2013年第15届世界肺癌大会（WCLC）靶向治疗相关信息

6楼的翻译 - 第二部分

MO21.12 AZD9291: AN IRREVERSIBLE, POTENT AND SELECTIVE TYROSINE KINASE INHIBITOR (TKI) OF ACTIVATING (EGFRM+) AND RESISTANCE (T790M) MUTATIONS IN ADVANCED NSCLC

MO21.12 AZD9291：一种用于晚期NSCLC患者激活突变(EGFRM+)和耐药突变(T790M)的高效选择性不可逆TKI

Malcolm Ranson1, William Pao2, Dong-Wan Kim3, Sang-We Kim4, Yuichiro Ohe5, Enriqueta Felip6, David Planchard7, Serban Ghiorghiu8, Mireille Cantarini8, Darren Cross8, Pasi A. Jänne9

Background: The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced EGFR mutant NSCLC but many patients ultimately develop disease progression due to acquired resistance. The EGFR T790M mutation is the most common mechanism of acquired drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for NSCLC patients with EGFR T790M.

背景：第一代EGFR TKIs如吉非替尼和厄洛替尼极大地提高了具有EGFR突变的晚期NSCLC患者的临床获益，但许多患者最终不可避免地因获得性耐药的出现而导致疾病进展。EGFR T790M突变是最常见的获得性耐药机制，其在超过50%的对吉非替尼/厄洛替尼耐药的患者中被检测到。当前对带有EGFR T790M的NSCLC患者的治疗手段是有限的。

Methods: AZD9291 is an oral, irreversible, third generation inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M). The mechanistic and functional activity of AZD9291 was characterised in vitro across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Efficacy of AZD9291 was further evaluated across a number of different EGFR-mutant xenograft and transgenic models in vivo. One open label, dose escalation phase I study of AZD9291 (NCT01802632) is ongoing to determine the safety and tolerability [primary measure], pharmacokinetics and preliminary efficacy profiles of AZD9291, in patients with advanced NSCLC who have progressed following EGFR TKI. Sequential cohorts of 3-6 patients with advanced NSCLC who have had at least one prior regimen containing an EGFR TKI agent (with confirmed EGFRm+ status or Jackman criteria), were treated with AZD9291 once daily. Other key inclusion criteria were PS 0-1, measurable disease, and no prior history of ILD. RECIST assessments were scheduled 6 weekly. Dose escalation can occur after ≥ 3 patients complete both single dose and the first 21-day cycle of AZD9291 multiple dosing with no DLT.

方法：AZD9291是一种口服的不可逆第三代抑制剂，既能作用于EGFR激活突变(EGFRm+)，也能用于耐药突变(T790M)。其作用机理和功能活性在多种具有不同的EGFR突变型或者野性型的细胞系体外实验中被确定。通过一系列针对不同的EGFR突变的异种移植物和转基因模型的体内试验，AZD9291的效果进一步得到确认。一个开放标签、剂量递增的Phase I临床试验(NCT01802632)正在进行中，用于确定AZD9291的安全性和耐受性（主要测量终点）、药代动力学和临床前活性模型，该临床在接受EGFR TKI治疗后疾病进展的晚期NSCLC患者群中展开。由3至6名至少接受过一个前期治疗周期包括EGFR TKI治疗（同时具有确定的EGFRm+状态或者Jackman准则）的晚期NSCLC患者组成的顺序队列，每日接受一次AZD9291。其他入选标准包括：体能状态(PS)0-1，可测量病灶以及无间质性肺炎史(ILD)。每6周接受一次RECIST评估。在多于3位患者完成了单剂量以及多剂量的第一个21天周期且未出现剂量限制毒性之后，可作剂量的递增。

Results: AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (PC9; 14nM) and EGFRm+/T790M (H1975; 13nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (LoVo; 400nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 treatment caused profound growth regression across multiple EGFRm+ (PC9; 250% growth inhibition) and EGFRm+/T790M (H1975; 132% growth inhibition) tumour models in vivo, at doses as low as 5mg/kg after 14 days. Tumour growth inhibition was associated with profound inhibition of EGFR activity and key downstream signaling pathways. Chronic long-term treatment of in vivo PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response. In the phase I study, clinical activity with RECIST responses have already been observed at the starting dose level of 20mg once daily, with good tolerability, no reported events of EGFR wild-type rash, and only grade 1 diarrhoea (based on preliminary data, unvalidated and subject to change).

