CN112423745A - 波齐替尼与抗-her1抗体、抗-her2抗体或抗-her4抗体的组合物及其使用方法 - Google Patents
波齐替尼与抗-her1抗体、抗-her2抗体或抗-her4抗体的组合物及其使用方法 Download PDFInfo
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- CN112423745A CN112423745A CN201980029655.2A CN201980029655A CN112423745A CN 112423745 A CN112423745 A CN 112423745A CN 201980029655 A CN201980029655 A CN 201980029655A CN 112423745 A CN112423745 A CN 112423745A
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Abstract
本发明提供了一种波齐替尼和抗‑HER1抗体、抗‑HER2抗体或抗‑HER4抗体的组合物(可选地与其他药物一起使用),以及所述组合物在治疗癌症中的应用。
Description
交叉引用
本申请要求2019年3月1日提交的申请号为62/812,656的美国临时申请与2018年6月25日提交的申请号为62/689,282的美国临时申请的优先权,并通过引用将其全部内容合并于此。
技术领域
本公开总体上涉及一种通过向受试者施用药物组合物来治疗癌症的方法,所述药物组合物包括抗-HER1抗体、抗-HER2抗体或抗-HER4抗体与波齐替尼的组合物,可选地进一步包括其他抗癌药物的组合物。
背景技术
表皮生长因子受体(EGFR)家族已知包括4个成员,即HER1/ErbB1(通常称为“EGFR”)、HER2/ErbB2、HER3/ErbB3和HER4/ErbB4。EGFRs通过细胞内信号转导在正常细胞调节中发挥重要作用,这些蛋白质调节细胞的生长、凋亡、迁移、粘附和分化。EGFRs在大多数实体肿瘤细胞中异常过表达或突变,这些受体的超活化触发了复杂的、多层次的相互关联的信号通路网络,包括下游的促丝裂原活化蛋白激酶(MARK)、磷脂酰肌醇-3-激酶/蛋白激酶(PI3K/AKT)和Janus激酶/信号转导子途径以及转录激活子(JAK/STAT)途径,促进癌症的生长、分化、血管生成、转移和耐药性。例如,HER2在大约20%至25%的乳腺癌中过表达,并且作为乳腺癌的预后标志。HER2阳性乳腺癌比HER2阴性亚型具有更高的临床侵袭性和浸润性,与肿瘤生长率增加、早期全身转移和预后不良有关。因此,阻断表皮生长因子受体介导的肿瘤细胞信号通路是一个理想的抗肿瘤作用的靶点。
靶向EGFRs的抗癌药物分为两类:靶向胞外结构域的单克隆抗体和靶向细胞内酪氨酸激酶的小分子药物。单克隆抗体与表皮生长因子受体选择性结合,具有药效好、副作用小的优点。但是,单克隆抗体的缺点是价格昂贵,必须通过注射给药。同时,靶向酪氨酸激酶的小分子药物相对便宜且可口服,并且它们通过选择性地与受体亚型(如EGFR、HER2、HER3或HER4)相互作用或同时与多种受体亚型相互作用而具有良好的药效。
曲妥珠单抗抗体-药物偶联物(T-DM1)是靶向HER2的抗体-药物偶联物的一个实例,将其中的抗体(人源化抗-HER2 lgG1,即曲妥珠单抗)与微管抑制药物DM1(一种美坦新衍生物)通过稳定的硫醚连接体MCC[即4-(N-马来酰亚胺基甲基)环己烷-1-羧酸盐]共价连接。“美坦新偶联物(Emtansine)”是指MCC-DM1配合物。T-DM1被认为是曾接受过曲妥珠单抗和紫杉醇单药治疗或联合用药的HER2阳性转移性乳腺癌患者的单一药物。曲妥珠单抗-DM1偶联物(T-DM1)的结构式如下所示。
波齐替尼(HM781-36B)是专利号为8,188,102的美国专利中描述的一种新型口服不可逆pan-HER抑制剂,通过引用将其全部内容并入本文中。波齐替尼是一种基于喹唑啉的酪氨酸酶激酶抑制剂(结构如下所示),其不可逆地阻断通过酪氨酸酶激酶受体EGFR家族的信号传导,包括HER1(EGFR)、HER2和HER4野生型受体以及具有激活突变的受体。继而抑制过度表达上述受体的肿瘤细胞的增殖。给予波齐替尼可抑制过度表达上述受体的肿瘤细胞的增殖。波齐替尼的化学式如下:1-[4-[4-(3,4-二氯-2-氟苯氨基)-7-甲氧基喹唑啉-6-氧基]-哌啶-1-基]丙-2-烯-1-酮。
近年来,有报道称在EGFR靶向治疗中耐药性的表达会缩短药物的疗效时间。据报道,使用吉非替尼或厄洛替尼治疗的具有EGFR激活突变的非小细胞肺癌(NSCLC)患者在治疗约8至16个月后对该药物产生耐药性,并且观察到约60%的患者由于EGFR T790M突变而产生耐药性(HelenaA.Yu等,Cli.Cancer Res.19(8),2240,2013)。此外,在使用抗体药物曲妥珠单抗治疗的HER2阳性转移性乳腺癌患者中,已知66%至88%的患者由于各种机制表现出原发性耐药或获得性耐药(Alice Chung等,Cli.Breast Cancer 13(4),223,2013)。基于此,尽管EGFR靶向治疗HER2过表达的实体癌具有显著效果,但由于产生原发性耐药和继发性耐药,EGFR靶向治疗剂的疗效无法长期维持,因此其开发受到限制。
胃癌是世界上第五大常见癌症,也是癌症相关死亡的第三大原因。化疗是大多数转移性或复发性胃癌患者的基础疗法。虽然目前还没有普遍接受的化疗方案,但氟嘧啶和铂类药物联合应用是最常用的。一些医生在这种双重组合中加入多西紫杉醇或表阿霉素。然而,出于毒性考虑,三联疗法并不常用。
因此,在治疗EGFR过表达或突变,特别是HER2的实体癌时,迫切需要一种有效的治疗方法来提高疗效并克服耐药性。本发明满足了这种需求。
发明内容
在一个方面,本公开提供了一种治疗受试者癌症的方法,该方法包括向受试者施用有效治疗量的波齐替尼和抗-HER1抗体、抗-HER2抗体或抗-HER4抗体、抗体偶联物或其片段,其中,所述癌症与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关。适宜地,抗-HER2抗体为曲妥珠单抗或其药物偶联物,如恩美曲妥珠单抗(T-DM1)。该方法还可进一步包括施用紫杉醇、顺铂、5-氟尿嘧啶、长春瑞滨、西妥昔单抗或其任意组合的至少一种。该方法适用于非小细胞肺癌、乳腺癌、胃癌、结肠癌、胰腺癌、前列腺癌、骨髓瘤、头颈癌、卵巢癌、食管癌和转移性细胞癌等癌症。这些癌症可能是原发性或继发性的。适宜地,所述治疗癌症的方法针对患有乳腺癌、肺癌或胃癌的受试者。适宜地,所述乳腺癌包括转移性乳腺癌。适宜地,所述治疗癌症的方法针对患有胃癌的受试者,优选为HER2阳性胃癌的受试者,更优选为曾接受过一种或多种化疗药物治疗的HER2阳性胃癌受试者。
