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扩展的非小细胞肺癌II期临床试验启动，阿斯利康向和黄医药支付1000万美元里程金

此研究的开展是基于沃利替尼早先与Tagrisso或Iressa联合用药治疗c-Met扩增非小细胞肺癌的初始小型II期临床试验获得的良好数据

2016年6月20日：和黄医药今日宣布在目前正进行的选择性c-Met抑制剂沃利替尼（AZD6094）治疗非小细胞肺癌II期临床试验TATTON （NCT02143466）的基础上，启动针对EGFR突变病人的扩展II期临床试验。沃利替尼有潜力能够满足针对c-Met相关亚组的非小细胞肺癌未被满足的医疗需求，预计涉及全世界每年新增病例约170万。

此试验是一项单臂全球II期临床试验，沃利替尼将与Tagrisso（奥希替尼/AZD9291）联合用药治疗EGFR酪氨酸激酶抑制剂（TKI）耐药的晚期非小细胞肺癌患者。此项扩展研究的启动是基于沃利替尼在与Tagrisso联合用药的TATTON研究中已获得的鼓舞人心的早期数据。

根据2011年12月阿斯利康与和黄医药所签订的协议条款，阿斯利康此次向和黄医药支付1000万美元里程金用于启动扩展II期临床试验。目前，合作双方正在开展沃利替尼单药疗法，或同时与Tagrisso/Iressa（吉非替尼）联合用药以非小细胞肺癌为适应症的II期临床试验。阿斯利康继续投资和负责沃利替尼以非小细胞肺癌为适应症的全球研发项目。

阿斯利康肿瘤创新药物部负责人，资深副总裁Susan Galbraith表示：“沃利替尼是一种高选择性的c-Met抑制剂，目前正在多种肿瘤类型中开展研究，包括c-Met / HGF信号通路异常的肺癌。沃利替尼与我们的EGFR酪氨酸激酶抑制剂联合用药所获得的试验数据让我们为之振奋，并将致力于继续推进各项研究，争取早日为肺癌患者带来更多有效的治疗方案选择。“

和黄中国医药科技有限公司的首席执行官贺隽表示：“据估计，每年美国、欧盟及日本因MET异常非小细胞肺癌发病的人数约为4-5万人，所采用的治疗方式各异。我们认为沃利替尼具有非常高的选择性，能够有效覆盖c-Met靶点，并且与其他肿瘤药物联合用药时安全及耐受性能良好，沃利替尼无论是作为单一用药治疗一线非小细胞肺癌，或是与阿斯利康的Tagrisso或Iressa联合用药治疗二三线非小细胞肺癌，都将能够有效的抑制因基因突变而诱导的癌细胞增殖这一关键因素，为这些“难治的”非小细胞肺癌患者带来福音。基于此次试验的最终数据，我们希望能在2017年推进开展III期临床试验。”

非小细胞肺癌研发项目概要

沃利替尼在各种类型的MET异常非小细胞肺癌中持续开展研究， 包括：

• 沃利替尼 + Tagrisso或Iressa联合用药治疗EGFR突变非小细胞肺癌的II期临床扩展研究
• 沃利替尼 + Tagrisso联合用药治疗三线非小细胞肺癌（受试者为接受针对T790M突变治疗后疾病进展的患者）的II期临床研究
• 沃利替尼单药治疗非小细胞肺癌的II期临床研究

沃利替尼正在多种MET异常实体瘤，包括非小细胞肺癌、肾癌、胃癌及结直肠癌开展临床研究。关于沃利替尼目前在多类患者群体中进行的所有临床试验的详细信息，请点击此处。

关于非小细胞肺癌及用酪氨酸激酶抑制剂治疗MET异常和EGFR突变的非小细胞肺癌

据Frost & Sullivan数据显示，每年全球新增非小细胞肺癌病例约为170万例。肺癌是死亡率最高的恶性肿瘤，约占全部癌症死亡人数的三分之一，超过乳腺癌、前列腺癌和结直肠癌死亡人数的总和。酪氨酸激酶抑制剂是一种被广泛使用的癌症疗法，它能够阻断癌细胞的信号通路从而抑制肿瘤的生长。

一线非小细胞肺癌中约4-5%伴有MET异常，包括约3-4% MET14外显子突变和约1-2% c-Met基因过度表达，一般对沃利替尼这类的选择性c-Met抑制剂疗法有响应。目前还没有针对非小细胞肺癌的选择性c-Met酪氨酸激酶抑制剂获批上市。

