派姆單抗商品名為Keytruda，俗稱「PD-1」是當前世界矚目的新一類抗癌免疫療法使用藥品，由默沙東公司開發，是美國FDA批准的第一個PD-1免疫檢測點抑製劑。

派姆單抗是一個人源化單克隆抗體，它阻斷PD-1和其配體，PD-L1和PD-L2間相互作用。PD-1配體，PD-L1和PD-L2，與T細胞上發現的PD-1受體的結合，抑制T細胞增殖和細胞因子的產生。在某些腫瘤中發生PD-1配體的上調和通過這個途徑信號對腫瘤活性的T-細胞免疫監視抑制作用可能有貢獻。派姆單抗結合至PD-1受體和阻斷其與PD-L1和PD-L2相互作用，釋放免疫反應的PD-1通路-介導抑制作用，包括抗-腫瘤免疫反應。

派姆單抗臨床證實在包括肺癌、腎癌、黑色素瘤、頭頸癌、膀胱癌、乳腺癌、肝癌、胃癌、食管癌、腦膠質瘤、結腸癌、霍奇金淋巴瘤等晚期癌症治療方面有顯著療效，有望實質性改善患者生存期。

Ipilimumab是一種單克隆抗體，能有效阻滯一種叫做細胞毒性T細胞抗原-4（CTLA-4）的分子。CTLA-4會影

響人體的免疫系統，削弱其殺死癌細胞的能力。Yervoy的作用機制可能是幫助人體免疫系統識別、瞄準並攻擊黑色素瘤癌細胞。

美國FDA於2011年3月25日批准ipilimumab（商標名稱為Yervoy）用於治療晚期黑色素瘤。其給藥方式是靜脈注射。

《壹篇》按

《柳葉刀》2017年8月16日在線先發

http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)31601-X/fulltext

派姆單抗對比伊匹單抗治療晚期黑色素瘤：一項多中心、隨機化、開放標籤3期研究（KEYNOTE-006試驗）的總生存率的最終結果

背景

3期KEYNOTE-006研究的中期分析顯示，在晚期黑色素瘤患者中派姆單抗對比伊匹單抗的總生存和無進展生存均佔優，現在，我們提供按照研究方案進行的最終生存分析結果。

方法

在這項多中心、開放標籤、隨機化3期臨床試驗中，我們從16個國家（澳大利亞、奧地利、比利時、加拿大、智利、哥倫比亞、法國、德國、以色列、荷蘭、紐西蘭、挪威、西班牙、瑞典、英國和美國）的87家研究所、醫院和癌症中心招募患者。我們採用一種集中由計算機生成的分組方案，隨機將參試者分組（1：1：1）為派姆單抗兩種劑量治療方案之一或伊匹單抗治療方案組。治療分組採用區組隨機化並分層。符合條件的患者為≥18歲、ECOG體能狀況評分0或1分、按照「實體瘤療效評價標準1.1版（RECISTv1.1）」至少有一處可測量病灶、不可手術切除的III或IV期黑色素瘤（剔除眼黑色素瘤）、既往有1次以上的全身治療（除外抗CTLA-4、PD-1、PD-L1藥物）。次要入組標準隨後描述。若患者有活躍的腦轉移或需要全身類固醇激素治療的活躍性自身免疫性疾病，則予以剔除。主要終點為總生存期（自隨機化分組至全因死亡的時間為總生存期）。12周時按照「實體瘤療效評價標準1.1版（RECISTv1.1）」、由獨立的集中審閱進行療效評價，以後每6周評價1次，直至48周，此後每12周評價1次。每12周評價1次生存率，所有患者隨訪至少12個月以後進行終期分析。在意向性治療患者（所有進行了隨機化分組的患者）中進行初步分析，在治療的患者中（所有接受過至少1次研究治療劑量的隨機化分組患者）進行安全性分析。進行分析的數據截止日期為2015年12月3日。本研究已在ClinicalTrials.gov網站註冊，註冊號NCT01866319。