在另一方面,本公开提供了一种治疗受试者乳腺癌的方法,其中所述乳腺癌与HER1、HER2、HER4或HER2突变体的过表达或扩增有关,其中所述方法包括a)在21天(±3天)周期内的步骤,i)单剂量给予标准剂量的抗-HER2抗体或其偶联物,例如T-DM1;及ii)给予每日剂量的波齐替尼;及b)可选择地重复所述周期。适宜地,通过静脉(IV)输注给予T-DM1。适宜地,T-DM1标准剂量为0.5~10mg/kg。适宜地,T-DM1的剂量为3.6mg/kg。适宜地,波齐替尼的给药方式为口服。波齐替尼的口服剂量为0.5~50mg/d。
在另一方面,本公开提供了一种改善正在接受与HER2或HER2突变体的过表达或扩增有关的乳腺癌治疗的受试者发生不良事件的方法,所述方法包括a)在21天(±3天)周期内,i)单剂量给予T-DM1;和ii)给予每日剂量的波齐替尼;和b)可选地重复所述周期。
本公开的另一方面提供了一种治疗受试者癌症的组合物,其中所述癌症与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关,并且所述组合物包括有效治疗量的波齐替尼和T-DM1,其中,波齐替尼口服给药,T-DM1通过静脉输注给药。
通过阅读以下详细描述,本公开的进步和优点对于本领域的普通技术人员来说是显而易见的。虽然治疗癌症的方法和药物组合物易受各种形式的实施例的影响,但下文的描述包括具体实施例,应当理解,这些实施例是说明性的,并不旨在将本发明限定于此。
附图说明
图1a和图1b示出了I期和II期结合的患者的中位无进展生存期曲线(1a)和中位总生存期曲线(1b);
图2a和图2b:图2a示出了I期和II期结合的靶标病变肿瘤直径的最佳百分比变化的瀑布图(2a);图2b仅显示了II期的瀑布图;
图3示出了实施例3中第Ⅱ期无进展生存期累计条形图(Swimmerplot),治疗持续时间:[(根据事件发生或最后一次给药日期)-首次给药日期+1]/(365.25/52)。如果没有采集最后给药日期,则使用研究结束日期。最佳总体反应率(BOR)显示在每个研究持续时间栏的右侧。[]:确定的BOR。如未指定,BOR与确定的BOR相同。
具体实施方式
定义
如本文所公开的,本公开提供了许多范围值。应理解的是,除非上下文另有明确规定,否则该范围值的上限和下限之间的每个介于下限单位的十分之一的中间值都是具体公开的。在所述范围内的任何所述值或中间值与所述范围内的任何其它所述值或中间值之间的每个较小范围均应包括在本发明中。这些较小范围的上限和下限可以独立地包括或排除在所述范围内,并且只包括一个限值、两个限值都不包括或两个限值都包括的较小范围也在本发明范围内,但受所述范围内任意具体排除的限值限制。在所述范围包括一个或两个限值的情况下,排除其中一个或两个限值的范围也包括在本发明中。
如本文所用,术语“约”通常是指所述数字的正负10%。例如,“约10%”可能表示9~11%的范围,“约20”可能表示18~22。从上下文来看,“约”的其他含义可能是显而易见的,例如四舍五入,因此,例如“约1”也可以表示0.5~1.4。如本文所使用的,术语“和/或”包括一个或多个所列相关项目的任一个及所有组合。“至少一个”之类的表达在元素列表前面时,修饰整个元素列表,而不是修饰列表中的单个元素。当提及给药方案时,术语“天”、“每天”等是指一个日历日内从午夜开始到下一个午夜结束的时间。
本文所用术语“治疗”或“诊治”及其任何衍生物是指治疗疗法。就某一特定病症而言,治疗是指:(1)改善或预防一种或多种生物学表现的病症,(2)干扰(a)导致所述疾病或导致所述疾病的生物级联中的一个或多个点,或(b)所述疾病的一种或多种生物学表现,(3)减轻与所述疾病或其治疗相关的一种或多种症状、作用或副作用,或(4)减缓病情的进展或减缓病症的一种或多种生物学表现。因此,预防性治疗也在考虑之中。技术人员会意识到“预防”不是一个绝对的术语。在医学中,“预防”应理解为预防性给药,以大幅降低某一疾病或其生物表现的可能性或严重性,或延迟该疾病或其生物表现的发生。例如,当受试者被认为具有发展成癌症的高风险时,如当受试者有很强的癌症家族史或当受试者接触过致癌物时,预防性治疗是适宜的。
如本文所用,术语“有效治疗量”是指将引起组织、系统、动物或人的生物或医学反应的药物或药剂的量,所述生物或医学反应是由诸如研究人员或临床医生所寻求的。此外,术语“有效治疗量”是指与未接受该量的相应受试者相比,能够治疗、治愈、预防或改善疾病、紊乱或副作用,或降低疾病或紊乱的进展速度的任何剂量。该术语还包括在其范围内有效地增强正常生理功能的剂量。本领域技术人员使用常规方法容易确定具体剂量。
本文所使用的术语“联合应用”是指有效治疗量的组成药物同时给药或以任何方式单独顺序给药。优选地,如果不是同时给药,则在彼此接近的时间内给予药物。适宜地,两种药物在约24、约12、约11、约10、约9、约8、约7、约6、约5、约4、约3、约2或约1小时内给予。如本文所用,当波齐替尼和T-DM1的给药间隔小于大约45分钟时被认为是同时给药。
如本文所用,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理上与受试者和活性组分相容的载体和/或赋形剂。药学上可接受的载体包括但不限于pH调节剂、表面活性剂、佐剂和离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲溶液;表面活性剂包括但不限于阳离子、阴离子或非离子表面活性剂,例如吐温-80;离子强度增强剂包括但不限于氯化钠。
如本文所用,“有需要的受试者”指患有与HER1、HER2或HER4或其任何突变体的过表达相关的病症或疾病的受试者或患者,其将受益于施用包括波齐替尼及抗-HER1抗体、抗-HER2抗体或抗-HER4抗体的药物(例如曲妥珠单抗或其药物偶联物如T-DM1)的药物组合物。这些受试者特别包括那些患有HER2阳性乳腺癌、转移性HER2阳性乳腺癌或HER2阳性胃癌的患者。适宜的,癌症可以为原发性乳腺癌,也就是说,起源于乳腺的癌症。或者癌症可能是继发性的,比如转移性乳腺癌,也就是说,癌细胞从乳腺开始转移到继发性部位。适宜地,治疗癌症的方法针对患有胃癌的受试者,优选为HER2阳性胃癌的受试者,更优选为曾施用过一种或多种化疗药物的HER2阳性胃癌受试者。
如本文所使用的术语“野生型”在本领域是可以理解的,其是指在未经遗传修饰的天然群体中出现的多肽或核苷酸序列。也如本领域所理解的,“突变体”包括与分别存在于野生型多肽或核苷酸序列中的相应多肽或核苷酸序列相比,至少对氨基酸或核酸进行一次修饰的多肽或核苷酸序列,突变体一词包括单核苷酸多态性(SNP),与最常见的(野生型)核酸序列相比,在核酸序列中存在单个碱基对的差异。通过已知的方法可鉴定出HER1、HER2或HER4的野生型或突变型;HER1、HER2或HER4基因扩增;HER1、HER2或HER4蛋白过表达的癌症。
