Venue: The 13^th International Conference of the Asian Clinical Oncology Society in Chiang Mai, Thailand

Abstract #: ABS093

Authors: Jin Li, Shukui Qin, Yuxian Bai, Yanhong Deng, Lei Yang, Zhendong Chen, Haijun Zhong, Rui-hua Xu, Hongming Pan, Weijian Guo, Yongqian Shu, Ying Yuan, Jianfeng Zhou, Nong Xu, Tianshu Liu, Dong Ma, Changping Wu, Ying Cheng, Jianming Xu, Donghui Chen, Wei Li, Sanyuan Sun, Zhuang Yu, Peiguo Cao, Lin Shen, Haihui Chen, Jiejun Wang, Shubin Wang, Hongbing Wang, Rubing Han, Songhua Fan, Xin Wang, Ye Hua, Hongyan Li, Xiaojun Guo

Presenter: Dr. Lei Yang (Nantong Tumor Hospital, Nantong, China)

Session: Abstract Session 2: Colorectal Cancer, Lung

Date: Saturday, 24 February, 2018

Location: Empress Grand Hall

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Savolitinib in Patients with Metastatic Renal Cell Carcinoma

S Vari¹, B Szabados¹, A GomezdeLiano¹, K Mousa², L Rammazzo², A Prendergast², T Powles¹

Background:

Anti-PD-L1 and CTLA-4 antibodies are associated with clinical benefit in mRCC. MET dysregulation plays an important role in papillary RCC pathogenesis and is a mechanism of resistance against TKIs in ccRCC. Pre-clinical data suggests benefit in dual MET plus PD-L1 inhibition. The phase Ib part of this trial was designed to determine the RP2D of savolitinib (c-Met kinase inhibitor) and durvalumab (PD-L1 mAb) when given in combination (NCT028195996).

Methods:

International, investigator led phase Ib/IIa study with a dose de-escalation (3+3) part in patients with metastatic renal cell cancer (irrespective of PD-L1 and MET alteration status). Dose level 0 (600mg OD savolitinib and 1500mg Q4wk durvalumab) and -1A (400mg OD savolitinib and 1500mg Q4wk durvalumab) were investigated. Patients received a 28 day cycle of savolitinib before commencing durvalumab treatment on day 1 of cycle 2. Treatment given until PD (RECIST v1.1) or intolerable toxicity. Primary endpoint was DLTs over a 2 month period. Secondary endpoints included PK and safety (CTCAE v4.03).

Results:

6 evaluable patients enrolled at dose level 0 with no reported DLTs. Median age 46 years (25-59), median ECOG 1. ccRCC (n=4), papillary cell (n=2). All 6 patients had Intermediate Heng risk score. 3 ccRCC patients had 3 previous lines of therapy and 1 ccRCC received 1 prior therapy. 1 papillary cell patient entered with no prior lines of therapy and 1 received 4 prior lines. Worst reported toxicity related to IMP was fatigue G2-3 (n=2). Other toxicities: G1-2 pain (n=3), G2 Caugh (n=1), G2 diarrhoea (n=1), G1 gastritis (n=1), G1 nausea (n=2), G2 Peripheral edema (n=2), Rash G2 (n=1), G1 transaminitis (n=1), PPE G2 (n=1). Two AESIs were reported, gastritis G1 and G3 numbness. At 12 weeks best response by RECIST v1.1 was SD (n=4).

Conclusions:

Based on DLTs and cumulative toxicity, dose level 0 was selected as the RP2D for the expansion phase. Dose level -1A was not investigated. Adverse events were in keeping with established single agent safety profiles. The expansion phase is open to recruitment in the UK and Spain and is investigating two cohort populations. mccRCC or sarcomatoid RCC patients (n=156) randomised (1:1:1:1) to savolitinib alone, durvalumab alone, savolitinib plus durvalumab or tremelimumab and durvalumab followed by durvalumab alone. Metastatic papillary patients (n=39) receive durvalumab plus savolitinib. A biomarker enrichment phase in tumours positive for MET or PD-L1 alterations may be investigated.

2018 年2 月13 日：和黃醫藥今日宣布呋喹替尼（HMPL-013）以非小細胞肺癌為適應症的III 期臨床試驗“FALUCA” 順利完成患者入組工作。呋喹替尼是一種高選擇性強效口服血管內皮生長因子受體（VEGFR）1,2 及3 的抑製劑。呋喹替尼在中國以結直腸癌、肺癌或胃癌為適應症的多項II 期和III 期臨床研究均達到了主要終點。FALUCA 試驗的結果預計將於2018 年末，即患者的總體生存（“OS”）數據成熟時公佈。如果試驗成功，和黃醫藥將向中國食品藥品監督管理局（”CFDA”）遞交呋喹替尼的第二個新藥上市（”NDA“）。呋喹替尼的首個以結直腸癌為適應症的NDA 申請，已於2017 年6 月獲CFDA 受理。