另外，EGFR突变非小细胞肺癌占欧洲非小细胞肺癌患者总数的10-15%，在亚洲为30-40%，现已上市的EGFR-TKIs对EGFR突变非小细胞肺癌疗效显著。但是，肿瘤对此疗法易产生耐药而导致疾病进展，中位无进展生存期大约为9个月。非小细胞肺癌患者在接受已获批的EGFR-TKIs如Iressa，Tarceva或Gilotrif的治疗后产生耐药而进展成为二线患者，其中约半数是由T790M突变导致的，约五分之一是由c-Met基因扩增导致的。

随着接受针对EGFR T790M突变阳性的临床试验中TKIs受试者人数的增加，以及Tagrisso目前在美国，欧盟，日本及韩国获批上市，新的耐药机制正逐渐显现，虽然数据仍然有限，但当受试者对Tagrisso产生耐药（中位无进展生存期为9个月）时，c-Met基因扩增是一条重要的耐药变化路径。

沃利替尼，独特的高选择性c-Met抑制剂

沃利替尼是一种高选择性口服c-Met（也被称作间充质上皮转移因子）受体酪氨酸激酶抑制剂，研究发现这种酪氨酸激酶在多种实体瘤中表现异常。沃利替尼作为一种强效的高选择性口服抑制剂，旨在克服第一代c-Met抑制剂在临床上表现出的问题，包括肾毒性。

Tagrisso，针对EGFR和T790M突变的选择性抑制剂

阿斯利康的新药Tagrisso（奥希替尼）每日一次80mg片剂，是第一个针对成人局部晚期或转移性的EGFR T790M突变阳性非小细胞肺癌的药物。非临床体外研究显示奥希替尼对一系列临床相关EGFRm和T790M突变的非小细胞肺癌细胞株的突变EGFR磷酸化具有很强的药效和抑制作用，但是对野生型EGFR作用相对很小。

以经过EGFR-TKI治疗后疾病进展的局部晚期或转移性EGFR T790M阳性的非小细胞肺癌患者为受试者，AURA3临床III期验证性研究正在将Tagrisso与含铂双重化疗方案进行比较。Tagrisso同时也在接受辅助治疗或转移性的一线患者中进行研究，包括伴随/未伴随脑转移，患软脑膜疾病以及联合其他药物进行治疗。

Iressa，EGFR突变抑制剂

阿斯利康研发的Iressa（吉非替尼）是一种治疗晚期或转移性EGFR突变阳性非小细胞肺癌的靶向单药。Iressa通过抑制EGFR中的酪氨酸激酶阻断肿瘤细胞增长和扩散的信号传达。EGFR突变约占高加索人非小细胞肺癌患者人群的10-15%，占亚洲非小细胞肺癌患者人群的30-40% 。Iressa已在全球91个国家获批上市。

London: Wednesday, June 15, 2016: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) today announces that an application has been made to the London Stock Exchange plc for a block admission of 1,000,000 ordinary shares, par value of US$1.00 each (“Ordinary Shares”) to be admitted to trading on AIM. It is expected that such admission will become effective on June 20, 2016.

These Ordinary Shares will be issued from time to time pursuant to the exercise of share options under the Share Option Scheme adopted by Chi-Med on May 13, 2016. When issued, these Ordinary Shares will be credited as fully paid and will rank pari passu with the existing Ordinary Shares in issue.

Notes to Editors

About Chi-Med

Chi-Med is a China-based, globally-focused healthcare group which researches, develops, manufactures and sells pharmaceuticals and health-related consumer products. Its Innovation Platform, Hutchison MediPharma Limited, is focused on discovering, developing and commercializing innovative therapeutics in oncology and autoimmune diseases. Its pipeline of eight novel oral compounds for cancer and inflammation is in development in North America, Europe, Australia and Greater China.

Chi-Med’s Commercial Platform manufactures, markets and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.

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The safety profile of a selective EGFR TKI epitinib (HMPL-813) in patients with advanced solid tumors and preliminary clinical efficacy in EGFRm+ NSCLC patients with brain metastasis

Authors: Qing Zhou, Bin Gan, Liwei Yuan, Ye Hua, Yi-Long Wu

Background: Epitinib is a selective EGFR-TKI designed for optimal brain penetration. In preclinical species, epitinib demonstrated favorable drug exposures in the brain and is warranted clinical investigation for CNS tumors with EGFRm+ such as NSCLC brain metastases.

