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：和黄医药今日宣布呋喹替尼（HMPL-013）以非小细胞肺癌为适应症的III期临床试验“FALUCA”顺利完成患者入组工作。呋喹替尼是一种高选择性强效口服血管内皮生长因子受体（VEGFR）1,2及3的抑制剂。呋喹替尼在中国以结直肠癌、肺癌或胃癌为适应症的多项II期和III期临床研究均达到了主要终点。FALUCA试验的结果预计将于2018年末，即患者的总体生存（“OS”）数据成熟时公布。如果试验成功，和黄医药将向中国食品药品监督管理局（”CFDA”）递交呋喹替尼的第二个新药上市（”NDA“）。呋喹替尼的首个以结直肠癌为适应症的NDA申请，已于2017年6月获CFDA受理。

关于呋喹替尼

呋喹替尼（HMPL-013）是一种新型的高选择性小分子候选药物。临床研究证实：通过一日一次的口服剂量即可有效的抑制血管内皮生长因子受体（VEGFR），且脱靶毒性低于其他靶向疗法。呋喹替尼良好的耐受性以及无药物间相互作用的特性，为其与其它癌症疗法相联合提供了理论支持，例如当前正在进行的呋喹替尼联合化疗或其他靶向治疗的临床研究。

关于FALUCA

FALUCA是一项研究呋喹替尼以晚期非鳞非小细胞肺癌为适应症，随机双盲安慰剂对照的多中心III期注册性临床试验。目标受试者为晚期非鳞状非小细胞肺癌患者，这些受试者至少经过2轮抗肿瘤治疗的失败。受试者以2:1的比例随机接受每天口服一次5毫克的呋喹替尼（服药三周/停药一周为一周期）加最佳支持治疗（“BSC”）或安慰剂加最佳支持治疗。随机分层因素包括患者EGFR基因的状态以及既往VEGF抑制剂的使用情况。研究的主要试验终点为总生存期，次试验终点包括无进展生存期，客观缓解率，疾病控制率和缓解持续时间。该研究详情可登录clinicaltrials.gov，检索NCT02691299查看。

FALUCA研究基于一项设计相似、以非小细胞肺癌为适应症的II期临床试验。91名受试者根据2：1的比例接受呋喹替尼加最佳支持治疗或安慰剂加最佳支持治疗。结果显示该试验成功达到了无进展生存期的主要疗效终点，并未出现重大不良安全事件。研究结果已于第17届世界肺癌大会上以口头报告的形式公布（clinicaltrials.gov 注册号 NCT02590965）。

其它呋喹替尼临床研究概览

肺癌（中国）：呋喹替尼联合易瑞沙^®（吉非替尼）作为一线疗法，治疗晚期或转移性非小细胞肺癌（clinicaltrials.gov 注册号 NCT02976116）的一项II期临床试验与FALUCA同期进行。初步研究结果已于2017年10月16日第18届世界肺癌大会上以口头报告的形式公布。

结直肠癌（中国）：2017年6月，中国食品药品监督管理总局（CFDA）受理呋喹替尼以晚期结直肠癌（CRC）为适应症的新药上市申请；2017年9月，CFDA公布因呋喹替尼具有明显临床价值而授予其优先审评的资格。呋喹替尼的新药上市申请基于一项在中国成功完成的III期关键性注册研究FRESCO。该研究共计纳入416名CRC患者，其结果于2017年6月5日在美国临床肿瘤学会年会上以口头报告的形式公布（clinicaltrials.gov 注册号 NCT02314819）。呋喹替尼的3项早期临床研究为FRESCO研究的开展奠定了基础，这3项早期临床研究包括：纳入40名实体瘤患者的I期临床研究、纳入62名结直肠癌患者的Ib期临床研究以及纳入71名结直肠癌患者的II期临床研究。

胃癌（中国）：FRUTIGA（clinicaltrials.gov 注册号NCT03223376）是一项随机双盲III期临床试验，旨在评估呋喹替尼联合泰素^®（紫杉醇）对比泰素^®单药化疗治疗二线晚期胃癌或GEJ腺癌的疗效和安全性。研究已于2017年10月启动，预计将纳入超过500名患者，目标受试者为经组织学或细胞学确诊为晚期胃癌或GEJ腺癌，且对含有铂类和氟尿嘧啶的一线标准化疗无应答的患者。FRUTIGA基于一项呋喹替尼联合泰素^®以二线晚期胃癌为适应症的多中心开放标签Ib期剂量探索/剂量扩展临床试验（clinicaltrials.gov 注册号 NCT02415023）。该项Ib期临床试验结果显示，接受呋喹替尼联合泰素^®治疗的患者疗效显著且耐受性良好。

在中国范围内，呋喹替尼由和黄医药和礼来合作开发。

美国桥接试验：和黄医药于2017年12月在美国启动一项多中心开放标签的I期临床试验，旨在评估呋喹替尼在美国晚期实体瘤患者中的安全性、耐受性和药代动力学特性。首位受试者已于12月初接受给药治疗。该研究详情可登录clinicaltrials.gov，检索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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