如本文所用,术语“抗体”是指通常由两对多肽链(每对含有一条轻链(L)和一条重链(H))组成的免疫球蛋白。抗体轻链可分为κ轻链或λ轻链。重链可分为μ、δ、γ、α或ε,抗体的同型分别定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链中,可变区和恒定区通过一个含有大约12个或更多个氨基酸的“J”区连接,并且重链还包括一个具有大约3个或更多个氨基酸的“D”区。每个重链由一个重链可变区(VH)和一个重链恒定区(CH)组成。重链由3个结构域(CH1、CH2和CH3)组成。每个轻链由一个轻链可变区(VL)和一个轻链恒定区(CL)组成。抗体的恒定区域可介导免疫球蛋白与宿主组织或因子结合,包括免疫系统的各种细胞(如效应细胞)和经典的补体系统的第一组分。
如本文所用,术语“抗原结合片段”是指含有全长抗体片段的多肽,该片段保留特异性结合全长抗体所结合的相同抗原的能力,和/或与全长抗体竞争以特异性结合所述抗原。
药物组合物
根据本公开,所述药物组合物包括波齐替尼和抗-HER1抗体、抗-HER2抗体或抗-HER4抗体或其抗原片段。适宜地,抗体选自曲妥珠单抗、西妥昔单抗、HER 4抗体、MA1-861、HFR1、H4.77.16、抗原片段或其组成的组合。适宜地,所述抗体选自曲妥珠单抗、西妥昔单抗或恩美曲妥珠单抗(T-DM1),并包含波齐替尼或其任何药学上可接受的盐。药学上可接受的盐可包括但不限于无机酸盐或有机酸盐。无机酸盐包括例如盐酸、氢溴酸、硫酸、二硫酸、硝酸、磷酸、高氯酸盐或溴酸的盐;有机酸盐可包括例如甲酸、乙酸、丙酸、草酸、琥珀酸、苯甲酸,柠檬酸、马来酸、丙二酸、苹果酸、酒石酸、葡萄糖酸、乳酸、扁桃酸、乙醇酸、丙酮酸、戊二酸、抗坏血酸、棕榈酸、羟基马来酸、羟基苯甲酸、苯乙酸、肉桂酸、甲磺酸、苯磺酸、甲苯磺酸、乙二磺酸、孕三烯酸、富马酸、乳糖酸、水杨酸、邻苯二甲酸、双羟奈酸、天冬氨酸、谷氨酸、迷迭香酸、苯水杨酸或乙酰水杨酸(阿司匹林)的盐。
给予有效治疗量的本发明药物组合物优于单独的药物组分,因为与单独给予有效治疗量的药物组分相比,所述组合物提供了以下一种或多种改善;i)比活性最强的单一药物组分具有更好的抗癌效果,ii)协同或高度协同的抗癌活性,iii)提供可增强抗癌活性,并减少副作用的给药方案,iv)毒性作用的降低,v)治疗窗口的增加,vi)一种或多种组分化合物的生物利用度增加,或vii)与单个组分化合物相比细胞凋亡增加。
本发明还涉及波齐替尼与抗-HER2抗体或其抗原结合片段的组合物或波齐替尼与所述抗体部分的偶联物在制备试剂盒中的用途,其中,试剂盒用于在向患者给予有效量的组合物之前检测样本中HER2的存在或水平。该试剂盒可选地包括检测患者生物样本中HER2或HER2水平的说明书。
组合物用药施用方法
几种恶性肿瘤,包括肺癌、乳腺癌、胃癌、结肠直肠癌、头颈癌和胰腺癌,都与EGFR受体家族成员的突变或过表达有关。波齐替尼针对此类癌症具有治疗作用,包括肺癌、胃癌、乳腺癌和头颈癌。
本公开还提供了治疗癌症的方法,包括向有需要的受试者施用所述的药物组合物。适宜地,向有需要的受试者给予有效治疗量的波齐替尼和抗-HER2抗体的药物组合物,所述抗-HER2抗体识别具有高达0.1nmol/L的抗原亲和力常数的HER2胞外结构域表位。适宜地,抗-HER2抗体是人源化单克隆抗体,如曲妥珠单抗,其识别HER2胞外结构域IV的近膜表位,抗原亲和力常数可高达0.1nmol/L。适宜地,所述抗体识别位于第Ⅳ节的C端的由3个环(557~561,570~573和593~603)组成的表位。适宜地,所述抗体可以是人源化双特异性抗HER2抗体或其双特异性抗原结合片段,所述抗体包括一个含有曲妥珠单抗重链和轻链可变区的抗原结合位点,和另一个含有重链和轻链可变区的抗原结合位点。双特异性抗体优选识别HER2胞外结构域IV和II。适宜地,所述抗体可以是嵌合(小鼠/人)单克隆抗体,例如西妥昔单抗。
适宜地,药物组合物是波齐替尼和恩美曲妥珠单抗(T-DM1)的组合。波齐替尼的给药剂量为0.1~50mg。T-DM1可按每千克患者体重0.5~10mg的剂量给予。优选地,以每千克体重1.5~5.5mg的量给予T-DM1。该组合物可进一步包括口服紫杉醇。
可替代地,抗体是西妥昔单抗,一种表皮生长因子受体(EGFR)抑制剂,用于治疗转移性结肠癌、转移性非小细胞肺癌和头颈癌。西妥昔单抗是一种通过静脉输注给药的嵌合(小鼠/人)单克隆抗体,其商品名为ErbituxTM,在美国和加拿大由百时美施贵宝制药公司销售,在美国和加拿大以外由默克制药公司销售。在日本,默克公司、百时美施贵宝公司和礼来公司联合推广销售。作为波齐替尼/T-DM1组合物的另一种制剂,西妥昔单抗可按100~500mg/m2体表面积给药。
长春瑞滨(NVB),以NavelbineTM为商品名销售,是一种用于治疗包括乳腺癌和非小细胞肺癌在内的多种癌症的化疗药物。通过静脉注射或口服给药。长春瑞滨属于长春花生物碱类。在不受任何特定理论约束的情况下,长春瑞滨被认为是通过破坏微管的正常功能从而阻止细胞分裂而起效。作为波齐替尼/T-DM1组合物的另一种制剂,长春瑞滨可按0.5~50mg/m2体表面积给药。
紫杉醇(PTX),以TaxolTM为商品名销售,是一种用于治疗包括卵巢癌、乳腺癌、肺癌、卡波西肉瘤、宫颈癌和胰腺癌在内的多种癌症的化疗药物。通过静脉注射给药。作为波齐替尼/T-DM1组合的另一种制剂,紫杉醇可按100~300mg/m2体表面积给药。
适宜地,波齐替尼和T-DM1的组合可以进一步包括有丝分裂抑制剂。有丝分裂抑制剂可选自BT-062、HMN-214、甲磺酸艾日布林、长春地辛、EC-1069、EC-1456、EC-531、长春夫利(vintafolide)、2-甲氧基雌二醇、GTx-230、克罗利布林(crolibulin)、D1302A-美登木素生物碱缀合物、IMGN-529、莫星-洛沃妥珠单抗(lorvotuzumab mertansine)、SAR-3419、SAR-566658、IMP-03138、拓扑替康/长春新碱组合物、BPH-8、氟布巴坦三甲胺(fosbretabulin tromethamine)、雌莫司汀磷酸钠、长春新碱、长春氟宁、长春瑞滨、RX-21101、卡巴他赛、STA-9584、长春花碱、埃博霉素A、帕图匹隆(patupilone)、伊沙匹隆、埃博霉素D、紫杉醇、多西紫杉醇、DJ-927、盘状皮内酯(discodermolide)、五加素及其药学上可接受的盐或其组合物。例如,该组合物可进一步包括紫杉烷、长春花生物碱或其组合物。长春花生物碱可以选自长春花碱、长春新碱、长春地辛、长春瑞滨及其组合中的至少一种。紫杉烷可以是紫杉醇或多西紫杉醇。适宜地,波齐替尼和T-DM1的组合可进一步包括紫杉醇或长春瑞滨。优选地,波齐替尼和T-DM1的组合还包括紫杉醇。