Methods: This is a first-in-human study. Patients with advanced solid tumors were enrolled in dose escalation phase. In expansion phase, only EGFRm+ NSCLC patients with brain metastases were eligible. Epitinib was administered orally q.d. Dose escalation started at 20 mg and followed a classic 3+3 design. All patients were assessed for AEs/ DLTs, PK, and tumor response.

Results: A total of 36 patients were enrolled in dose escalation phase at 7 dose levels up to 240 mg. No DLT was observed. Although MTD was not reached, 160 mg q.d. was selected as the RP2D. The most common AEs were skin rash (60.0%), diarrhea (34.3%), elevated AST (34.3%)/ALT (31.4%) and hyperbilirubinemia (28.6%). AEs of Elevated AST (2.9%)/ALT (2.9%) and hyperbilirubinemia (5.7%) were grade 3. Among 34 evaluable patients, one (2.9%) patient (80 mg cohort, EGFRm+ and TKI naïve) reached PR with a duration of response over 36 months. Epitinib drug exposure increased proportionally up to 160 mg and appeared to plateau above 160 mg. The average T _1/2 ranged between 38 and 54h. A dose expansion study in EGFRm+ NSCLC patients with brain metastases is ongoing. As of 30 Oct, 2015, 12 patients were treated with epitinib at 160 mg q.d. Among 12 evaluable patients, 5 reached PR (all treatment naïve) and showed dramatic shrinkage of brain lesions. The rest 5 prior -TKI treated patients had SD in the brain. 2 progression events observed with one in liver and the other in brain, respectively.

Conclusions: Epitinib was well tolerated in patients with advanced solid tumors. Its safety profile is consistent to EGFR-TKIs. The RP2D of 160 mg q.d. was selected based on safety, PK and preliminary efficacy data. Clear clinical efficacy was observed in untreated EGFRm+ NSCLC patients with brain metastases. Taken together, these data support further development of epitinib for the treatment of EGFRm+ NSCLC patients with brain metastasis. Clinical trial information: NCT02590952

Authors: Jin-Ji Yang, Liu Yang, Andrew Farnsworth, Amir Handzel, Tanya Coleman, Shethah Morgan, Yi-Long Wu

Background: Savolitinib (AZD6094, volitinib, HMPL-504) is a potent & selective small molecule MET inhibitor. In preclinical models the combination of savolitinib & gefitnib was more effective than either compound alone (D’Cruz et al, 2014; Zhou et al, 2013). EGFR TKI failure is frequently attributable to MET amplification.

Methods: The intent of the study is to test that NSCLC pts who progressed on previous EGFR-TKI treatment, can receive treatment with gefitinib & savolitinib and potentially demonstrate an improved clinical response. This study (NCT02374645) has 2 phases: safety run-in phase (n~12) & expansion phase (n~20). Eligibility requires advanced EGFRm+ NSCLC, measurable disease, adequate PS (0-1) & organ function, progression on any prior EGFR-TKI. MET status is not required for the safety run-in but MET amplification by tumor biopsy confirmation is mandatory in the expansion phase. Data from the safety run-in phase presented here are unvalidated & preliminary.

Results: As of 17 January 2016, 13pts have completed the DLT assessment with fixed dose of gefintinib 250 mg QD in combination with savolitinib at 600 mg QD (n = 6) & 800 mg QD (n = 7). No DLT in the 600mg QD cohort & a potential DLT of G3 febrile neutropenia in the 800 mg QD cohort. 11pts are evaluable for response & 12pts are evaluable for safety analysis at the data cut off. Drug-related (either gefitinib or savolitinib) adverse events most common across both dose levels were nausea (40% – G1), blood bilirubin increased (30% – G1/2), vomiting (30% – G1). Two confirmed partial responses (pts METamp neg) were reported at 12wks so far with this combination, at 18wks 1pt had PD & 1pt is ongoing. Exposure & PK parameters for gefitinib & savolitinib lie within range& align well with historical data.

Conclusions: The toxicity & PK profile of savolitinib makes rational combination with gefitinib feasible in EGFRm+ NSCLC pts who failed EGFR TKI. The expansion phase in pts with MET amplification will evaluate anti-tumor activity.

Reference: D’Cruz, C et al Cancer Res 2014;74(19 Suppl):Abstract nr 3114. Zhou, F et al Cancer Res 2013;73(8 Suppl):Abstract nr 971. Clinical trial information: NCT02374645