引领HER2+胃癌治疗新突破，复宏汉霖 HER2双靶向疗法揽获MED和ESMO GI认可

2024-07-10

近期，由上海市东方医院李进教授担任主要研究者的创新型抗HER2单抗HLX22联合汉曲优®（HLX02，曲妥珠单抗，美国商品名：HERCESSI™️，欧洲商品名：Zercepac®）和化疗用于一线治疗HER2阳性晚期或转移性胃/胃食管交界部（G/GEJ）癌的II期临床研究（HLX22-GC-201）结果相继于2024年欧洲肿瘤学会胃肠道肿瘤研讨会（ESMO GI）和Cell Press细胞出版社旗下的综合性医学旗舰期刊MED发布。研究结果显示，在HLX02（曲妥珠单抗）联用化疗的基础上加入HLX22可明显改善HER2阳性G/GEJ癌 HER2阳性G/GEJ癌患者一线治疗的效果，且安全性可控。 HLX22-GC-201研究数据首次发布于2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI），其后该研究数据及数据更新亦分别获选发布于MED和2024年ESMO GI壁报环节，多次验证了研究结果可靠性的同时，更进一步提升了该研究在学术界的影响力。迄今为止，胃癌/胃食管连接部（G/GEJ）癌依旧构成了一大全球健康问题。据GLOBOCAN数据显示，2022年全球约有100万新发病例[1]。多数G/GEJ癌患者确诊时已处于疾病晚期，总体预后不良，5年生存率仅为6%[2,3]，这其中HER2 阳性患者占比约为12%-23%，且其预后较HER2阴性患者更差[2,4]。目前，对于HER2阳性的局部晚期/转移性G/GEJ患者，其标准一线疗法为曲妥珠单抗联用化疗，针对PD-L1 阳性（PD-L1 CPS≥1）的患者，一些指南亦推荐进一步叠加联用免疫治疗，但持续疗效和预后仍有待进一步改善[5]，存在巨大的未满足临床需求。目前，全球尚无同类用于治疗HER2阳性胃癌 HER2阳性胃癌的HER2双靶向疗法获批准上市。 HLX22为复宏汉霖自AbClon, Inc.许可引进、并后续自主研发的靶向HER2的创新型单克隆抗体。可结合在HER2的亚结构域IV，但结合表位与曲妥珠单抗有所不同，使得HLX22和曲妥珠单抗能够同时与HER2结合，从而产生更强的HER2受体阻断效果。临床前研究表明，HLX22与曲妥珠单抗联合治疗可抑制表皮生长因子（EGF）和HRG1（Histidine-Rich Glycoprotein 1）诱导的细胞增殖，增强体外和体内的抗肿瘤活性，且HLX22的I期临床试验证实产品安全且可耐受[6]。 HLX22-GC-201是一项比较HLX22或安慰剂分别联合注射用曲妥珠单抗（HLX02）及化疗（XELOX）一线治疗HER2阳性的局部晚期/转移性胃癌 HER2阳性的局部晚期/转移性胃癌患者的疗效和安全性的两阶段临床研究。第一阶段为安全导入期。第二阶段为一项随机、双盲、多中心II期临床研究，分为两个部分。在第一部分中，合格的受试者按1:1:1的比例随机分组，分别接受HLX22 25 mg/kg + HLX02 + XELOX（A组）、HLX22 15 mg/kg + HLX02 + XELOX（B组）或安慰剂 + HLX02 + XELOX（C组）治疗。主要终点是由IRRC根据RECIST v1.1评估的无进展生存期（PFS）和客观缓解率（ORR）。次要终点包括其他疗效指标和安全性。截至2024年3月25日（更新数据截止日期），53例患者被随机分配至A组（n = 18）、B组（n = 17）和C组（n = 18），中位随访时间为22.1个月。中位年龄为60岁，44（83.0%）例患者为男性，30（56.6%）例患者的 ECOG 表现状态为1。与C组（安慰剂组）相比，A组的IRRC评估的中位PFS明显更长（13.7 vs. 8.2个月；分层HR 0.40，95% CI 0.16–1.03），B组的中位PFS未达到（分层HR 0.1，95% CI 0.03–0.43）。 IRRC评估的无进展生存期（PFS）各组的IRRC评估的ORR分别为77.8%、82.4%和88.9%。各组分别有18（100.0%）例、16（94.1%）例和17（94.4%）例患者发生治疗相关不良事件（TRAE）。A组、B组和C组各有6（33.3%）例、1（5.9%）例和1（5.6%）例患者发生严重TRAE。仅C组有1（5.6%）例患者报告了5级TRAE。研究结果显示，HLX22联合HLX02及化疗在HER2阳性晚期G/GEJ癌 HER2阳性晚期G/GEJ癌患者中耐受性良好。 IRRC评估的客观缓解率（ORR）各组的IRRC评估的ORR分别为77.8%、82.4%和88.9%。各组分别有18（100.0%）例、16（94.1%）例和17（94.4%）例患者发生治疗相关不良事件（TRAE）。A组、B组和C组各有6（33.3%）例、1（5.9%）例和1（5.6%）例患者发生严重TRAE。仅C组有1（5.6%）例患者报告了5级TRAE。研究结果显示，HLX22联合HLX02及化疗在HER2阳性晚期G/GEJ癌 HER2阳性晚期G/GEJ癌患者中耐受性良好。【参考文献】 [1] Bray F, Laversanne M, Sung H, et al. CA Cancer J Clin. 2024: 1-35. [2] Ajani JA. et al. J Natl Compr Canc Netw 2022;20(2):167-92. [3] Alsina M. et al. Nat Rev Gastroenterol Hepatol 2023;20(3):155-70. [4] Gravalos C. et al. Ann Oncol 2008;19(9):1523-9. [5] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.1.2024 [6] Zhu X, Ding Y, Wang Q, Yang G, Zhou L, Wang Q. HLX22, an anti-HER-2 monoclonal antibody, in patients with advanced solid tumors overexpressing human epidermal growth factor receptor 2: an open-label, dose-escalation, phase 1 trial. Invest New Drugs. 2023;41(3):473-482. doi:10.1007/s10637-023-01338-7 关于复宏汉霖复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已在中国上市5款产品，在国际获批上市3款产品，23项适应症获批，3个上市申请分别获中国药监局和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，公司商业化生产基地已相继获得中国、欧盟和美国GMP认证。复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状®的肿瘤免疫联合疗法。