适宜地,波齐替尼和T-DM1的组合可进一步包括mTOR抑制剂。mTOR抑制剂可选自佐他莫司、乌米罗莫司(umirolimus)、坦罗莫司、西罗莫司、西罗莫司纳米晶TM(NanoCrystalTM)、西罗莫司透皮制剂TM(TransDermTM)、西罗莫司-PNP、依维莫司、biolimusA9、地磷莫司、雷帕霉素、TCD-10023、DE-109、MS-R001、MS-R002、MS-R003、Perceiva、XL-765、奎纳克林、PKI-587、PF-04691502、GDC-0980、dactolisib、CC-223、PWT-33597、P-7170、LY-3023414、INK-128、GDC-0084、DS-7423、DS-3078、CC-115、CBLC-137、AZD-2014、X-480、X-414、EC-0371、VS-5584、PQR-401、PQR-316、PQR-311、PQR-309、PF-06465603、NV-128、nPT-MTOR、BC-210、WAY-600、WYE-354、WYE-687、LOR-220、HMPL-518、GNE-317、EC-0565、CC-214、ABTL-0812及其药学上可接受的盐或其组合物。例如,波齐替尼与T-DM1的组合物可进一步包括雷帕霉素。雷帕霉素可以是注射剂的形式。雷帕霉素,又称西罗莫司,是一种由吸水链霉菌产生的化合物。雷帕霉素可以0.5~10mg/m2的体表面积给药。
适宜地,波齐替尼和T-DM1的组合物可进一步包括抗代谢物。抗代谢物可选自卡培他滨、5-氟尿嘧啶、吉西他滨、培美曲塞、甲氨蝶呤、6-巯基嘌呤、克拉屈滨、阿糖胞苷、多西氟丁、氟尿苷、氟达拉滨、羟基脲、达卡巴嗪、羟基脲和天冬酰胺酶。例如,波齐替尼与T-DM1的组合物可进一步包括5-氟尿嘧啶。5-氟尿嘧啶可以是注射剂的形式。5-氟尿嘧啶可按100~3000mg/m2体表面积给药。
5-氟尿嘧啶(5-FU),以AdrucilTM为商品名销售,其是一种用来治疗癌症的嘧啶类似物。静脉注射给药,用于治疗结肠癌、食管癌、胃癌、胰腺癌、乳腺癌和宫颈癌。作为外用乳膏,用于基底细胞癌。其作用机制还不完全清楚,但是,在不受到任何特定理论约束的情况下,它被认为与阻断胸苷酸合成酶的作用有关,从而阻止DNA的复制。
适宜地,波齐替尼和T-DM1的组合物可进一步包括铂类抗肿瘤药物。铂类抗肿瘤药物可选自顺铂、卡铂、双环铂、依铂、洛铂、米铂、奈达铂、奥沙利铂、甲啶铂和赛特铂。例如,波齐替尼/T-DM1组合物可进一步包括顺铂。顺铂可以是注射剂的形式。顺铂可按1~100mg/m2体表面积给药。不被任何特定的理论所束缚的情况下,顺铂的部分作用是通过与DNA结合,从而抑制DNA复制来实现的。
给予人有效治疗量的本发明组合物。通常,本发明药物制剂的有效治疗量取决于许多因素,例如,受试者的年龄和体重、需要治疗的具体病情、病情的严重程度、制剂的性质和给药途径。最终,有效治疗量将由主治医师决定。
适宜地,在每个治疗周期中同时或依次给予所述化合物。当不同时给药时,它们都在约24、约12、约11、约10、约9、约8、约7、约6、约5、约4、约3、约2或约1小时内给药,在这种情况下,指定的时间段约为24、约12、约10、约9、约8、约7、约6、约5、约4、约3、约2或约1小时。如本文所用,对于双组分药物组合物,例如波齐替尼和T-DM1,波齐替尼和T-DM1的给药间隔不超过45分钟被认为是同时给药。
适宜地,在至少1天、至少2天、至少3天、至少5天、至少7天、至少14天、至少21天或至少30天的每个治疗周期中,在指定的时间内施用两种化合物,在这种情况下,治疗周期的持续时间至少为1、2、3、5、7、14、21或30天。如果在治疗过程中,两种化合物都在规定的时间内给药超过30天,则该治疗被视为长期治疗,并一直持续到出现变更事件,例如癌症状态的重新评估或患者病情的改变,或一个或多个严重的不良反应,需要对方案进行调整。
适宜地,在治疗过程中,例如波齐替尼和T-DM1的药物组合物,两种组分药物在规定的时间段内至少给药1天,然后单独给予波齐替尼至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28或29天,因此,在本实施例中,所述治疗周期最少为2~30天。适宜地,治疗周期为21天±3天。适宜地,治疗周期为21天。
同样,本文构想休药期或停药期,所述休药期或停药期在依次施用波齐替尼和另一种药物组分中的一种,与施用另一种药物之间。如本文所用,休药期(停药期)是在连续给予波齐替尼布和另一种药物组分中的一种之后,在另一种药物给药之前,没有给予波齐替尼或其他组分的一段时间。适宜地,休药期选自以下的天数:1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天和14天。
应理解的是,每个治疗周期之后可以是一个或多个重复给药周期,或者可以是一个替代给药方案,并且在重复给药或替代给药方案之前进行休药期。
如果受试者患有HER2外显子20突变型乳腺癌,HER2外显子20突变可包括HER2框内外显子20插入突变、HER2外显子20点突变,或两者兼有。HER2框内外显子20插入突变可以选自A775_G776insYVMA、G776_V777insVC、P780_Y781insGSP及其组合。HER2外显子20突变可选自L775S、G776V、V777L及其组合。HER2外显子20突变不是T790M点突变。
野生型或突变型HER1、HER2和HER4肿瘤细胞可通过DNA扩增和测序技术、DNA和RNA检测技术(包括但不限于分别应用Northern和Southernblot)、和/或各种生物芯片和阵列技术或原位杂交进行鉴定。野生型和突变型多肽可通过多种技术检测,包括但不限于免疫诊断技术,如ELISA、Westernblot或免疫细胞化学。
优选地,所述方法包括向有需要的受试者给予含有波齐替尼和T-DM1的药物组合物,以及任选的其它化疗剂。优选地,所述化疗剂包括紫杉醇。
适宜地,对患者进行HER1、HER2或HER4状态的评估。本领域技术人员应当理解,本文所述的药物组合物的每日用量将由医生在合理的医学范围内判断决定。任何特定患者的具体用量将取决于多种因素,包括所治疗的癌症类型及其严重程度;药物组合物中波齐替尼活性;所使用的特定药物组分;有需要的受试者的年龄、体重、一般健康状况、性别以及饮食;给药时间:每次给药的规定剂量;治疗的持续时间;组合物中的药物或与所使用的特定药物组合物的联合用药;以及医学领域中公知的类似因素。
例如,以低于达到预期治疗效果所需剂量开始,并逐渐增加剂量以达到预期的治疗效果,在本领域技术人员的技能范围内。适宜地,与单独接受标准剂量的波齐替尼或抗-HER1抗体、抗-HER2抗体或抗-HER4抗体的受试者相比,接受本组合物的受试者的毒性得以降低。适宜地,降低的毒性与心脏毒性的降低有关,如肌钙蛋白I升高至超出测定的正常范围上限(URL)的99%以上,或任何3级心血管毒性。适宜地,降低的毒性与血液毒性的降低有关。例如,与接受单独药物治疗的受试者相比,接受联合用药治疗的受试者的血小板与中性粒细胞减少的比率有统计学上的改善。
适宜地,接受联合用药治疗的受试者在发生非流变性毒性如腹泻、皮疹、粘膜炎、疲劳、电解质或肝毒性方面表现出改善和有利的下降率。
本发明的另一方面涉及一种治疗受试者癌症的方法,所述方法包括向所述受试者给予有效治疗量的波齐替尼和抗-HER1抗体、抗-HER2抗体或抗-HER4抗体,其中癌症与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关。该方法还可包括给予紫杉醇、顺铂、5-氟尿嘧啶、长春瑞滨、西妥昔单抗或其任意组合中的至少一种药物。抗体优选为从曲妥珠单抗、西妥昔单抗或其任意抗原结合片段组合中选择的抗-HER2抗体。癌症可以为非小细胞肺癌、乳腺癌、胃癌、结肠癌、胰腺癌、前列腺癌、骨髓瘤、头癌、颈癌、卵巢癌、食管癌或转移性细胞癌。
