洲癌症研究和治疗组织（EORTC）执行，由默克赞助。Eggermont获得了为科学咨询委员会和数据监督委员会准备的酬谢金，酬谢金出资方为Actelion、Agenus、Bayer、Bristol-Myers Squibb、GlaxoSmithKline、HalioDx、Incyte、ISA Pharmaceuticals、Merck、Merck Serono、Nektar、Novartis、Pfizer和Sanofi。

English Version

Pembrolizumab Reduced the Risk for Recurrence of Stage 3 Melanoma

CHICAGO — A one-year course of 18 doses of pembrolizumab (Keytruda) significantly reduced the risk of recurrence for patients with stage 3 melanoma who were at high risk of recurrence after surgery, according to data from the KEYNOTE-054/EORTC 1325-MG phase III clinical trial, presented at the AACR Annual Meeting 2018, April 14–18.

This study is being published simultaneously in The New England Journal of Medicine.

"Patients with stage 3 melanoma have metastatic disease in one or more regional lymph nodes,"said Alexander M. M. Eggermont, MD, PhD, director general of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France. "A patient’s risk of recurrence depends on the number of lymph nodes affected and the tumor load. Those classified as having a high risk of recurrence have one or more regional lymph nodes with melanoma metastasis. In the case of a single positive node, the diameter must be greater than 1 millimeter."

"We were pleased to see that adjuvant pembrolizumab, given as a flat dose of 200 milligrams every three weeks after surgery for up to a year, which is 18 doses, significantly reduced the risk of recurrence for patients with high-risk stage 3 melanoma that has been completely resected," continued Eggermont. "We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients."

For all the patients randomized to pembrolizumab, the 12-month recurrence-free survival rate was 75.4 percent, compared with 61.0 percent for all those randomized to placebo. Thus, overall, patients randomized to pembrolizumab were 43 percent less likely to have recurrence.

The FDA approved ipilumumab (Yervoy) and nivolumab (Opdivo) for use as an adjuvant treatment for patients with high-risk stage 3 melanoma that has been completely resected in October 2015 and December 2017, respectively.

Eggermont and colleagues enrolled 1,019 patients with stage 3 melanoma who were at high risk of recurrence after complete resection of their tumors in the KEYNOTE-054/EORTC 1325-MG phase III clinical trial. Patients were randomized 1:1 to a flat dose of 200 milligrams of pembrolizumab or placebo every three weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity.

After a median follow-up of 1.25 years, 135 of the 514 patients randomized to pembrolizumab and 216 of the 505 patients randomized to placebo had been diagnosed with recurrent disease or had died.

The benefits of pembrolizumab were similar when patients with PD-L1-positive and PD-L1-negative tumors were analyzed separately. Among the 852 patients with PD-L1-positive tumors, those randomized to pembrolizumab were 46 percent less likely to have a recurrence or death event compared with those randomized to placebo. Among the 116 patients with PD-L1-negative tumors, those randomized to pembrolizumab were 53 percent less likely to have a recurrence or death event.

"An important aspect of this trial is that patients randomized to placebo who have recurrence are offered access to pembrolizumab," said Eggermont. "This cross-over design is unique in the world of adjuvant trials in melanoma and will permit us to analyze if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse."

According to Eggermont, the main limitation of the study is that we need more time before we can determine whether these positive recurrence-free survival results will lead to improvement in overall survival for the patients.

This study was conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and sponsored by Merck. Eggermont has received honoraria for scientific advisory board and data monitoring board functions from Actelion, Agenus, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, HalioDx, Incyte, ISA Pharmaceuticals, Merck, Merck Serono, Nektar, Novartis, Pfizer, and Sanofi.