關於呋喹替尼

呋喹替尼（HMPL-013）是一種新型的高選擇性小分子候選藥物。臨床研究證實：通過一日一次的口服劑量即可有效的抑制血管內皮生長因子受體（VEGFR），且脫靶毒性低於其他靶向療法。呋喹替尼良好的耐受性以及無藥物間相互作用的特性，為其與其它癌症療法相聯合提供了理論支持，例如當前正在進行的呋喹替尼聯合化療或其他靶向治療的臨床研究。

關於FALUCA

FALUCA是一項研究呋喹替尼以晚期非鱗非小細胞肺癌為適應症，隨機雙盲安慰劑對照的多中心III期註冊性臨床試驗。目標受試者為晚期非鱗狀非小細胞肺癌患者，這些受試者至少經過2 輪抗腫瘤治療的失敗。受試者以2:1的比例隨機接受每天口服一次5毫克的呋喹替尼（服藥三週/停藥一周為一周期）加最佳支持治療（“BSC”）或安慰劑加最佳支持治療。隨機分層因素包括患者EGFR基因的狀態以及既往VEGF抑製劑的使用情況。研究的主要試驗終點為總生存期，次試驗終點包括無進展生存期，客觀緩解率，疾病控制率和緩解持續時間。該研究詳情可登錄clinicaltrials.gov，檢索NCT02691299查看。

FALUCA研究基於一項設計相似、以非小細胞肺癌為適應症的II期臨床試驗。91名受試者根據2：1的比例接受呋喹替尼加最佳支持治療或安慰劑加最佳支持治療。結果顯示該試驗成功達到了無進展生存期的主要療效終點，並未出現重大不良安全事件。研究結果已於第17屆世界肺癌大會上以口頭報告的形式公佈（clinicaltrials.gov註冊號NCT02590965）。

其它呋喹替尼臨床研究概覽

肺癌（中國）：呋喹替尼聯合易瑞沙^® （吉非替尼）作為一線療法，治療晚期或轉移性非小細胞肺癌（clinicaltrials.gov註冊號NCT02976116）的一項II期臨床試驗與FALUCA同期進行。初步研究結果已於2017年10月16日第18屆世界肺癌大會上以口頭報告的形式公佈。

結直腸癌（中國）：2017年6月，中國食品藥品監督管理總局（CFDA）受理呋喹替尼以晚期結直腸癌（CRC）為適應症的新藥上市申請；2017年9月，CFDA公佈因呋喹替尼具有明顯臨床價值而授予其優先審評的資格。呋喹替尼的新藥上市申請基於一項在中國成功完成的III期關鍵性註冊研究FRESCO。該研究共計納入416名CRC患者，其結果於2017年6月5日在美國臨床腫瘤學會年會上以口頭報告的形式公佈（clinicaltrials.gov註冊號NCT02314819）。呋喹替尼的3 項早期臨床研究為FRESCO研究的開展奠定了基礎，這3 項早期臨床研究包括：納入40名實體瘤患者的I期臨床研究、納入62名結直腸癌患者的Ib期臨床研究以及納入71名結直腸癌患者的II期臨床研究。

胃癌（中國）：FRUTIGA（clinicaltrials.gov註冊號NCT03223376）是一項隨機雙盲III期臨床試驗，旨在評估呋喹替尼聯合泰素^® （紫杉醇）對比泰素^® 單藥化療治療二線晚期胃癌或GEJ腺癌的療效和安全性。研究已於2017年10月啟動，預計將納入超過500名患者，目標受試者為經組織學或細胞學確診為晚期胃癌或GEJ腺癌，且對含有鉑類和氟尿嘧啶的一線標準化療無應答的患者。FRUTIGA基於一項呋喹替尼聯合泰素^® 以二線晚期胃癌為適應症的多中心開放標籤Ib期劑量探索/ 劑量擴展臨床試驗（clinicaltrials.gov註冊號NCT02415023）。該項Ib期臨床試驗結果顯示，接受呋喹替尼聯合泰素^® 治療的患者療效顯著且耐受性良好。

在中國范圍內，呋喹替尼由和黃醫藥和禮來合作開發。

美國橋接試驗：和黃醫藥於2017年12月在美國啟動一項多中心開放標籤的I期臨床試驗，旨在評估呋喹替尼在美國晚期實體瘤患者中的安全性、耐受性和藥代動力學特性。首位受試者已於12月初接受給藥治療。該研究詳情可登錄clinicaltrials.gov，檢索NCT03251378查看。

London: Monday, February 5, 2018: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) will be announcing its final results for the year ended December 31, 2017 on Monday, March 12, 2018 at 7:00 am Greenwich Mean Time (GMT).

An analyst presentation will be held at 9:00 am GMT (5:00 pm Hong Kong Time) on the same day at Citigate Dewe Rogerson, 3 London Wall Buildings, London, EC2M 5SY, UK, which will be webcast via the company website at www.chi-med.com/investors/event-information/. The presentation will be available to download before the analyst presentation begins.

For North America based analysts and investors, Chi-Med will also host a conference call with Q&A at 9:00 am Eastern Daylight Time (1:00 pm GMT).

Details of the analyst presentation and conference call dial-in will be provided in the financial results announcement. A replay will also be available on the website shortly after each event.

About Chi-Med

Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its 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: 1). For more information, please visit: www.chi-med.com.

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