默沙东Keytruda治疗三阴性乳腺癌扩大标签申请未能获得FDA支持

2021-02-15 网络 网络

2月9日,美国食品和药物管理局(FDA)ODAC专家咨询小组以10票对0票的投票结果一致对默沙东I-O巨星Keytruda的加速批准表示反对,投票通过了“美国FDA应该推迟决定默沙东Key

2月9日,美国食品和药物管理局(FDA)ODAC专家咨询小组以10票对0票的投票结果一致对默沙东I-O巨星Keytruda的加速批准表示反对,投票通过了“美国FDA应该推迟决定默沙东Keytruda(pembrolizumab)在三阴性乳腺癌(TNBC)适应症中寻求扩大标签的申请,直到该公司能够提供更多三期临床试验KEYNOTE-522的数据”。此前默沙东宣布试验取得成功:默沙东宣布PD-1单抗Keytruda治疗三阴性乳腺癌的III期临床成功

这标志着这家制药巨头受到了罕见的冷落,而这一冷落早在周二的会议召开之前就已经明确发出了信号。实际上就在上周,美国FDA的工作人员就对KEYNOTE-522的研究结果进行了否定性的评价,他们对此表示怀疑,并指出无论是研究的设计还是结果都不支持在高危早期TNBC患者的辅助治疗中批准抗PD-1疗法。所有10位小组成员都同意美国FDA的评估,即默克应该等待KEYNOTE-522的更明确的数据。

这项随机试验KEYNOTE-522比较了Keytruda与安慰剂在新辅助治疗时中联合化疗,以及在辅助治疗时中作为单一疗法,在1174例高危早期TNBC患者中的疗效。共同的主要终点是病理完全应答率(pCR)和无事件生存率(EFS),而总生存率(OS)被评估为主要的次要目标。

2019年公布的KEYNOTE-522第一次中期分析数据显示,与单纯化疗相比,Keytruda加入化疗后实现pCR的TNBC患者数量显著增加,比率分别为64.8%和51.2%,治疗差异为13.6%。

最近的中期分析数据显示,Keytruda治疗组和安慰剂组的pCR率分别为63%和55.5%,基于所有随机患者的比率差异“仅为7.5%”。美国FDA专家认为,无论肿瘤PD-L1状态如何,新辅助剂Keytruda的pCR仅显示出“微小改善”,具有“值得怀疑的临床意义”。此外,EFS终点未达到其预先规定的统计显著性阈值,且仍不成熟;OS终点无法正式测试,而且还不成熟。下一次中期分析数据预计将在2021年第三季度公布。

与此同时,美国FDA工作人员还指出,与安慰剂相比,接受Keytruda治疗的患者出现免疫介导的不良事件(AEs)或输液反应的人数更多。此外,接受默沙东药物治疗的患者中有4例死亡。评审人员认为,这可能是由于免疫介导所致的不良事件。”添加Keytruda与免疫介导的AEs增加导致的毒性增加有关,其中一些AEs可能是严重的、不可逆的,并且/或者需要对可能治愈的或者其他健康的患者进行终生药物治疗。

2019年,美国FDA批准罗氏Tecentriq(atezolizumab,阿替利珠单抗)与化疗联合用于PD-L1阳性、不可切除、局部晚期或转移性TNBC的成人患者。Tecentriq在2020年第四季度的销售额为7.23亿瑞士法郎(8.01亿美元),比前一年同期增长了25%。默沙东紧追其后,2020年11月,Keytruda获得了美国FDA对其首个乳腺癌适应症的批准,当时美国FDA批准将其与化疗联合使用,以治疗局部复发、不可切除或转移性TNBC的患者,这些患者的肿瘤表达PD-L1,其综合阳性分为10分或更高。默沙东目前正在寻求拓宽标签,将治疗高危、早期TNBC的患者包括在内,在新辅助治疗中联合化疗,并作为单一药物用于术后辅助治疗。美国FDA已将该适应症审批目标行动日期定为3月29日。

默沙东指出,KEYNOTE-522研究达到了pCR的双重主要临床终点之一。该公司全球临床开发主管罗伊·贝恩斯(Roy Baynes)表示,“尽管公司对今天会议的结果感到失望,但我们相信Keytruda能够帮助满足这些患者尚未得到满足的医疗需求。默沙东对迄今为止的KEYNOTE-522结果‘充满信心’,包括pCR率以及‘令人鼓舞的’临时EFS数据,并且将继续与美国FDA合作审查我们的申请。”

