納武單抗（Nivolumab，商品名Opdivo），一種由百時美施貴寶公司研製的單克隆抗體，是程序性死亡受體（PD-1）阻斷劑，Nivolumab與PD-1受體相結合並阻斷其與PD-L1、PD-L2的相互作用，用於黑素瘤等多種腫瘤的抗腫瘤免疫應答研究中。至2015年10月，FDA已批准其單用或聯用易普單抗（ipilimumab，商品名Yervoy）用於黑色素瘤的治療。Ipilimumab也是百時美施貴寶公司研製的、阻斷另一個免疫檢查點CTLA-4的單克隆抗體。Nivolumab作為目前最受關注的新一類抗腫瘤藥物，可治療多種類型的腫瘤，能夠實質性提高客觀響應率，其通過結合PD-1並阻斷腫瘤細胞內部PD-1通路對T細胞的抑制作用，同時聯用ipilimumab抑制CTLA-4對T細胞的負調控作用，共同增強活化T細胞，攻擊腫瘤，這種治療手段是目前免疫治療的研究熱點之一。從發表在各種國際頂級醫學期刊的一系列臨床試驗結果可以看出，大型跨國醫藥企業一直快速在佔領著抗腫瘤藥物研發的制高點，培養著一代代腫瘤醫學領域的各色專家和大咖，影響著腫瘤診療的各種指南，多麼高明的營銷策略！

《壹篇》按

《新英格蘭醫學雜誌》2017年9月11日在線先發

http://www.nejm.org/doi/full/10.1056/NEJMoa1709684

納武單抗聯合易普單抗對晚期黑色素瘤總生存的影響

Jedd D. Wolchok, M.D., Ph.D., Vanna Chiarion-Sileni, M.D., Rene Gonzalez, M.D., Piotr Rutkowski, M.D., Ph.D., Jean-Jacques Grob, M.D., C. Lance Cowey, M.D., Christopher D. Lao, M.D., M.P.H., John Wagstaff, M.D., Dirk Schadendorf, M.D., Pier F. Ferrucci, M.D., Michael Smylie, M.D., Reinhard Dummer, M.D., Andrew Hill, M.D., David Hogg, M.D., John Haanen, M.D., Matteo S. Carlino, M.D., Oliver Bechter, M.D., Ph.D., Michele Maio, M.D., Ph.D., Ivan Marquez-Rodas, M.D., Ph.D., Massimo Guidoboni, M.D., Grant McArthur, M.D., Celeste Lebbé, M.D., Ph.D., Paolo A. Ascierto, M.D., Georgina V. Long, M.B., B.S., Ph.D., Jonathan Cebon, M.B., B.S., Ph.D., Jeffrey Sosman, M.D., Michael A. Postow, M.D., Margaret K. Callahan, M.D., Ph.D., Dana Walker, M.D., M.S.C.E., Linda Rollin, Ph.D., Rafia Bhore, Ph.D., F. Stephen Hodi, M.D., and James Larkin, F.R.C.P., Ph.D.

September 11, 2017DOI: 10.1056/NEJMoa1709684

背景

在一項涉及晚期黑色素瘤患者的3期臨床試驗中，納武單抗（Nivolumab,Opdivo）聯合易普單抗（Yervoy,Ipilimumab）較單用易普單抗，可以明顯延長無進展生存期、提高客觀緩解率，現在我們報告這項臨床試驗的3年總生存結果。

方法

我們按1：1：1的比例，將既往未治療過的晚期黑色素瘤患者隨機分組，一組接受劑量為1mg/公斤體重的納武單抗+劑量為3mg/公斤體重的易普單抗，每3周給4個劑量，隨後每2周給一次劑量3mg/公斤體重的納武單抗；一組每2周接受一次劑量為3mg/公斤體重的納武單抗+安慰劑；一組每3周接受4次劑量每次劑量為3mg/公斤體重的易普單抗+安慰劑；這3組均在有腫瘤進展、出現不可接受的毒性作用或撤銷試驗的知情同意時，停用試驗藥物。按照程序性死亡配體1（PD-1）情況、BRAF突變情況和轉移分期情況進行隨機化分層。兩個主要終點為納武單抗+易普單抗組、納武單抗組對比易普單抗組的無進展生存和總生存。

結果

最少隨訪36個月時，納武單抗+易普單抗組未達到中位總生存期、納武單抗組中位總生存期為37.6個月，而易普單抗組為19.9個月（納武單抗+易普單抗組對比易普單抗組的死亡風險比為0.55[P<0.001]，納武單抗組對比易普單抗組的死亡風險比為0.65[P<0.001]）。納武單抗+易普單抗組3年總生存率為58%、納武單抗組52%、易普單抗組34%。自最初的報告以來，安全性問題沒有變化。納武單抗+易普單抗組有59%的患者出現3、4級治療相關性不良事件，納武單抗組有21%，易普單抗組有28%。

結論

在晚期黑色素瘤患者中，用納武單抗+易普單抗聯合治療或單用納武單抗治療比單用易普單抗，總生存期明顯延長。

南南和北北

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Jedd D. Wolchok, M.D., Ph.D., Vanna Chiarion-Sileni, M.D., Rene Gonzalez, M.D., Piotr Rutkowski, M.D., Ph.D., Jean-Jacques Grob, M.D., C. Lance Cowey, M.D., Christopher D. Lao, M.D., M.P.H., John Wagstaff, M.D., Dirk Schadendorf, M.D., Pier F. Ferrucci, M.D., Michael Smylie, M.D., Reinhard Dummer, M.D., Andrew Hill, M.D., David Hogg, M.D., John Haanen, M.D., Matteo S. Carlino, M.D., Oliver Bechter, M.D., Ph.D., Michele Maio, M.D., Ph.D., Ivan Marquez-Rodas, M.D., Ph.D., Massimo Guidoboni, M.D., Grant McArthur, M.D., Celeste Lebbé, M.D., Ph.D., Paolo A. Ascierto, M.D., Georgina V. Long, M.B., B.S., Ph.D., Jonathan Cebon, M.B., B.S., Ph.D., Jeffrey Sosman, M.D., Michael A. Postow, M.D., Margaret K. Callahan, M.D., Ph.D., Dana Walker, M.D., M.S.C.E., Linda Rollin, Ph.D., Rafia Bhore, Ph.D., F. Stephen Hodi, M.D., and James Larkin, F.R.C.P., Ph.D.

September 11, 2017DOI: 10.1056/NEJMoa1709684

Background

Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial.

Methods

We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group.

Results

At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group.

Conclusions

Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)

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