結果

2013年9月18日至2014年3月3日，入組了834名晚期黑色素瘤患者，並將患者隨機分組到每2周靜脈用1次派姆單抗組（n=279）、每3周靜脈用1次派姆單抗組（n=277）、每3周靜脈用1次伊匹單抗組（伊匹單抗4個劑量，n=278）。每2周1次派姆單抗組中有1名患者、伊匹單抗組有22名患者撤回了知情同意而未接受治療。共計811名患者接受了至少1個劑量的研究治療。中位隨訪時間22.9個月，383名患者死亡，2個派姆單抗組的中位總生存期均未達到，伊匹單抗組中位總生存期為16.0個月（每2周1次派姆單抗組對比伊匹單抗組的風險比[HR]0.68，95%CI，0.53-0.87，p=0.0009；每3周1次派姆單抗組對比伊匹單抗組為HR0.68，0.53-0.86，p=0.0008）。2周組24個月時的總生存率為55%、3周組為55%、伊匹單抗組43%。

解釋

派姆單抗對比伊匹單抗總生存佔優，且兩個派姆單抗劑量組之間沒有差異，從而進一步使KEYNOTE-006試驗中期分析結果得到證實。

資助

默克公司.

南南和北北

Pembrolizumab versus ipilimumab for advanced melanoma:final overall survival results of a multicentre, randomised,open-label phase 3 study (KEYNOTE-006)

Background

Interim analyses of the phase 3 KEYNOTE-006 study showedsuperior overall and progression-free survival of pembrolizumabversus ipilimumab in patients with advanced melanoma. We presentthe final protocol-specified survival analysis.

Methods

In this multicentre, open-label, randomised, phase 3 trial, werecruited patients from 87 academic institutions, hospitals, andcancer centres in 16 countries (Australia, Austria, Belgium,Canada, Chile, Colombia, France, Germany, Israel, Netherlands, NewZealand, Norway, Spain, Sweden, UK, and USA). We randomly assignedparticipants (1:1:1) to one of two dose regimens of pembrolizumab,or one regimen of ipilimumab, using a centralised,computer-generated allocation schedule. Treatment assignments usedblocked randomisation within strata. Eligible patients were atleast 18 years old, with an Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1, at least one measurable lesionper Response Evaluation Criteria In Solid Tumors version 1.1(RECIST v1.1), unresectable stage III or IV melanoma (excludingocular melanoma), and up to one previous systemic therapy(excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondaryeligibility criteria are described later. Patients were excluded ifthey had active brain metastases or active autoimmune diseaserequiring systemic steroids. The primary outcome was overallsurvival (defined as the time from randomisation to death from anycause). Response was assessed per RECIST v1.1 by independentcentral review at week 12, then every 6 weeks up to week 48, andthen every 12 weeks thereafter. Survival was assessed every 12weeks, and final analysis occurred after all patients were followedup for at least 21 months. Primary analysis was done on theintention-to-treat population (all randomly assigned patients) andsafety analyses were done in the treated population (all randomlyassigned patients who received at least one dose of studytreatment). Data cutoff date for this analysis was Dec 3, 2015.This study was registered with ClinicalTrials.gov, numberNCT01866319.

Findings

Between Sept 18, 2013, and March 3, 2014, 834 patients withadvanced melanoma were enrolled and randomly assigned to receiveintravenous pembrolizumab every 2 weeks (n=279), intravenouspembrolizumab every 3 weeks (n=277), or intravenous ipilimumabevery 3 weeks (ipilimumab for four doses; n=278). One patient inthe pembrolizumab 2 week group and 22 patients in the ipilimumabgroup withdrew consent and did not receive treatment. A total of811 patients received at least one dose of study treatment. Medianfollow-up was 22·9 months; 383 patients died. Median overallsurvival was not reached in either pembrolizumab group and was 16·0months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53–0·87for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68,0·53–0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008).24-month overall survival rate was 55% in the 2-week group, 55% inthe 3-week group, and 43% in the ipilimumab group.

Interpretation

Substantiating the results of the interim analyses ofKEYNOTE-006, pembrolizumab continued to provide superior overallsurvival versus ipilimumab, with no difference betweenpembrolizumab dosing schedules. These conclusions further supportthe use of pembrolizumab as a standard of care for advancedmelanoma.

Funding

Merck & Co.

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