其实在投票之前,领导咨询小组的美国FDA肿瘤卓越中心主任理查德·帕兹杜尔(Richard Pazdur)博士曾亲自告诫过默沙东,因该公司基本上希望并猜测KEYNOTE-522研究在统计上会证明是积极的,所以把加速审批置于数据之前。评审人员说,“美国FDA多次向默沙东表达了对KEYNOTE-522试验设计和结果的担忧,并不鼓励提交这一营销申请。”并且在2016年的一次会议上,该机构曾声明,“提议的pCR率提高15%的目标可能不足以预测早期TNBC患者长期预后的改善。”

就连专家组中的消费者权益倡导者也投了“不通过”票,决定等待更多试验结果,因为他们注意到该治疗方案对患者的毒性程度很高,但其益处尚不确定,对于患者合理希望达到的效果,他们仍然一无所知。

病人代表娜塔莉·波蒂斯(Natalie Portis)表示:“尽管美国FDA表示让我们等待审批完成吧,但我有点困惑,为什么要这么匆忙。”一些专家组成员的观点是,他们需要看到生存益处的“确凿证据”,而不是默沙东提供的预测。

这次投票在许多方面都是一次了不起的会议。ODAC通常会对一种药物进行上下投票——通常会在药品监管机构的热切支持下大力支持开绿灯——而不是要求一家制药公司简单地等待更成熟的数据。这次投票也回避了一个问题,即为什么默沙东会决定加速审批,尽管美国FDA明确指出他们在朝着错误的方向前进。

或许,默沙东已经习惯了用他们的Keytruda/化疗组合取胜,所以选择快速推进,期待着以往经验帮他们冲过审批。相反,随着他们资深的首席问题官(CSO)罗杰·帕尔穆特(Roger Perlmutter)的离开,首席执行官(CEO)肯·弗雷泽(Ken Frazier)即将退休,此次加速审批失败事件似乎标志着一个令人不安的迹象,表明这家世界顶级药品专营公司也面临困惑。

其实默沙东于2020年5月提交了这项申请,远远早于帕尔穆特博士最近退休。默沙东称:“我们之所以提交这项申请,是因为这一患者群体的大量需求没有得到满足,也是因为我们和该领域的其他专家坚信数据的力量。”

原始出处:

1.UPDATED: FDA panel admonishes Merck with a gentle — and rare — slapdown for rushing its pitch on an accelerated OK for adjuvant Keytruda in TNBC

2.Merck & Co. fails to secure FDA panel backing for adjuvant Keytruda in TNBC

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    2021-03-07 ms3000000952102971

    学习新知识

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    2021-02-17 yese
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    2021-02-17 xlysu
  5. [GetPortalCommentsPageByObjectIdResponse(id=2048082, encodeId=774b204808266, content=<a href='/topic/show?id=12e49e53102' target=_blank style='color:#2F92EE;'>#阴性乳腺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97531, encryptionId=12e49e53102, topicName=阴性乳腺癌)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f65b226, createdName=circumcision, createdTime=Sat Aug 28 10:03:22 CST 2021, time=2021-08-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=946252, encodeId=ece8946252a8, content=学习新知识, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=179c5443072, createdName=ms3000000952102971, createdTime=Sun Mar 07 21:36:34 CST 2021, time=2021-03-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1259983, encodeId=bbb612599830d, content=<a href='/topic/show?id=6ff910336054' target=_blank style='color:#2F92EE;'>#默沙东#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103360, encryptionId=6ff910336054, topicName=默沙东)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28d456, createdName=yese, createdTime=Wed Feb 17 11:03:22 CST 2021, time=2021-02-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1458802, encodeId=bcae1458802c9, content=<a href='/topic/show?id=3ef91982030' target=_blank style='color:#2F92EE;'>#三阴性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19820, encryptionId=3ef91982030, topicName=三阴性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a5666112721, createdName=xlysu, createdTime=Wed Feb 17 11:03:22 CST 2021, time=2021-02-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=924786, encodeId=2a0a924e8693, content=好文章!, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Mon Feb 15 20:14:03 CST 2021, time=2021-02-15, status=1, ipAttribution=)]
    2021-02-15 jyzxjiangqin

    好文章!

    0

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