张力

教授、主任医师，博士生导师

中山大学附属肿瘤医院内科 主任，博导，肺癌首席专家
中国抗癌协会肿瘤康复与姑息治疗专业委员会候任主任委员
中国抗癌协会临床试验专业委员会副主任委员
中国临床肿瘤学会（CSCO）常务理事
CSCO-免疫治疗专家委员会候任主委
广东省抗癌协会肿瘤化疗专业委员会主任委员
广东省抗癌协会肺癌专业委员会副主任委员
广东省医学领军人才、“特支计划”杰出人才（南粤百杰）
国家重点研发计划“精准医学研究”肺癌的诊疗规范及应用方案的精准化研究项目负责人

此项研究为Ⅱ期单臂多中心注册临床研究，入组患者为克唑替尼治疗耐药后的晚期或转移性ALK阳性NSCLC，给予恩沙替尼225mg QD治疗方案（空腹或与食物同服），主要研究终点为独立评审委员会（IRC）评估的客观缓解率（ORR）（图1），次要研究终点是无进展生存期（PFS），颅内客观缓解率（iORR）。

This was a phase II,one-arm,multicenter registered clinical study,patients with advanced or metastatic ALK-positive NSCLC who had resistance to crizotinib were enrolled in this study to receive ensartinib 225 mg QD (fasting or with food),the primary endpoint was the objective response rate (ORR) evaluated by the Independent Review Committee (Figure 1),and the secondary endpoints were progression-free survival (PFS) and intracranial objective response rate (iORR).

     图1.研究设计(Figure 1.Study design)

在2017年9月—2018年4月期间，一共招募了160例患者，156名患者接受了治疗，147名患者纳入独立评审委员会的疗效评估，入组人群的中位随访时间为294天（表1），数据截止时间为2019年4月29日。

From September 2017 to April 2018,a total of 160 patients were enrolled,156 patients were treated,and 147 patients were included in the IRC's efficacy evaluation.The median follow-up duration of the enrolled patients was 294 days (Table 1),the data deadline was April 29,2019.

     表1.基线特征(Table 1.Baseline characteristics)

总体疗效：恩沙替尼治疗克唑替尼耐药后总体人群的IRC-ORR为52%（95%CI，43%～60%），疾病控制率（DCR）为93%（95%CI，88%～97%）（表2）。研究者评估的中位无进展生存期为9.6个月（95%CI，7.4个月～11.6个月）（图2）。

Overall efficacy:After treatment of crizotinib resistance with ensartinib,the overall population IRC-ORR was 52% (95% CI, 43%-60%),and the disease control rate (DCR) was 93% (95% CI, 88%-97%) (Table 2).The median progression-free survival evaluated by the investigators was 9.6 months (95% CI, 7.4-11.6m) (Figure 2).

     表2.客观反应率(Table 2.Objective response rate)

     图2.研究者评估的PFS

 (Figure 2.PFS evaluated by the investigators)

颅内疗效：40例基线有可测量脑转移病灶的患者中，颅内客观缓解率（iORR）为70%（28/40；95%CI，53～83），颅内疾病控制率（iDCR）为98%（39/40；95%CI，87～100）（表3），恩沙替尼对颅内有显著的疗效。

Intracranial efficacy:In the 40 patients with baseline measurable cerebral metastasis,the intracranial objective response rate (iORR) was 70% (28/40), and the intracranial disease control rate (iDCR) was 98% (39/40) (Table 3),indicating that ensartinib has significant intracranial efficacy.

     表3.颅内疗效(Table 3.Intracranial efficacy)

对ALK二次突变的疗效：恩沙替尼对二次突变的总体疗效为44%（20/45），其中对第二代共有耐药突变位点G1202R的有效率为33%，对阿来替尼常见耐药位点I1171T/S的ORR为50%，对塞瑞替尼常见耐药位点F1174L/V的ORR为71%（表4），提示恩沙替尼对第二代ALK抑制剂的耐药位点仍有一定的疗效。

Efficacy on secondary ALK mutation:The overall efficacy of ensartinib on secondary mutation was 44% (20/45),in which,the effective rate on the second-generation common resistant mutation site G1202R was 33%,the ORR on common alectinib resistance site I1171T/S was 50%,and the ORR on common ceritinib resistance site F1174L/V was 71% (Table 4),suggesting that ensartinib still has certain efficacy on second-generation drug resistance sites.

     表4.恩沙替尼对ALK二次突变的疗效

(Table 4.Efficacy of ensartinib on secondary ALK mutations)

安全性分析研究结果显示：接受恩沙替尼治疗后，主要治疗相关的不良反应为皮疹、谷丙转氨酶（ALT）、谷草转氨酶（AST）的升高，但多为1～2级，发生率分别为56%、46%、41%；3～4级不良事件发生率仅为6%、6%、3%（表5），与阿来替尼最常见的3～4级AE发生率相近。

The results of the safety analysis showed that after treatment with ensartinib,the main treatment relatedadverse events included rash and elevated ALT and AST,mostly at grades 1-2,with an incidence of 56%,46% and 41%,respectively;the incidence of grades 3-4 AEs was only 6%,6% and 3%,respectively (Table 5),similar to the incidence of the most common grades 3-4 AEs of alectinib.