在至少一个实施例中,治疗癌症的方法针对患有乳腺癌或胃癌的受试者。
适宜地,该方法的目标癌症为乳腺癌,其中乳腺癌选自:(i)雌激素受体阴性乳腺癌,HER1和/或HER2过表达;(ii)雌激素受体和孕酮受体双阳性乳腺癌,HER2表达,但没有过表达;(iii)曲妥珠单抗耐药乳腺癌,HER2过表达;和(iv)三阴乳腺癌,PR、HER2和雌激素受体阴性,HER1过表达。乳腺癌宜为转移性乳腺癌。所述方法还可包括从受试者收集乳腺癌细胞;评估乳腺癌细胞以确认HER2的过表达、HER2突变体的过表达、HER2的扩增或HER2突变体的扩增。适宜地,评价步骤包括免疫组织化学(IHC)和证实性荧光原位杂交(FISH),其中IHC可以是IHC3+或IHC2+。
在一个实施例中,治疗癌症的方法针对患有胃癌的受试者,优选为HER2阳性胃癌的受试者,更优选为曾施用一种或多种化疗药物的HER2阳性胃癌受试者。
本发明的另一方面涉及一种治疗有需要的受试者乳腺癌的方法,其中乳腺癌与HER2的过表达或扩增或HER2突变体的过表达或扩增有关,所述方法包括a)在21天(±3天)周期内,i)单剂量给予T-DM11.5~5.5mg/kg;ii)每日给予波齐替尼0.5~50mg/d;和b)可选地重复所述周期。适宜地,通过静脉(IV)输注给予T-DM1。适宜地,T-DM1标准剂量为3.6mg/kg。适宜地,波齐替尼可口服,口服剂量可选自6、8、10、12、16和24mg,每日一次。
本发明的另一方面涉及一种改善正在接受与HER2或HER2突变体的过表达或扩增相关的乳腺癌治疗的受试者发生不良事件的方法,所述方法包括a)在21天(±3天)周期内,i)单剂量给予T-DM1;ii)给予每日剂量的波齐替尼;和b)可选地重复所述周期,其中不良事件选自心脏毒性、血液毒性、腹泻、皮疹、粘膜炎、疲劳、电解质异常和肝毒性。
本发明的另一方面涉及一种用于治疗受试者癌症的组合物,其中所述癌症与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增相关,并且该组合包括有效治疗量的波齐替尼和T-DM1,其中,波齐替尼口服给药,T-DM1静脉输注给药。该组合物可进一步包括通过静脉(IV)输注给予有效治疗量的紫杉醇。
本发明的另一方面涉及一种在有需要的受试者中治疗胃癌的方法,其中胃癌与HER2的过表达或扩增、或HER2突变体的过表达或扩增相关,并且所述方法包括以下步骤:a)在21天(±3天)周期内;i)单剂量给予曲妥珠单抗6~8mg/kg;ii)单剂量给予紫杉醇105~175mg/m2;iii)每日给予波齐替尼4~16mg/d;b)可选择地重复上述周期。优选在第1天通过静脉(IV)输注给予曲妥珠单抗。优选地,曲妥珠单抗的标准剂量为8mg/kg负荷量,然后再输注6mg/kg。紫杉醇优选在第1天通过静脉(IV)输注给药。紫杉醇标准剂量优选为175mg/m2。波齐替尼口服14±3天,口服剂量选自4、6、8、10、12和16mg,每日一次。波齐替尼给药14天后的适宜休药期为7天。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1:HER2阳性乳腺癌的治疗方法
通常,鉴定出患有乳腺癌的女性患者,进行基线成像,获取乳腺组织进行肿瘤基因分型,患者经历基于肿瘤分型的治疗期,评估治疗方案并选择性地继续或调整。
通过免疫组织化学(IHC)标记IHC3+或IHC2+,通过荧光原位杂交(FISH)确认患者存在HER2过表达或基因扩增肿瘤。IHC测试提供了0到3+的分数,用于测量乳腺癌组织样本中细胞表面HER2受体蛋白的数量。如果得分为0到1+,则该组织样本被认定为“HER2阴性”;如果得分为2+,则该组织样本被认定为“临界”;得分为3+的组织样本被认定为“HER2阳性”
患者按21天±3天周期进行治疗,第1天静脉滴注3.6mg/kg T-DM1,第1~21天口服波齐替尼,剂量为每天6mg、8mg、10mg、12mg或16mg。可以口服波齐替尼高剂量(每天24mg)给药,但给药方案包括1周的休药期。在第1~14天给予24mg/d,然后在21天周期的第15~21天休药一次。重复21天的周期至疾病有进展、死亡或发生不可忍受的不良事件(AE)。
对晚期或转移性HER2阳性乳腺癌患者进行1b期开放标签多中心研究,以确定在给予标准剂量的T-DM1时,波齐替尼的最大耐受剂量(MTD)或最大给药剂量(MAD)。本研究第1部分中确定的波齐替尼剂量与第2部分中的T-DM1标准起始剂量(每个21天周期的第1天静脉注射3.6mg/kg)结合使用,以进行疗效评估。
因此,本研究的第一部分是剂量测定。第一组开始时口服8mg波齐替尼,并在每个周期的第1天与标准起始剂量的T-DM1(3.6mg/kg静脉注射)联合应用,随后每天口服8mg波齐替尼。根据“3+3”设计,基于当前剂量组第I周期内剂量限制性毒性(DLT)的发生,进行波齐替尼剂量增减。
DLT是指在第一个治疗周期内发生的任何与治疗相关的毒性:
心脏毒性:
肌钙蛋白I升高至超出检测的正常范围或超出任何3级心血管毒性的参考上限(URL)的99%
血液毒性:
3级血小板减少伴出血;
4级中性粒细胞减少>7天或3级发热性中性粒细胞减少症
非血液毒性:
3级或3级以上腹泻,持续时间>3天,或伴有高于100.5°F(38.1℃)的发热至少2天或严重脱水;
4级皮疹或粘膜炎;
级3级或3级以上疲劳至少1周;
根据海氏定律的肝毒性证据(ALT或AST≥3×ULN,总胆红素>2×ULN,无病毒性肝炎、肝病或肝转移;有肝转移的患者,持续时间≥14天ALT或AST>8×ULN或AST或ALT>5×ULN;
持续时间>72小时的≥3级电解质异常,除非患者有临床症状,在这种情况下,所有≥3级的电解质异常,无论持续时间长短,都应算作DLT;与胰腺炎症状或临床表现无关的≥3级淀粉酶或脂肪酶升高不需要计为DLT;
其他任何≥3级与治疗相关的非血液学毒性;
因未明确的潜在疾病或外部原因而死亡的。
毒性评估是基于不良事件的等级,使用美国国家癌症研究所(NCI)国际常见不良反应标准(CTCAE)4.03版进行。
在第1b期第1部分中,与T-DM1(3.6mg/kg静脉注射)联合应用的波齐替尼在每个周期的起始剂量采用“3+3”设计确定,从8mg/天开始最多测试3个剂量水平。根据当前剂量组第I周期中剂量限制性毒性(DLT)的发生情况,对下一个剂量组进行波齐替尼剂量增减。完成第I周期的患者,继续按该组剂量进行治疗,直到停止治疗。四个可能的剂量组包括8、10和12mg/d的波齐替尼,加上6mg/d的波齐替尼减少剂量组。
在1b期研究的第2部分中,大约有10例患者进行MTD/MAD治疗,以确定联合用药的安全剂量,并评估初步疗效。所有患者的治疗一直持续到疾病有进展、不可接受的毒性或研究认为继续治疗对患者无益。