结果：AZD9291能高效抑制具有EGFRm+(PC9; 14nM)和EGFRm+/T790M(H1975; 13nM)的EGFR磷酸化，并且表现出对野生型EGFR更低的抑制活性(LoVo; 400nM)。与此一致的是，在体内试验中AZD9291也表现出了对突变型EGFR细胞系的增值，比对野生型EGFR，具有更强的抑制效果。另外，体外实验中以低至5mg/kg的剂量给药14天之后，多种肿瘤模型都出现了极大的生长消退，包括多重EGFRm+（PC9; 250%生长抑制）和EGFRm+/T790M（H1975; 132%生长抑制）。EGFR活性和下游关键信号通路的抑制用于评估肿瘤生长抑制情况。对体外PC9细胞系和H1975异种移植物的长效治疗导致了完全的和持续的宏观响应。在这个Phase I研究中，在起始剂量每日20mg的患者中已经观察到了基于RECIST响应的临床活性，其具有良好的耐受性，没有EGFR野生型抑制相关皮疹事件的报道，不良事件仅包括1级腹泻（基于临床前数据，未验证，可能有改变）

Conclusion: Preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M) whilst sparing wild-type EGFR and, early clinical data have been promising. Taken together, these data support the further clinical investigation of AZD9291 in advanced EGFR mutant NSCLC.

总结：临床前数据表明AZD9291是一种高效的抑制剂，能作用于EGFR激活突变(EGFRm+)和耐药突变(T790M)，同时避开野生型EGFR，早期临床数据已经展现出有希望的应用前景。综上所述，这些数据支持将AZD9291应用于晚期具有EGFR突变的患者中的进一步临床研究。

1686是值得期待的，但从现在展现的数据来看，20mg起始有效剂量，极小的副作用，对T790M的强大抑制效果，9291已经完全碾压1686，用老马的话来讲就是两个字：牛逼！

AZD9291请参阅以下链接：
阿斯利康的T790M牛逼新药AZD9291的1期临床结果出来了

9291确实相当值得期待啊，千呼万唤等它的结构式了！

7楼的翻译：

O03.05 ACTIVITY OF AFATINIB IN UNCOMMON EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS: FINDINGS FROM THREE TRIALS OF AFATINIB IN EGFR MUTATION-POSITIVE LUNG CANCER

O03.05 阿法替尼在罕见EGFR突变中的活性：来源于三个应用阿法替尼治疗EGFR突变阳性肺癌患者的临床试验的研究成果

James C. Yang1, Lecia V. Sequist2, Sarayut Lucien Geater3, Chun-Ming Tsai4, Tony Shu Kam Mok5, Martin Schuler6, Nobuyuki Yamamoto7, Daniel Massey8, Victoria Zazulina9, Yi-Long Wu10

Background: EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.

背景：EGFR(ErbB1)突变定义了对EGFR TKI高度敏感的肺癌亚型。在NSCLC中，虽然外显子19缺失(Del19)和外显子21点突变(L858R)是两种最常见的EGFR敏感突变，但还是有近10%的EGFR突变阳性的肿瘤具有罕见的突变类型。这些突变类型代表了发生在外显子18-21中少见的分子改变（或者融合）的异质性群组，该群组中不同基因突变的致瘤性和对EGFR TKI的敏感性各不相同，而且未得到前瞻性的研究。在这里，我们展示了将阿法替尼，一种不可逆ErbB家族抑制剂，应用于带有罕见EGFR突变的患者的第一份前瞻性数据。

Methods: This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

方法：该分析基于包括LUX-Lung 2 (Phase II)，LUX-Lung 3以及LUX-Lung 6 (both Phase III)等针对EGFR突变阳性患者研究的数据。在LUX-Lung 2中，EGFR突变状态由直接测序法识别，而在LUX-Lung 3和LUX-Lung 6则应用heraScreen EGFR RGQ PCR kit进行中心检测。患者被划分为常见突变类型(Del19或L858R)以及罕见突变类型（其他的单突变或复合突变）。罕见突变类型再分为三个组：原发T790M（单独出现或者联合其他突变）、外显子20插入突变、其他突变。分别独立地评估各组的客观缓解率(ORR)、疾病控制率(DCR)、响应时间以及无进展时间(PFS)。

Results: Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.

结果：75位患者具有罕见突变(LUX-Lung 2: n=23; LUX-Lung 3: n=26; LUX-Lung 6: n=26)，在这三个研究中占使用阿法替尼治疗的患者数目的12.5%。大多数患者以阿法替尼作为一线治疗方案，13位患者之前接受过化疗。这些患者再细分为三个组：T790M: n=14; 外显子21插入: n=23; 其他: n=38 (绝大多数类型为L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3)。对于每个组的治疗效果如下表所示。更多的关于突变状态的细节将被展示。



Conclusion: Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.