继国内首个生物类似药汉利康®（利妥昔单抗）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac®）、汉达远®（阿达木单抗）和汉贝泰®（贝伐珠单抗）相继获批上市，创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。 Advances in HER2+ GC: Dual HER2 Blockade Therapy Presented on MED and ESMO GI Recently, results of the phase 2 study of HLX22, an innovative anti-HER2 monoclonal antibody (mAb), in combination with HANQUYOU (HLX02, trastuzumab, trade name: HERCESSI™️ in the U.S., Zercepac® in Europe) and chemotherapy for the first-line treatment of HER2-positive advanced gastric/gastroesophageal junction (G/GEJ) cancer were presented on 2024 ESMO Gastrointestinal Cancers Congress (ESMO GI) and MED, a flagship clinical and translational research monthly journal by Cell Press. The leading principal investigator for this study is Professor Jin Li from Shanghai East Hospital, School of Medicine, Tongji University. The results showed that the addition of HLX22 to HLX02 (trastuzumab) plus chemotherapy as first-line therapy improved efficacy in HER2-positive G/GEJ cancer patients with manageable safety. The results of HLX22-GC-201 were first presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI). The study data and updated results with another 7.8 months of follow-up were accepted for publication on MED and for presentation at the 2024 ESCO GI, respectively, which validated the reliability of the results of the study repeatedly and further enhanced the impact of the study in the academic community. Until now, G/GEJ cancer still constitutes a major global health problem. Globally, there were around 1 million new cases in 2022 [1]. G/GEJ cancer is often diagnosed at an advanced stage, with a poor prognosis and a 5-year relative survival rate of only 6% [2,3]. The reported rates of HER2 positivity in patients with gastric cancer range from 12% to 23%, and the prognosis for patients with HER2-positive disease used to be even worse than those with HER2-negative disease [2-4]. Currently, for patients with HER2-positive locally advanced/metastatic G/GEJ cancer, the standard first-line treatment is trastuzumab plus chemotherapy. Immunotherapies are recommended to be added for tumours with positive PD-L1 expression defined by combined positive score greater than 1. However, the sustained efficacy and prognosis for these treatments need to be further improved [5], indicating a significant unmet medical need. To date, no dual HER2 blockade therapy for the treatment of HER2-positive gastric cancer has been approved. HLX22 is an innovative anti-HER2 mAb that was introduced from AbClon, Inc. and further investigated and developed by Henlius. HLX22 can bind to HER2 subdomain IV at a different binding site from trastuzumab, which allows the simultaneous binding of HLX22 and trastuzumab to HER2. Pre-clinical studies showed that the combination therapy of HLX22 and trastuzumab inhibited the cell proliferation induced by epidermal growth factor (EGF) and Histidine-Rich Glycoprotein 1 (HRG1) and enhanced the antitumour activity in vitro and in vivo. The phase 1 clinical trial of HLX22 demonstrates that HLX22 was