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擴展的非小細胞肺癌II期臨床試驗啟動，阿斯利康向和黃醫藥支付1000萬美元里程金

此研究的開展是基於沃利替尼早先與Tagrisso 或Iressa 聯合用藥治療c-Met擴增非小細胞肺癌的初始小型II期臨床試驗獲得的良好數據

2016年6月20日：和黃醫藥今日宣佈在目前正進行的選擇性c-Met抑製劑沃利替尼（AZD6094）治療非小細胞肺癌II期臨床試驗TATTON （NCT02143466）的基礎上，啟動針對EGFR 突變病人的擴展II期臨床試驗。沃利替尼有潛力能夠滿足針對c-Met相關亞組的非小細胞肺癌未被滿足的醫療需求，預計涉及全世界每年新增病例約170萬。

此試驗是一項單臂全球II期臨床試驗，沃利替尼將與Tagrisso （奧希替尼/AZD9291）聯合用藥治療EGFR酪氨酸激酶抑製劑（TKI）耐藥的晚期非小細胞肺癌患者。此項擴展研究的啟動是基於沃利替尼在與Tagrisso 聯合用藥的TATTON研究中已獲得的鼓舞人心的早期數據。

根據2011年12月阿斯利康與和黃醫藥所簽訂的協議條款，阿斯利康此次向和黃醫藥支付1000萬美元里程金用於啟動擴展II期臨床試驗。目前，合作雙方正在開展沃利替尼單藥療法，或同時與Tagrisso / Iressa （吉非替尼）聯合用藥以非小細胞肺癌為適應症的II期臨床試驗。阿斯利康繼續投資和負責沃利替尼以非小細胞肺癌為適應症的全球研發項目。

阿斯利康腫瘤創新藥物部負責人，資深副總裁Susan Galbraith表示：“沃利替尼是一種高選擇性的c-Met抑製劑，目前正在多種腫瘤類型中開展研究，包括c-Met / HGF信號通路異常的肺癌。沃利替尼與我們的EGFR酪氨酸激酶抑製劑聯合用藥所獲得的試驗數據讓我們為之振奮，並將致力於繼續推進各項研究，爭取早日為肺癌患者帶來更多有效的治療方案選擇。“

和黃中國醫藥科技有限公司的首席執行官賀雋表示：“據估計，每年美國、歐盟及日本因MET異常非小細胞肺癌發病的人數約為4-5萬人，所採用的治療方式各異。我們認為沃利替尼具有非常高的選擇性，能夠有效覆蓋c-Met靶點，並且與其他腫瘤藥物聯合用藥時安全及耐受性能良好，沃利替尼無論是作為單一用藥治療一線非小細胞肺癌，或是與阿斯利康的Tagrisso 或Iressa 聯合用藥治療二三線非小細胞肺癌，都將能夠有效的抑制因基因突變而誘導的癌細胞增殖這一關鍵因素，為這些“ 難治的”非小細胞肺癌患者帶來福音。基於此次試驗的最終數據，我們希望能在2017年推進開展III期臨床試驗。”

非小細胞肺癌研發項目概要

沃利替尼在各種類型的MET異常非小細胞肺癌中持續開展研究，包括：

• 沃利替尼+ Tagrisso或Iressa聯合用藥治療EGFR突變非小細胞肺癌的II期臨床擴展研究
• 沃利替尼+ Tagrisso 聯合用藥治療三線非小細胞肺癌（受試者為接受針對T790M突變治療後疾病進展的患者）的II期臨床研究
• 沃利替尼單藥治療非小細胞肺癌的II期臨床研究

沃利替尼正在多種MET異常實體瘤，包括非小細胞肺癌、腎癌、胃癌及結直腸癌開展臨床研究。關於沃利替尼目前在多類患者群體中進行的所有臨床試驗的詳細信息，請點擊此處。

關於非小細胞肺癌及用酪氨酸激酶抑製劑治療MET異常和EGFR突變的非小細胞肺癌

據Frost & Sullivan數據顯示，每年全球新增非小細胞肺癌病例約為170萬例。肺癌是死亡率最高的惡性腫瘤，約佔全部癌症死亡人數的三分之一，超過乳腺癌、前列腺癌和結直腸癌死亡人數的總和。酪氨酸激酶抑製劑是一種被廣泛使用的癌症療法，它能夠阻斷癌細胞的信號通路從而抑制腫瘤的生長。

一線非小細胞肺癌中約4-5%伴有MET異常，包括約3-4% MET14外顯子突變和約1-2% c-Met基因過度表達，一般對沃利替尼這類的選擇性c-Met抑製劑療法有響應。目前還沒有針對非小細胞肺癌的選擇性c-Met酪氨酸激酶抑製劑獲批上市。

另外，EGFR突變非小細胞肺癌佔歐洲非小細胞肺癌患者總數的10-15%，在亞洲為30-40%，現已上市的EGFR-TKIs 對EGFR突變非小細胞肺癌療效顯著。但是，腫瘤對此療法易產生耐藥而導致疾病進展，中位無進展生存期大約為9個月。非小細胞肺癌患者在接受已獲批的EGFR-TKIs如Iressa ，Tarceva 或Gilotrif 的治療後產生耐藥而進展成為二線患者，其中約半數是由T790M突變導致的，約五分之一是由c-Met基因擴增導致的。

隨著接受針對EGFR T790M突變陽性的臨床試驗中TKIs受試者人數的增加，以及Tagrisso 目前在美國，歐盟，日本及韓國獲批上市，新的耐藥機制正逐漸顯現，雖然數據仍然有限，但當受試者對Tagrisso 產生耐藥（中位無進展生存期為9個月）時，c-Met基因擴增是一條重要的耐藥變化路徑。

沃利替尼，獨特的高選擇性c-Met抑製劑

沃利替尼是一種高選擇性口服c-Met（也被稱作間充質上皮轉移因子）受體酪氨酸激酶抑製劑，研究發現這種酪氨酸激酶在多種實體瘤中表現異常。沃利替尼作為一種強效的高選擇性口服抑製劑，旨在克服第一代c-Met抑製劑在臨床上表現出的問題，包括腎毒性。

Tagrisso ，針對EGFR和T790M突變的選擇性抑製劑

阿斯利康的新藥Tagrisso （奧希替尼）每日一次80mg片劑，是第一個針對成人局部晚期或轉移性的EGFR T790M突變陽性非小細胞肺癌的藥物。非臨床體外研究顯示奧希替尼對一系列臨床相關EGFRm 和T790M突變的非小細胞肺癌細胞株的突變EGFR磷酸化具有很強的藥效和抑製作用，但是對野生型EGFR作用相對很小。

以經過EGFR-TKI治療後疾病進展的局部晚期或轉移性EGFR T790M陽性的非小細胞肺癌患者為受試者，AURA3 臨床III期驗證性研究正在將Tagrisso 與含鉑雙重化療方案進行比較。Tagrisso 同時也在接受輔助治療或轉移性的一線患者中進行研究，包括伴隨/未伴隨腦轉移，患軟腦膜疾病以及聯合其他藥物進行治療。

Iressa ，EGFR突變抑製劑

阿斯利康研發的Iressa （吉非替尼）是一種治療晚期或轉移性EGFR突變陽性非小細胞肺癌的靶向單藥。Iressa 通過抑制EGFR中的酪氨酸激酶阻斷腫瘤細胞增長和擴散的信號傳達。EGFR突變約佔高加索人非小細胞肺癌患者人群的10-15%，佔亞洲非小細胞肺癌患者人群的30-40% 。Iressa 已在全球91個國家獲批上市。

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