总结：阿法替尼在含有罕见的EGFR突变类型如G719X, L861Q, S768I等肺癌肿瘤的中具有一定的活性。响应率和响应时间都接近于之前在含有常见突变类型的患者观测到的情形。对于原发T790M突变和外显子20插入突变，阿法替尼的响应率较低，但部分患者表现出了持续的肿瘤控制。截止到目前，这是对于在具有罕见突变类型患者中最大的前瞻性分析数据，我们将会进一步探讨对于这些异质性肿瘤群组的治疗方案。

感谢辛勤付出，希望好药早点出来。

感觉9291和4002作用挺接近的，新的前沿版主真心牛，敬佩

11月29-30日，羊城广州迎来世界肺癌大会会后会（Best of WCLC）的首次“到访”。据会议主席、广东省人民医院吴一龙教授介绍，本届世界肺癌大会（WCLC）的中国特色随处可见——首日即设置了中国肺癌防治联盟（CALC）专场，全国百余位医生参会，近百篇中国口头报告和壁报研究，CTONG 0806研究入选WCLC新闻发布会……而随着莫树锦教授当选2013-2015年度国际肺癌研究协会（IASLC）主席及吴一龙教授当选为IASLC的理事会（Board of Director）委员，我国学者在国际肺癌舞台上将有更大发言权，在中国举办WCLC指日可待。下文摘选本次Best of WCLC精华内容，以飨读者。

国际肺癌领域“中国好声音”

上海交通大学医学院附属上海市胸科医院  陆舜教授：

多项中国胸部肿瘤研究协作组（CTONG）研究“亮相”本届WCLC。

CTONG 0806研究结果提示，对于EGFR基因野生型晚期非鳞非小细胞肺癌（NSCLC）的二线治疗，培美曲塞组无进展生存（PFS）和疾病控制率均显著优于吉非替尼组，且扩增受阻突变体系（ARMS）方法优于直接测序。

另外，FASTACT研究证实，EGFR酪氨酸激酶抑制剂（TKI）与化疗交替治疗模式可改善EGFR突变和部分未知突变晚期NSCLC的客观有效率（ORR）、PFS及总生存（OS）。会上，CTONG 1101研究的初步结果显示，厄洛替尼与GC（吉西他滨+铂类）交替使用新辅助治疗ⅢA期NSCLC，ORR达46.2%。

而另一项CTONG 0904研究（TFINE）则表明，多西他赛60 mg/m2与75 mg/m2的疗效相似，但前者更适合中国患者；且多西他赛60 mg/m2维持治疗较最佳支持治疗能延长晚期NSCLC患者的PFS期。

开启克服靶向治疗耐药新时代

中山大学附属肿瘤医院  张力教授：

会上，3项阿法替尼（二代TKI）治疗EGFR突变阳性者的研究（LUX-lung 2、3、6）结果提示了其对非经典突变肺癌（外显子18 G719X突变、外显子20 S768I突变及外显子21 L861Q突变）有一定疗效。

抑制EGFR、ALK基因的药物发生耐药的常见机制包括耐药突变、旁路通道激活及其他。会上，AURA研究显示，EGFR敏感突变和耐药T790M突变的不可逆抑制剂AZD9291显示了初步疗效，患者耐受佳，值得未来在EGFR突变NSCLC中进一步研究。

而对于克唑替尼（crizotinib）治疗失败的ALK阳性NSCLC，AF-002JGⅠ期研究提示，alectinib对脑转移者有作用：治疗6周后患者脑部病灶明显缩小。

可见，新型高选择TKI为存在驱动基因突变（包括耐药突变）的肺腺癌提供了更有效、安全的治疗。对于EGFR突变NSCLC，TKI已成为治疗主要组成部分。在此基础上探索各种手段的联合治疗可能改善疗效。

肺癌化疗进展和思考

同济大学附属上海市肺科医院  周彩存教授：

近年来，肺癌化疗进展主要集中在以下方面：根据组织学类型选择治疗方案；高效、低毒化疗药物维持治疗有生存益处；靶向治疗的加入进一步改善疗效。

BEYOND研究结果显示，对于我国晚期或复发非鳞NSCLC的一线治疗，PC方案（紫杉醇+卡铂）联合贝伐珠单抗可延长PFS期，EGFR突变阳性是患者预后的影响因素，但不是贝伐珠单抗疗效的预测因素。

会上，对两项Ⅲ期研究的研究间分析探讨了培美曲塞治疗晚期非鳞NSCLC的模式。结果显示，PARAMOUNT研究的治疗模式（一线至少4个周期培美曲塞+顺铂诱导治疗后培美曲塞维持）较JMDB研究的治疗模式（最多6个周期培美曲塞+顺铂）显著延长了晚期非鳞NSCLC患者的OS期和PFS期。未来，如何个体化选择维持治疗将是重点。

ESOGIA-GFPC 08-02Ⅲ期研究未能证明根据综合老年评估（CGA）制定治疗决策可改善老年Ⅳ期NSCLC患者无治疗失败生存，但以卡铂为基础联合培美曲塞或吉西他滨方案可行，患者耐受良好。

