新英格蘭醫學雜誌：納武單抗聯合伊匹單抗治療肺癌優於化療

PD-1抑制劑， 包括PD-1抗體、PD-L1抗體， 單獨使用的有效率偏低；但是一旦起效， 療效相對十分持久， 甚至部分晚期癌症患者可以實現臨床治癒，

長期生存。 學術界已經開發出眾多的預測標誌物， 如：PD-L1表達、TMB檢測、MSI檢測、dMMR檢測、TIL檢測、甚至腸道菌群分析等。

TMB， 全稱為“腫瘤基因突變負荷”（tumor mutational burden）， 代表的是患者腫瘤組織中到底有多少個基因突變。 腫瘤組織中突變的基因越多， 就越有可能產生更多的異常蛋白質；這些異常蛋白質， 就越有可能被免疫系統識破， 從而啟動人體的抗癌免疫反應， 因此對腫瘤免疫治療的療效就越好。 人體中每一個細胞， 大約有3萬多個基因， 每個基因都有可能發生多種多樣的突變（點突變、缺失突變、插入突變、融合突變、重複突變等）。 目前已有越來越多的證據顯示， 尤其是美國最大的基因檢測公司Foundation Medicine的科學家做的相關研究顯示， 只要對人體3萬多個基因中的數百個有代表性的基因做深入分析，

相當於抽樣調查， 就可以大致反應總體情況。 因此， 目前國內外的公司基本採用的都是各自設計出來的數百個基因的一個套裝， 這數百個基因恰好可以用來指導靶向藥的選擇， 又可以用來作為抽樣調查的標本， 從而推算出患者TMB的高低， 用每百萬個堿基所含有的突變個數來度量。 一般認為：TMB超過20個突變/Mb（Mb代表的就是每百萬個堿基）， 就是腫瘤基因突變負荷高；低於10個突變/Mb， 就是腫瘤基因突變負荷低。 目前已經公佈的各大常見腫瘤接受PD-1抑制劑治療的有效率， 和TMB大小幾乎是線性關係。 TMB越大， PD-1抑制劑有效率越高。 TMB高低和PD-L1表達沒有關係。 PD-L1低的患者， 不要灰心， 可以再測一下TMB；TMB低者， 也不要灰心， 可以再測一下PD-L1；這兩個檢測只要有一個有好消息， 都是可以酌情考慮接受PD-1抑制劑治療的（當然， 具體病情， 具體分析）。

CheckMate-032、checkmate227、checkmate568試驗證實了TMB檢測的高選擇性。

《壹篇》吳永勇按

《新英格蘭醫學雜誌》2018年4月16日線上先發

DOI: 10.1056/NEJMoa1801946

納武單抗聯合伊匹單抗治療高腫瘤突變負荷肺癌

背景

在一項1期臨床試驗中， 納武單抗（Nivolumab）聯合伊匹單抗（Ipilimumab）治療非小細胞肺癌（NSCLC）顯示出良好的療效， 且腫瘤突變負荷已成為判斷患者是否獲益的潛在生物標誌物。 在一項開放標籤、包含多部分的3期臨床試驗的這個部分中， 我們在高腫瘤突變負荷（≥10個突變/百萬個堿基）患者中， 檢測了納武單抗聯合伊匹單抗對比化療的無進展生存期。

方法

我們入組了既往未化療過的IV期或復發性非小細胞肺癌患者。

將那些腫瘤程式性死亡配體1（PD-L1）表達水準≥1％的患者按1：1：1的比例隨機分組， 一組接受納武單抗聯合伊匹單抗治療， 一組接受納武單抗單藥治療， 一組接受化療；將那些腫瘤PD-L1表達水準＜1％的患者按1：1：1的比例隨機分組， 一組接受納武單抗聯合伊匹單抗治療， 一組接受納武單抗+化療， 一組接受化療。 通過FoundationOne CDx檢測確定腫瘤突變負荷。

結果

在高腫瘤突變負荷患者中， 納武單抗聯合伊匹單抗治療的無進展生存期顯著長於化療。 納武單抗聯合伊匹單抗組1年無進展生存率為42.6％， 對比化療組為13.2％， 中位無進展生存期為7.2個月（95％置信區間[CI]， 5.5-13.2）對比5.5個月（95％CI， 4.4-5.8）（疾病進展或死亡風險比， 0.58；97.5％CI， 0.41-0.81；P<0.001）。 納武單抗聯合伊匹單抗組客觀緩解率為45.3％， 對比化療組為26.9％。

納武單抗聯合伊匹單抗比化療獲益在各個亞組中大體一致， 包括PD-L1表達水準≥1％的患者和＜1％的患者。 納武單抗聯合伊匹單抗組3、4級治療相關不良事件率為31.2％， 化療組36.1％。

結論

無論PD-L1表達水準如何， 納武單抗聯合伊匹單抗一線治療高腫瘤突變負荷的非小細胞肺癌患者， 無進展生存期顯著長於化療。 結果證實， 納武單抗聯合伊匹單抗在非小細胞肺癌中獲益， 並證實了腫瘤突變負荷作為患者選擇的一種生物標誌物的作用。 （由Bristol-Myers Squibb和Ono Pharmaceutical資助， CheckMate 227在ClinicalTrials.gov上的編號， NCT02477826）。

《壹篇》吳永勇

April 16, 2018

DOI: 10.1056/NEJMoa1801946

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

BACKGROUND

Nivolumab plus ipilimumab showed promising efficacy for the treatment of non–small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).

METHODS

We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.

RESULTS

Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy.

CONCLUSIONS

Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.)

《壹篇》（與微信公眾號“桓興醫訊”同步）系主要面向醫務人員的公益性頭條號，不以營利為目的，不進行任何有償和無償諮詢服務，不出售任何產品，與ASCO、CSCO等所有專業學會和機構沒有任何關係和聯繫，也不代表任何官方學會發聲。歡迎轉載，以讓更多的專業人員瞭解醫學前沿進展。

文章圖片均來自網路，不做商業用途，若有版權爭議請與《壹篇》聯繫。

堅持點贊、讚賞和轉發是一種態度和支持。

April 16, 2018

DOI: 10.1056/NEJMoa1801946

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

BACKGROUND

Nivolumab plus ipilimumab showed promising efficacy for the treatment of non–small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).

METHODS

We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.

RESULTS

Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy.

CONCLUSIONS

Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.)

《壹篇》（與微信公眾號“桓興醫訊”同步）系主要面向醫務人員的公益性頭條號，不以營利為目的，不進行任何有償和無償諮詢服務，不出售任何產品，與ASCO、CSCO等所有專業學會和機構沒有任何關係和聯繫，也不代表任何官方學會發聲。歡迎轉載，以讓更多的專業人員瞭解醫學前沿進展。

文章圖片均來自網路，不做商業用途，若有版權爭議請與《壹篇》聯繫。

堅持點贊、讚賞和轉發是一種態度和支持。