ASCO-GI 2019:KEYNOTE-181研究亮相2019 ASCO-GI,PD-1单抗首次为晚期食管癌患者带来生存获益!

2019-01-18 肿瘤资讯 肿瘤资讯

食管癌是我国重要的疾病负担之一,新发和死亡患者占全球55%左右。目前,对于晚期食管癌治疗,缺乏有效的治疗手段,患者预后较差,免疫治疗为晚期食管癌带来新的希望。

食管癌是我国重要的疾病负担之一,新发和死亡患者占全球55%左右。目前,对于晚期食管癌治疗,缺乏有效的治疗手段,患者预后较差,免疫治疗为晚期食管癌带来新的希望。KEYNOTE-028研究首次证实了帕博利珠单抗治疗晚期食管癌的疗效和安全性。II期临床研究KEYNOTE-180进一步确认了帕博利珠单抗三线及以上治疗晚期食管癌的持续疗效及可控的不良反应。美国东部时间2019年1月18日, ASCO-GI大会上公布了KEYNOTE-181研究,在更大样本量患者中,确立了帕博利珠单抗治疗晚期食管癌的地位:与标准化疗相比,帕博利珠单抗单药二线治疗PD-L1阳性(CPS≥10)晚期/转移性食管癌或食管结合部腺癌患者,可以显著延长患者的总生存期。未来,免疫联合治疗的开展和疗效预测标志物的探索,有望进一步改善免疫治疗的疗效,使得晚期食管癌长期生存成为可能。

晚期食管癌治疗现状:疗效不佳,手段匮乏

来自GLOBOCAN 2018年的最新全球癌症统计数据显示,食管癌是全球重要的疾病负担之一,每年新发食管癌病例57.2万,死亡50.9万例。其中,东亚地区是全球食管癌发病率最高的地区。2015年全国癌症统计数据显示,中国每年新发食管癌病例25.8万,死亡19.3万例,严重威胁我国人民的健康。我国城市人口食管癌5年生存率仅为18%,且有下降趋势。 

目前,晚期食管癌的治疗仍以化疗为主,然而疗效有限。虽然过去10余年,靶向治疗在食管癌中进行了诸多探索,但大多折戟沉沙,仅曲妥珠单抗获批用于HER2阳性的转移性/食管胃结合部癌、雷莫芦单抗获批用于化疗失败的晚期胃/食管胃结合部腺癌。针对食管癌的靶向治疗多处于临床研究阶段。晚期食管癌的治疗仍存在重重挑战,亟需探寻有效的治疗策略,改善患者的生存状态。 

新兴免疫治疗:为食管癌患者带来希望

近年来,免疫治疗在多个瘤种中遍地开花,取得了诸多进展,其中主要进展集中在PD-1/PD-L1抑制剂,其通过抑制肿瘤细胞上PD-L1与T细胞上PD-1结合,解除对T细胞的抑制,恢复T细胞攻击肿瘤细胞的能力,进而实现肿瘤杀伤作用。免疫治疗为晚期食管癌患者带来了新希望。

帕博利珠单抗是最早进入临床研发的的PD-1抑制剂,也是目前获批适应证最广的PD-1抑制剂。2018年,美国FDA批准帕博利珠单抗治疗PD-L1阳性的复发性局部晚期或转移性胃癌/食管胃结合部腺癌;NCCN指南推荐帕博利珠单抗用于三线治疗PD-L1阳性的食管和食管胃结合部腺癌,对于微卫星高度不稳定(MSI-H)/错配修复基因缺陷(dMMR)型患者,推荐二线治疗。 

2014年启动的KEYNOTE-028研究,食管癌队列入组了PD-L1阳性的晚期食管鳞癌或腺癌/食管胃结合部癌患者23例,给予帕博利珠单抗单药10mg/kg治疗,每2周给药1次,这是帕博利珠单抗在食管癌治疗中的首次尝试。结果显示,帕博利珠单抗治疗的最佳总体缓解率(ORR)达30%,其中鳞癌和腺癌患者ORR分别为28%和40%;52%的患者靶病灶负荷降低;中位缓解持续时间达15个月。生存分析显示,中位总生存期(OS)和中位无进展生存期(PFS)分别达到7个月和1.8个月。帕博利珠单抗的安全性良好,未发生预期外的不良事件。 

KEYNOTE-180研究则纳入了未选择PD-L1表达的既往多线经治的(三线以以上)晚期食管鳞癌或腺癌/食管胃结合部癌患者,予以帕博利珠单抗单药200mg治疗,每3周给药一次,治疗直至2年或PD或不可耐受的不良反应停药。主要研究终点为ORR,次要研究终点为DOR、PFS和OS。其中52%的患者为鳞癌,48%的患者为PD-L1阳性(CPS≥10)。

2018 ASCO公布的1年随访结果显示,帕博利珠单抗治疗的ORR达10%,鳞癌和腺癌的ORR分别为14%和5%。PD-L1阳性(CPS≥10)人群的ORR高于PD-L1阴性(CPS<10)(14% vs 6%)。中位PFS和OS分别为2个月和5.8个月。安全性与在之前研究中类似,不良反应可控。 