     表5.安全性分析(Table 5.Safety analysis)

此项中国Ⅱ期注册临床研究结果证实恩沙替尼二线治疗ALK阳性晚期NSCLC患者带来更长无进展生存期，同时安全性方面优于同类ALK抑制剂。为ALK阳性NSCLC患者二线治疗提供了全新选择，有望开启ALK二线治疗领域全新格局。

The results of this phase II Chinese registered clinical study confirm that second-line treatment with ensartinib brings longer progression-free survival to patients with ALK-positive advanced NSCLC,and its safety is better than that of ALK-TKI.It provides a new choice for second-line treatment of ALK-positive NSCLC,and it is expected to open a new pattern in the field of ALK second-line therapy.

恩沙替尼是贝达药业在肺癌领域继表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）后的又一重大布局产品。恩沙替尼已于2018年12月申报新药上市申请（NDA），于2019年2月被国家药品监督管理局（NMPA）纳入优先审评审批流程。9月2日贝达药业发布公告，更新了恩沙替尼注册临床研究最新数据：截止2019年5月31日，经独立评审委员会评估的整体人群ORR为52.6%（95%CI，44.4%～60.6%），DCR为87.8%（95%CI，81.6%～92.5%），中位PFS为11.2个月（95%CI，7.6个月～11.9个月）；颅内疗效方面：颅内ORR为71.4%（95%CI，55.4%～84.3%），颅内DCR为95.2%（95%CI，83.8%～99.4%）。期待恩沙替尼早日上市，为中国ALK阳性NSCLC患者带来一种全新的治疗选择，造福更多肺癌患者。

Ensartinib is another major product of Beta Pharma in the field of lung cancer following EGFR-TKI.Ensartinib was declared for NDA in December 2018 and was included in the priority review and approval process by the NMPA in February 2019.On September 2,Beta Pharma issued an announcement to update the latest data on the registered clinical study of ensartinib:As of May 31,2019,the overall population ORR evaluated by the Independent Review Committee (IRC) is 52.6% (95%CI,44.4%-60.6%),the DCR is 87.8% (95%CI,81.6%-92.5%),and the median PFS is 11.2 months (95% CI,7.6-11.9m);intracranial efficacy: the intracranial ORR is 71.4% (95%CI,55.4%-84.3%),and the intracranial DCR is 95.2% (95%CI, 83.8%-99.4%). It is expected that ensartinib will be listed soon to bring a new treatment option to Chinese patients with ALK-positive NSCLC and benefit more patients with lung cancer.

贝达药业股份有限公司，2003年由海归博士团队在杭州创办，是一家以自主知识产权创新药物研究、开发为核心，集研发、生产、营销于一体的国家级高新技术企业，始终聚焦于恶性肿瘤、糖尿病、心脑血管病等严重影响人类健康的疾病。

公司总部位于杭州余杭经济技术开发区，在北京、杭州分别设有新药研发中心，现有员工近千人，海归博士数十位，其中6位已入选国家“千人计划”。2016年11月7日，公司在深交所创业板挂牌上市。

贝达现有在研新药近30项，其中明星产品盐酸埃克替尼的研发及产业化成果荣获2015年国家科技进步一等奖，这是中国化学制药行业和浙江企业界第一次获此殊荣；2016年，盐酸埃克替尼获得我国工业领域的最高奖——“中国工业大奖”。

Betta Pharma Co.,Ltd. was founded by a team of doctorial returnees in Hangzhou in 2003.It is a state-level high-tech enterprise that integrates R&D,production and marketing,with the research and development of innovative drugs with independent intellectual property as its core,and focuses on malignant tumors,diabetes,cardiovascular and cerebrovascular diseases and other diseases that seriously affect human health.

The company,headquartered in Hangzhou Yuhang Economic and Technological Development Zone,has new drug research and development centers in Beijing and Hangzhou,nearly 1,000 employees and dozens of doctorial returnees,and 6 of them have been included in the national “Thousand Talents Program”.On November 7, 2016,the company was listed on the GEM in the Shenzhen Stock Exchange.

Betta Pharma has nearly 30 new drugs under research,among which the research,development and industrialization of star product icotinib hydrochloride has won the first prize of National Science and Technology Progress Award in 2015,and this is the first in China's chemical pharmaceutical industry and Zhejiang business circles;in 2016,icotinib hydrochloride won the highest award in China's industrial circle -"China Industrial Award".