well tolerated and had good safety profiles [6]. HLX22-GC-201 is a two-stage study aims to compare the efficacy and safety of HLX22 versus placebo in combination with trastuzumab injection (HLX02) and XELOX, as first-line therapy for HER2-positive locally advanced or metastatic gastric cancer patients. Stage 1 was a safety run-in stage while stage 2 was a randomised, double-blind, multi-centre, phase 2 study. Stage 2 was further divided into two parts. In part 1, eligible patients were randomised 1:1:1 to receive HLX22 (group A: HLX22, 25mg/kg; group B: HLX22, 15mg/kg) in combination with HLX02 and XELOX, or placebo in combination with HLX02 and XELOX (group C). The primary endpoints include progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC) per RECIST v1.1. The secondary objectives are to evaluate other efficacy endpoints, safety and tolerability. As of March 25, 2024 (updated data cutoff date), 53 patients were enrolled and randomised to group A (n=18), group B (n=17), and group C (n=18) with a median follow-up duration of 22.1 months. Of the 53 enrolled patients, 44 (83.0%) were male; the median age of all patients was 60.0 years. 30 (56.6%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 1. Compared with group C (placebo group), the IRRC-assessed median PFS was markedly prolonged (13.7 vs. 8.2 months; stratified HR 0.40, 95% CI 0.16-1.03) in group A; not reached in group B (stratified HR 0.10, 95% CI 0.03–0.43). ORRs were 77.8% vs 82.4% vs 88.9% in A, B and C, respectively. Treatment-related adverse events (TRAEs) were observed in 18 (100.0%), 16 (94.1%), and 17 (94.4%) patients in group A, B, and C, among whom 6 (33.3%), 1 (5.9%), and 1 (5.6%) patients experienced serious TRAEs. Only one (5.6%) patient in group C reported a grade 5 TRAE. HLX22 plus HLX02 and XELOX as first-line therapy was well tolerated in patients with HER2-positive advanced G/GEJ cancer. Recently, the investigational new drug application (IND) for phase 3 international multicenter clinical study of HLX22 in combination with trastuzumab and chemotherapy for the first-line treatment of HER2-positive advanced gastric cancer has been approved by the United States Food and Drug Administration (FDA). Moving forward, Henlius will actively improve efficiency through innovations, with a particular focus on addressing the unmet medical needs, and efficiently promote the clinical development of HLX22 globally, so as to provide more high-quality and affordable therapies for patients worldwide. About Henlius Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. Up to date, 5 products have been launched in China, 3 have been approved for marketing in overseas markets, 23 indications are approved worldwide, and 3 marketing applications have been accepted for review in China and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP. Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets. 联系方式媒体：PR@Henlius.com 投资者：IR@Henlius.com 喜欢本文内容点击下方按钮·分享 ·收藏 ·点赞 ·在看

引领HER2+胃癌治疗新突破，复宏汉霖HER2双靶向疗法揽获MED和ESMO GI认可

引领HER2+胃癌治疗新突破，复宏汉霖 HER2双靶向疗法揽获MED和ESMO GI认可