基于KEYNOTE-028和KEYNOTE-180研究中帕博利珠单抗显示的食管癌治疗前景,研究者进一步开展了III期KEYNOTE-181研究,在晚期或转移性食管鳞癌或腺癌/Siewert I型食管胃结合部腺癌患者的二线治疗中,头对头比较帕博利珠单抗与研究者选择的化疗。该研究共入组628例患者,按1:1的比例随机分配接受帕博利珠单抗200 mg、每3周1次连续治疗2年,或研究者选择的化疗(包括紫杉醇、多西他赛或伊立替康)。其中鳞癌401例,PD-L1阳性(CPS≥10)的患者222例。主要研究终点为鳞癌患者、PD-L1阳性(CPS≥10)患者和意向性治疗(ITT)人群的 OS。次要终点为PFS、OS和安全性。在本次ASCO GI大会上,Takashi Kojima教授在口头报告专场公布了这项关键性研究的结果。 

数据显示,帕博利珠单抗表现出了相当显著的疗效。OS方面,在PD-L1阳性的患者中,帕博利珠单抗组显著优于化疗组,中位OS达到9.3个月,而化疗组仅为6.7 个月,死亡风险降低31%,差异达到统计学意义(HR 0.69;95% CI 0.52~0.93;P=0.0074);18个月的OS率也更优,为26%,化疗组为11%(图1)。在食管鳞癌患者中,帕博利珠单抗组的OS也有临床意义上的改善,达到8.2个月,化疗组为7.1个月( HR 0.78;95% CI 0.63~0.96;P=0.0095);18个月的OS率两组分别为23%和12%(图2)。在ITT人群中,帕博利珠单抗组的OS较化疗组虽然无统计学差异(中位OS 分别为7.1个月和7.1 个月;HR 0.89;95% CI 0.75~1.05;P=0.0560),但有临床获益的趋势,18个月的OS率分别为18%和10%(图3)。



图1. PD-L1阳性CPS≥患者的总生存(OS) Kaplan–Meier曲线



图2. 食管鳞癌(SCC)患者的总生存期(OS) Kaplan–Meier曲线


图3. 意向性治疗(ITT)人群的总生存期(OS) Kaplan–Meier曲线

ORR方面,帕博利珠单抗组也显著优于化疗组。在PD-L1阳性的患者中,帕博利珠单抗组与化疗组的ORR分别为21.5%和6.1%(P=0.006);食管鳞癌患者中,两组分别为16.7%和7.4%( P=0.0022);在ITT人群中,两组分别为13.1%和6.7%(P=0.0037)(图4)。PD-L1阳性的患者中位持续缓解时间(DOR)帕博利珠单抗组显著长于化疗组(9.3个月和7.7个月,图4),但是在食管鳞癌和ITT人群中,帕博利珠单抗组中位DOR短于化疗组,但考虑到化疗组缓解人数较少,DOR的差异需在之后的研究进一步确认。



图4. PD-L1阳性CPS≥10患者、食管鳞癌(SCC)患者与意向性治疗人群的缓解率和持续缓解时间 

安全性方面,帕博利珠单抗组相比于化疗组,任意级别(64% vs 86%)或 3~5级不良事件 (18% vs 41%) 的发生率更低。帕博利珠单抗组与之前的研究相比,未发现新的不良事件。

KEYNOTE-181研究达到了主要的OS研究终点,这是PD-1单抗首次在食管癌免疫治疗中证实生存获益,验证了帕博利珠单抗在PD-L1阳性晚期食管癌患者中的疗效,且安全性良好,支持该药做为PD-L1阳性转移性食管癌的新的二线标准治疗。 

食管癌免疫治疗的未来:探索联合治疗与生物标志物

免疫治疗在晚期食管癌患者中取得了有前景的研究进展,开启了晚期食管癌免疫治疗新时代。如何进一步提高免疫治疗的疗效、为患者带来更大获益是研究者们进一步思考的问题。免疫治疗与其他治疗手段如化疗、靶向治疗、放疗、免疫与免疫联合,以及寻找免疫治疗有效的生物标志物是未来的研究方向。 

目前已有多项免疫治疗联合其他治疗用于晚期食管癌的研究正在进行中,如评价帕博利珠单抗联合化疗一线治疗的KEYNOTE-590,帕博利珠单抗联合放疗的I期研究NCT02642809以及II期研究NCT02830594,帕博利珠单抗联合曲妥珠单抗或西妥昔单抗的研究,纳武利尤单抗联合伊匹单抗的研究,结果值得期待。而有关生物标志物的研究显示,除PD-L1之外,MSI和肿瘤突变负荷可能是有前景的疗效预测标志物,但尚需临床数据的进一步证实,新的标志物组合亦有待进一步探寻。

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    2019-11-19 quxin068
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    2019-01-20 zhouqu_8
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