在每个21天的周期中,有资格参与的患者接受指定剂量的波齐替尼,口服,每天一次,并于每天早晨大约同一时间连续服用一杯水和早餐。在每个治疗周期的第1天,静脉注射3.6mg/kg的T-DM1。在给予T-DM1的当天,在输注结束后依次给予波齐替尼。
3个治疗周期后,每隔9周±14天评估一次肿瘤的缓解情况。
实施例2:HER2阳性乳腺癌的治疗方法、剂量方案、疗效和安全性/耐受性
根据第II周期、开放标签多中心研究制定剂量方案,并评估波齐替尼对HER2阳性转移性乳腺癌(MBC)患者的初步疗效和安全性/耐受性,这些患者至少接受过包括曲妥珠单抗和T-DM1两种HER2的定向治疗方案。波齐替尼以24mg/d(每2周休药1周)、16mg/d(每天连续给药)或12mg/d(每天连续给药)的剂量在21天的周期内施用。毒性评估是基于不良事件的等级,使用美国国家癌症研究所(NCI)国际常见不良反应标准(CTCAE)4.03版进行。
关于进一步包括另一种药物的联合治疗,当波齐替尼与紫杉醇、顺铂或5-FU联合用于HER2过表达且雌激素受体(ER)阴性的乳腺癌细胞BT-474细胞时,观察到了高度的协同作用。当波齐替尼与曲妥珠单抗联合应用时,在某些浓度等于或低于波齐替尼单独使用时的GI50时,表现出微弱的协同作用,其中GI50是导致癌细胞增殖减少50%的药物浓度。当波齐替尼与长春瑞滨联合应用时,在浓度等于或低于波齐替尼单独使用的GI50时,没有观察到协同作用。同样地,长春瑞滨与波齐替尼联合应用于HER2过表达和ER阴性的SK-BR-3细胞时,观察到了协同作用。然而,波齐替尼与长春瑞滨联合应用于HER2过表达、ER阳性和曲妥珠单抗耐药的MDA-MB-361细胞时,在某些浓度下表现出协同作用;并且波齐替尼和长春瑞滨联合应用于MCF-7细胞时,每一个浓度均表现出协同作用,而MCF-7细胞为ER阳性且HER1和HER2并没有过表达。另外,波齐替尼和长春瑞滨联合应用于HER2阴性、ER阴性和HER1-过表达的三阴性乳腺癌细胞MDA-MB-468细胞时,在某些浓度下也观察到了协同作用。紫杉醇、5-FU、顺铂或曲妥珠单抗与波齐替尼联合应用于HER2过表达且曲妥珠单抗耐药的乳腺癌细胞MBA-MB-453细胞时,当某些浓度等于或低于波齐替尼单独使用的GI50时,观察到一种显著的协同作用。
当波齐替尼与5-FU在TE细胞(一种HER2过表达的食管癌细胞系)中联合应用时,将波齐替尼与其他药物联合应用的协同效果也非常好。另外,当波齐替尼与曲妥珠单抗在HER2过度表达的胃癌细胞系N-87细胞中联合应用时,在某些浓度下观察到协同作用。
因此,波齐替尼和T-DM1的组合物,进一步包括其他靶向抗癌剂或细胞毒性抗癌剂,优选治疗与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增相关的癌症,在例如乳腺癌、胃癌、肺癌和食道癌等癌症时将是非常有效的,并能有效抑制对常规治疗药物具有耐药性的癌症。适宜地,所述癌症为HER2阳性乳腺癌。
实施例3:HER2阳性胃癌晚期的治疗方法
在韩国的11个治疗中心进行了一项前瞻性I/II期研究。招募曾接受过一种或多种化疗剂的HER2阳性胃癌患者。患者每天口服波齐替尼(8mg或12mg),连续14天,随后休药7天。紫杉醇(175mg/m2输注)和曲妥珠单抗(8mg/kg负荷剂量,然后6mg/kg输注)在每3周的第1天与波齐替尼同时给药。
方法
患者:招募标准主要包括:年龄≥19岁的患者;组织病理学证实局部晚期不可切除、复发性或转移性胃腺癌(包括食管胃结合部腺癌);HER2免疫组织化学(INC)3+或HER2IHC 2+和HER2荧光原位杂交(FISH)+;根据实体瘤的疗效评价标准(RECIST,1.1版)评估实体瘤中是否存在一个或多个可测量的病变;不考虑曲妥珠单抗的暴露史,曾用的化疗药物包括氟嘧啶或铂;以及足够的骨髓和肝功能。关键排除标准包括:有EL和曲妥珠单抗的药物过敏史;以前接触过紫杉烷类化合物,以及有症状性的中枢神经系统转移。
患者特征:共有44例患者(I期12名,II期32名)来自韩国11个不同的治疗中心。表1总结了研究人群的基础特征。
表1研究人群基础特征汇总
这项研究是根据《赫尔辛基宣言》和国际协调会议(ICH)关于临床试验管理规范(GCP)进行的,并得到了每个参与的治疗中心的机构审查委员会的批准。所有患者在登记前提供书面知情同意书。
治疗程序:每一个21天的周期包括口服波齐替尼,每日一次,共14天,第1天紫杉醇(175mg/m2输注)和曲妥珠单抗(8mg/kg负荷剂量,随后6g/kg输注)联合应用。在研究的第I期,增加波齐替尼(8mg、12mg或16mg)的剂量,推测波齐替尼与紫杉醇和曲妥珠单抗联合用药的RP2D。在每个剂量水平下,对6例患者的DLT进行评估。如果在≤1例患者中观察到DLT,则剂量继续增加到下一个剂量水平。如果≥2例患者观察到DLT,则停止增加剂量,并将MTD确定为≤1例患者发生DLT的最高水平。在研究的第II周期,32例患者进行RP2D波齐替尼联合紫杉醇和曲妥珠单抗治疗。
安全性分析和疗效:采用美国国家癌症研究所不良事件通用术语标准(4.03版)对不良事件(AE)和治疗期间出现的不良事件(TEAE)进行评估。DLT被定义为3级非血液学毒性(脱发除外);尽管使用了最大剂量的抗腹泻和/或止吐药,腹泻、恶心和呕吐≥3级(如适用);4级中性粒细胞减少症持续≥7天,3~4级中性粒细胞减少症伴发热或感染;4级血小板减少症和3级血小板减少症,持续7天,伴有出血或需要输血。前3个周期的第1天以及此后每3个周期进行一次左室射血分数(LVEF)基础评估。所有至少接受一次波齐替尼治疗的患者均纳入安全性分析。根据研究者的评估,每6周使用RECIST 1.1版对胸部、腹部和骨盆进行CT或MRI评估。
统计学分析:第I周期的主要目的是评估波齐替尼的安全性和耐受性,并确定波齐替尼与紫杉醇和曲妥珠单抗联合用药时的MTD。第II周期的主要目的是评估波齐替尼联合紫杉醇和曲妥珠单抗的客观缓解率(ORR)。次要目的是评价安全性和耐受性、无进展生存期(PFS)、疾病进展时间(TTP)和总体反应持续时间(DOR)。
对于第II周期,假设ORR<5%无效,ORR>20%被认为具有临床意义。样本量采用Simon二阶段极大值极小值计算,80%的有效率和5%的显著性水平。在27名目标受试者中,第I周期需要13名受试者。如果13例患者中肿瘤缓解为0例,则本研究设计提前终止。但是,如果至少观察到1例反应,那么另外14例患者将被纳入研究。
结果
第I周期
招募7名1级(波齐替尼8mg)剂量患者,但其中1例患者由于在第I个周期结束前未完成随访而无法评估DLT。其余6例患者中,1例(4级中性粒细胞减少症)出现DLT。在2级剂量水平(波齐替尼12mg)下,招募了5例患者,2例患者观察到出现DLT(一例患者出现4级中性粒细胞减少症,另一例患者出现发热性粒细胞减少症,伴有4级中性粒细胞减少症)。因此,根据上述标准,确定波齐替尼MTD为8mg。