NSCLC的多基因时代

华中科技大学同济医学院附属协和医院  伍钢教授：

莫树锦等在WCLC上报告，FASTACT-2研究中晚期NSCLC患者一线治疗时血浆EGFR（pEGFR）突变DNA的动态变化如下：血浆游离DNA及EGFR突变特异性DNA在治疗第3个周期（C3）降低，而当疾病进展时又升高；在接受GC联合厄洛替尼一线治疗的患者中，若基线和C3 pEGFR突变均阳性，则提示PFS和OS较差；对于EGFR突变并接受一线TKI治疗者，C3 pEGFR突变状态可能是疗效的预测因子，但这有待前瞻性研究的进一步证实。

另外，肺癌突变联盟（LCMC）研究通过筛查1007例肺腺癌基因表型发现，63%有驱动基因突变，根据驱动基因状态选择相应靶向治疗可改善生存，有驱动基因突变并接受靶向治疗者较未使用者生存改善。未来，NGS（二、三代测序技术）可显示肿瘤复杂网络，靶向治疗“轻松”应对癌症甚至癌前病变可能成为现实。

多学科治疗的思考

浙江省肿瘤医院  范云教授：

ENSURE研究结果曾表明，对于亚裔EGFR突变NSCLC，厄洛替尼较化疗能显著改善PFS。会上一项东亚Ⅲ期研究显示，对于EGFR野生型患者，一线TKI没有益处，这与目前共识一致。会上，RTOG 0617研究显示，对于Ⅲ期不可切除NSCLC，在标准放化疗基础上增加西妥昔单抗不改善总人群的OS或PFS；高剂量放疗（74 Gy）不优于标准剂量放疗（60 Gy）。另外，视频辅助胸腔镜（VAT）胸膜部分切除可改善胸腔积液控制，并改善患者生活质量，可考虑用于伴胸腔积液恶性胸膜间皮瘤的治疗。

谁将赢得肺癌未来发展的先机？

广东省人民医院  吴一龙教授：

迄今，肺癌分类的发展经过了一个从临床病理学到分子学的飞跃。但是，临床肿瘤学仍有极大的提升空间。

肺癌的分子事件并不简单。皮科尔（Pikor）等发现，不论是基因拷贝数的增加还是丢失，腺癌与鳞癌的表现都是不同的；而且，即使是对于同一信号传导通路，腺癌与鳞癌中的具体基因表达情况也不同。因此，并非我们了解了某个驱动基因就可以“一劳永逸”了。克里奥（Criello）等通过将常见癌症统一进行分析发现，其实癌症的分子事件，有的是以基因扩增为主，有的是以基因突变为主。具体到肺癌，腺癌是以基因突变为主，而鳞癌则是以基因扩增为主。这也解释了为何近年来肺癌靶向治疗的进展主要集中于腺癌而非鳞癌。在这些分子事件中，基因突变又可被进一步分为17种类型（M1-17），基因扩增则可被分为14种类型（C1-14），而每种类型都可能有相应的药物。因此，研究者进一步通过系统生物学方法列出了突变型和扩增型肺癌的治疗策略，即根据癌症基因是突变还是扩增，对治疗进行重新分配。例如，对于M4-8型肺癌，除须抑制PIK3CA通路外，还应同时抑制AKT和mTOR；而对于C2型肺癌，须同时抑制PIK3CA、AKT、CCNE1-CDK2、BRD4通路。

可见，未来对于肺癌的治疗，重要发展方向可能是先通过NGS方法将患者分为突变型或扩增型，然后再根据其具体突变或扩增的类型而给予更加针对性的治疗。

不过，我们还应该意识到，癌症的生长是多种因素共同作用的结果。其中，既包括癌症的局部因素，如基因突变导致细胞周期不受控制及癌症微环境（癌细胞刺激血管和淋巴管生成）的影响，还包括全身因素的作用，如免疫系统失活及激素、营养等的相互影响。因此，在不远的将来，泛组学和系统生物学将是重要挑战。谁能最先综合掌握这些先进技术，谁就可能赢得发展的先机。

MO12.04 BIOMARKER ANALYSIS OF NCIC CLINICAL TRIALS GROUP IND.196, A PHASE I STUDY OF ERLOTI-
NIB PLUS FORETINIB IN ADVANCED PRETREATED NON-SMALL CELL LUNG CANCER PATIENTS
Background: Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.
Methods: Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-fnding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples
(archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affnity purifed polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT
autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.
Results: Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a ecommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour
samples were submitted for 25 patients; 15 had suffcient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confrmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%).
PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXLnegative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive.
Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.
Conclusion: Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET
and AXL.

egrf野生型如果也有类似的就好了

感谢楼主和翻译者。

谢谢老马。