毒性和剂量调整。表2总结了12名I期TEAE患者的安全性分析数据集。12例患者(100%)均经历了≥1次TEAE,其中11例患者(91.7%)观察到出现≥3级毒性。3例患者(25.0%)出现与研究中止相关的TEAE。有1例(8.3%)的TEAE导致死亡(见表2)。最常见的波齐替尼相关不良事件为腹泻、皮疹、口腔炎、瘙痒和食欲不振(表3)。在9例(75%)和2例(16.7%)患者中分别观察到3级或更高级别的中性粒细胞减少症和发热性中性粒细胞减少症(补充表1)。6例患者中有1例(14.3%)接受了剂量减少(从8mg减少到6mg)的波齐替尼。分别对2例(28.6%)和1例(14.3%)患者进行紫杉醇剂量减少和停药(补充表2)。
表2治疗突发的不良事件(TEAE)的全面总结
表3安全性:与波齐替尼相关的不良事件(≥10%的患者)
补充表1波齐替尼最常见(≥10%)和≥3级TEAE的发生率
补充表2剂量调整
功效:共有11例患者可用于评价波齐替尼的疗效。在4例患者中观察到客观缓解(33.3%;95%CI,9.9~65.1)(表4)。四个人均有部分缓解。疾病控制率(DCR;PR+SD)为66.7%(95%CI,34.9~90.1)。中位生存期和中位总生存期分别为17.7周(95%CI,5.4~30.2)和30.6周(95%CI,12.2~195.0)(表5和图1)。
表4肿瘤缓解汇总
表5存活数据汇总
CI为置信区间。如未收集最后给药日期,则使用研究结束日期。在第I周期接受8mg和12mg治疗的患者数分别为2例和2例。第II周期(8mg)患者7例。根据总体反应的持续时间,总共计算出11例。
第II周期-见上表。
共有32例患者进入第II周期。20例患者(63%)接受了低剂量的波齐替尼。见上文补充表2。
安全分析:分别在4例(12.5%)和3例(9.4%)患者中出现3级或更高级别的TEAE中性粒细胞减少症和发热性中性粒细胞减少症(补充表1)。最常见的波齐替尼相关TEAE是腹泻、皮疹、口腔炎和食欲下降,与第I周期的结果相似(表3)。13例患者(40.6%)出现3级或更高级别的腹泻(补充表1)。4例患者(12.5%)因治疗相关毒性在首次评估前停止了研究。无3、4级左室收缩功能障碍(LVSD)。20例(62.5%)患者接受了低剂量的波齐替尼治疗。对12例患者(37.5%)给予减少剂量的紫杉醇,而有3例患者(9.4%)停用了紫杉醇(补充表2)。
功效:20例(62.5%)患者出现肿瘤变小(图1)。7例患者(21.9%;95%CI,9.3~40.0)出现确诊反应。2例(6.3%)完全缓解,5例(15.6%)部分缓解。疾病控制率为71.9%(95%CI,53.3~86.3)(表4)。平均PFS为13.0周(95%C,9.8~21.9)(表5,图1和3)。中位总生存期为29.5周(95%CI,17.9~59.2)(表5,图1)。中位TTP和DOR分别为15.0周(95%CI,10.0~23.1)和26.8周(95%CI,17.2~71.8)(表5)。当根据曲妥珠单抗暴露情况研究临床疗效时,曲妥珠单抗预处理和未经曲妥珠单抗治疗的患者的客观缓解率分别为12.5%和50.0%(表4)。曲妥珠单抗预处理患者的中位总生存期和中位生存期分别为29.5周(95%CI,17.9~40.9)和13.0周(9.8~18.7),曲妥珠单抗治疗患者的中位总生存期和中位生存期分别为42.6周(95%CI,3.0~111.5)和18.7周(95%CI,3.0~)(表5)。
讨论
在这项前瞻性、开放标签多中心的第II周期研究中,8mg波齐替尼联合紫杉醇与曲妥珠单抗治疗的晚期HER2阳性胃癌(GC)患者显示出毒性可控及良好的疗效。据我们所知,这项研究首次评估了pan-HER抑制剂联合化疗药物和曲妥珠单抗治疗HER2阳性肿瘤的疗效。
在先前的第I周期研究中,波齐替尼的MTD被确定为24mg/d(间断给药14天,休药7天)和18mg/d(连续给药)。在本研究的第I周期,波齐替尼的MTD被确定为8mg/d,远低于波齐替尼单独给药24mg/d的MTD。常见的TEAE有腹泻、皮疹、口腔炎和瘙痒。在本研究中,所有患者至少发生过一次TEAE,其发生率与波齐替尼单药治疗第I周期试验中报告的发生率相似。与第I周期单药治疗试验不同,我们研究中的所有DLT均为4级中性粒细胞减少症或伴4级中性粒细胞减少的发热性中性粒细胞减少症,而不是腹泻。
在上述第I周期试验中,波齐替尼单药治疗的客观缓解率和中位生存期分别为16%和12.0周(间断给药方案)和21%和9.0周(连续给药方案)。另一种pan-HER抑制剂达克替尼(dacomitinib)作为单药治疗,在HER2阳性胃癌中产生的客观缓解率为7.4%(95%CI,0~17.5),中位生存期为2.1个月(95%CI,2.3~3.4)。基于我们研究的客观缓解率和中位生存期,这些结果表明pan-HER抑制剂联合化疗可能比单独使用pan-HER抑制剂更有效。
HER2受体双重阻断已成为HER2阳性乳腺癌的标准疗法。帕妥珠单抗联合多西紫杉醇与曲妥珠单抗可显著增加HER2阳性乳腺癌的总生存期。然而,与HER2阳性乳腺癌相比,帕妥珠单抗联合化疗不能延长HER2阳性胃癌的总生存期。这个发现表明双重阻断剂对HER2阳性胃癌的疗效可能与对HER2阳性乳腺癌不同。然而,即使在体外,拉帕替尼和曲妥珠单抗双重阻断剂对HER2扩增的胃癌细胞也显示出高度协同的抗肿瘤活性。在目前的研究中,波齐替尼与曲妥珠单抗联合显示出良好的肿瘤缓解,这表明这种双重阻断策略,包括pan-HER抑制剂,将是HER2阳性胃癌挽救治疗的一个有前景的治疗选择。
在HER2阳性乳腺癌中,持续进行抗HER2靶向治疗是公认的治疗策略。一项回顾性研究报告称曲妥珠单抗增加了HER2阳性胃癌的无进展生存期和总生存期。然而,在一项前瞻性的第II周期研究中,进展以外的曲妥珠单抗作为二线药物未能改善HER2阳性胃癌患者的无进展生存期和客观缓解率,这表明进展以外的曲妥珠单抗在HER2阳性胃癌患者中的作用仍存在争议。
抗体-药物偶联物(ADC)是治疗HER2阳性肿瘤的新方法之一。在HER2阳性胃癌患者中进行了恩美曲妥珠单抗第3周期试验,所述患者先前使用氟嘧啶和铂类药物治疗失败。然而,恩美曲妥珠单抗并不优于紫杉醇。客观缓解率仅为20.6%(95%CI,15.26~26.45)。DS8201a是一种靶向HER2的新型ADC,已经显示出对HER2阳性的胃癌细胞具有较强的抗肿瘤活性。在第I周期研究中,DS8201a对曲妥珠单抗耐药的HER2阳性胃癌患者以及低HER2表达胃癌患者的客观缓解率为44%,疾病控制率为78%,这表明靶向HER2的ADC在HER2阳性胃癌中是一种很有前景的挽救治疗方法。
在本研究中,预处理前的活检不是强制性的,因此患者是根据最初诊断时HER2的表达来招募的。然而,HER2阳性胃癌患者在曲妥珠单抗治疗前后HER2的表达存在差异,接受曲妥珠单抗的患者中有32%甚至观察到HER2阳性的失活。这些观察结果表明,在再次用抗HER2靶向治疗之前,重新评估确切的HER2状态是必要的,因此,这是我们研究的一个局限性。
综上所述,波齐替尼(8mg)与紫杉醇和曲妥珠单抗联合应用对接受一线化疗的HER2阳性胃癌患者来说具有良好的临床疗效且毒性可控。曲妥珠单抗与pan-HER抑制剂的双重阻断抑制是克服曲妥珠单抗耐药性的一种有前景的策略。
应当理解的是,本文所描述的实施例仅应被视为说明性的,并不能对本发明的范围起到限制作用,每个实施例中的特征或各方面的描述通常应被视为可用于其他实施例中的其他类似特征或方面。本领域技术人员应理解,在不脱离权利要求所定义的本公开的精神和范围的情况下,可以在形式和细节上进行各种改变。
Claims (37)
1.一种治疗受试者癌症的方法,所述方法包括给予受试者有效治疗量的波齐替尼和抗-HER1抗体、抗-HER2抗体或抗-HER4抗体;
其中,所述癌症与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关;
所述癌症为非小细胞肺癌、乳腺癌、结肠癌、胃癌、胰腺癌、前列腺癌、骨髓瘤、头癌、颈癌、卵巢癌、食管癌或转移性细胞癌。
2.如权利要求1所述的方法,进一步包括给予紫杉醇、顺铂、5-氟尿嘧啶、长春瑞滨和西妥昔单抗或其任何药物组合中的至少一种。
3.如权利要求1或2所述的方法,其中,所述抗体为抗-HER2抗体,选自曲妥珠单抗、西妥昔单抗或其任何抗原结合片段。
4.如权利要求1~3中任一项所述的方法,其中所述癌症为乳腺癌。
5.如权利要求4所述的方法,其中所述乳腺癌选自
(i)雌激素受体阴性乳腺癌,HER1和/或HER2过表达;
(ii)雌激素受体和孕酮受体双阳性乳腺癌,HER2表达,但没有过表达;
(iii)曲妥珠单抗耐药乳腺癌,HER2过表达;
(iv)PR、HER2和雌激素受体阴性乳腺癌,HER1过表达。
6.如权利要求5所述的方法,其中所述乳腺癌为转移性乳腺癌。
7.如权利要求6所述的方法,进一步包括以下步骤:
收集所述受试者乳腺癌细胞;
评估所述乳腺癌细胞以确认HER2的过表达、HER2突变体的过表达、HER2的扩增或HER2突变体的扩增。
8.如权利要求7所述的方法,其中所述评估包括应用免疫组织化学(IHC)和荧光原位杂交(FISH)技术。
9.如权利要求8所述的方法,其中所述IHC为IHC 3+或IHC 2+。
10.一种治疗有需要的受试者乳腺癌的方法,其中所述乳腺癌与HER2的过表达或扩增,或HER2突变体的过表达或扩增有关,所述方法包括以下步骤:
a)在21天(±3天)周期内
i)单剂量给予T-DM11.5~5.5mg/kg;
ii)每日给予波齐替尼0.5~50mg/d;以及
iii)在21天周期内任选地停药一段时间;
b)可选择地重复所述周期,或者调整所述周期。
11.如权利要求10所述的方法,其中所述21天周期包括2周给药期和1周休药期。
12.如权利要求11所述的方法,其中所述21天周期选自
给药两周后,休药一周;
给药一周,接着休药一周,随后再给药一周;或者,
休药一周后,给药两周。
13.如权利要求10~12中任一项所述的方法,其中T-DM1的给药方式为静脉输注。
14.如权利要求13所述的方法,其中T-DM1的标准剂量为3.6mg/kg。
15.如权利要求10~14中任一项所述的方法,其中波齐替尼的给药方式为口服。
16.如权利要求15所述的方法,其中所述口服的剂量选自6、8、10、12、16或24mg,每日一次。
17.一种改善正在接受与HER2或HER2的突变体的过表达或扩增有关的乳腺癌治疗的受试者发生不良事件的方法,所述方法包括以下步骤:
a)在21天(±3天)周期内
ⅰ)单剂量给予T-DM1;
ⅱ)给予每日剂量的波齐替尼;和
b)可选地重复所述周期,
其中所述不良事件选自心脏毒性、血液毒性、腹泻、皮疹、粘膜炎、疲劳、电解质异常或肝毒性。
18.一种用于治疗受试者乳腺癌的组合物,其中所述乳腺癌与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关,所述组合物包括有效治疗量的波齐替尼和T-DM1,其中波齐替尼给药方式为口服,T-DM1给药方式为静脉输注。
19.如权利要求18所述的组合物,进一步包括通过静脉(IV)输注给予的有效治疗量的紫杉醇。
20.一种治疗受试者胃癌的方法,该方法包括给予受试者有效治疗量的波齐替尼和抗-HER1抗体、抗-HER2抗体或抗-HER4抗体;
其中,胃癌与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关。
21.如权利要求20所述的方法,进一步包括给予紫杉醇、顺铂、5-氟尿嘧啶、长春瑞滨和西妥昔单抗或其任何药物组合的至少一种。
22.如权利要求20或21所述的方法,其中所述抗体为抗-HER2抗体,选自曲妥珠单抗、西妥昔单抗或任何抗原结合片段。
23.如权利要求20~22中任一项所述的方法,进一步包括准备步骤:
收集所述受试者胃癌细胞;
评估胃癌细胞以确认HER2的过表达、HER2的突变体的过表达、HER2基因的扩增或HER2基因突变体的扩增。
24.如权利要求20~23中任一项所述的方法,所述评估包括用免疫组织化学(IHC)和荧光原位杂交(FISH)技术。
25.如权利要求24所述的方法,其中所述IHC为IHC 3+或IHC 2+。
26.如权利要求20~25中任一项所述的方法,其中所述胃癌曾应用化学疗法治疗。
27.一种治疗有需要的受试者胃癌的方法,其中所述胃癌与HER2的过表达或扩增、或HER2突变体的过表达或扩增有关,所述方法包括以下步骤:
a)在21天(±3天)周期内
ⅰ)单剂量给予曲妥珠单抗6~8mg/kg;
ⅱ)单剂量给予紫杉醇105~175mg/m2;
ⅲ)每日给予波齐替尼4~16mg/d;
b)可选择地重复上述周期。
28.如权利要求27所述的方法,其中曲妥珠单抗在第1天通过静脉(IV)输注给药。
29.如权利要求27或28所述的方法,其中曲妥珠单抗的标准剂量为8mg/kg负荷量,随后再输注6mg/kg。
30.如权利要求27~29中任一项所述的方法,其中所述紫杉醇于第1天通过静脉(IV)输注给药。
31.如权利要求30所述的方法,其中紫杉醇的标准剂量为175mg/m2输注。
32.如权利要求27~31中任一项所述的方法,其中波齐替尼口服给药14±3天。
33.如权利要求32所述的方法,其中所述口服剂量选自4、6、8、10、12或16mg,每日一次。
34.如权利要求33所述的方法,其中在所述波齐替尼给药14天后休药7天。
35.一种改善正在接受与HER2或HER2的突变体的过表达或扩增有关胃癌治疗的受试者发生不良事件的方法,所述方法包括以下步骤:
a)在21天(±3天)周期内
i)单剂量给予T-DM1;
ii)给予每日剂量的波齐替尼;和
b)可选地重复所述周期;
其中所述不良事件选自心脏毒性、血液毒性、腹泻、皮疹、粘膜炎、疲劳、电解质异常或肝毒性。
36.一种用于治疗受试者胃癌的组合物,其中所述胃癌与HER1、HER2、HER4、HER1的突变体、HER2的突变体或HER4的突变体的过表达或扩增有关,所述组合物包括有效治疗量的波齐替尼和T-DM1,其中波齐替尼给药方式为口服,T-DM1给药方式为静脉(IV)输注。
37.如权利要求36所述的组合物,进一步包括由静脉(IV)输注给予的有效治疗量的紫杉醇。
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