转自：复星医药
2024年1月17日，复宏汉霖（2696.HK）宣布，公司两项创新药最新临床研究结果以壁报形式入选2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI），分别是由中山大学肿瘤防治中心徐瑞华教授担任主要研究者的H药汉斯状®（斯鲁利单抗）联合汉贝泰®（HLX04，贝伐珠单抗）和化疗用于一线治疗转移性结直肠癌（mCRC）的II/III期临床研究（HLX10-015-CRC301），以及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®（曲妥珠单抗，欧洲商品名：Zercepac®，澳大利亚商品名：Tuzucip®和Trastucip®）和化疗用于一线治疗HER2阳性局部晚期或转移性胃/胃食管交界部（G/GEJ）癌的II期临床研究（HLX22-GC-201）。
HLX10-015-CRC301研究
结肠直肠癌（CRC）是全球最常见的恶性肿瘤之一。据GLOBOCAN数据显示，2020年全球约有超过190万新发病例，死亡病例逾90万例[1]。mCRC的标准一线治疗包括血管内皮生长因子（VEGF）抑制剂（如贝伐珠单抗）联用化疗[2-4]，但持续疗效和预后仍有待进一步改善。此前，斯鲁利单抗凭借良好的研究数据已于2022年3月获批用于治疗微卫星高度不稳定（MSI-H）实体瘤并被纳入《CSCO结直肠癌诊疗指南（2023版）》和《CSCO免疫检查点抑制剂临床应用指南（2023版）》。复宏汉霖通过HLX10-015-CRC301研究进一步开展免疫疗法探索，希望为更多结直肠癌患者提供更有效的治疗方法。该研究结果显示，H药联合汉贝泰®和化疗显著改善未经治疗的mCRC患者生存期，且安全性可控。
HLX22-GC-201研究
胃/胃食管交界部（G/GEJ）癌的治疗是一个全球性的挑战。据GLOBOCAN数据显示，2020年全球约有超过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年相对生存率仅为6%[5,6]，这其中HER2阳性患者的预后曾较HER2阴性患者更差[5,7]。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。与曲妥珠单抗类似，HLX22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。HLX22-GC-201研究结果显示，在HLX02 + XELOX的基础上加入HLX22可提高HER2阳性G/GEJ癌患者一线治疗的生存期和抗肿瘤反应，且安全性可控。目前，全球尚无同类用于治疗HER2阳性胃癌的HER2双靶点疗法获批准上市。
此次ASCO GI公布的数据详情如下：
摘要标题：
斯鲁利单抗联合HLX04和XELOX对比安慰剂联合贝伐珠单抗和XELOX一线治疗转移性结直肠癌：一项II/III期研究
试验设计：
这是一项随机、双盲、多中心的II/III期研究；此次将侧重于介绍II期部分。既往未接受过系统性治疗的不可切除转移性/复发性结直肠腺癌患者按1:1的比例随机分组，分别接受斯鲁利单抗（300 mg，Q3W IV）联合HLX04（贝伐珠单抗，7.5 mg/kg，Q3W IV）和XELOX（A组）或安慰剂联合贝伐珠单抗和XELOX（B组）治疗。随机化按PD-L1表达水平（CPS <1 vs. 1≤ CPS <50 vs. CPS ≥50）、ECOG PS评分（0 vs. 1）和原发肿瘤部位（左侧 vs. 右侧）进行分层。主要终点是IRRC根据RECIST 1.1评估的PFS。次要终点包括其他疗效终点、安全性、药代动力学、生物标志物探索和生活质量评估。
结果：
2021年7月16日至2022年1月20日，本试验共入组并随机分配114例患者（A组，n = 57；B组，n = 57）。其中83（72.8%）例为男性。所有患者均患有IV期结直肠癌（CRC）。94例有MSI状态评估结果的患者中有90（95.7%）例为MSS。本报告将重点介绍研究药物在接受了给药的患者（A组，n = 55；B组，n = 57）即调整的意向性治疗人群中的疗效和安全性。截至2023年6月1日（数据截止日期），中位随访时间为17.7个月。与B组相比，A组的IRRC评估的中位PFS明显更长（17.2 vs. 10.7个月；分层HR 0.60，95% CI 0.31–1.14）。两组的中位OS均未达到（分层HR 0.77，95% CI 0.41–1.45）。A组和B组各有36（65.5%）例患者和32（56.1%）例患者出现≥3级治疗相关不良事件，最常见的3级及以上治疗相关不良事件为中性粒细胞计数降低（21.8% vs. 10.5%）和血小板计数降低（16.4% vs. 10.5%）。A组和B组各有5（9.1%）例患者和1（1.8%）例患者发生了≥3级免疫相关不良事件。A组和B组各有4（7.3%）例患者和3（5.3%）例患者发生了治疗相关死亡。
结论：
与安慰剂联合贝伐珠单抗和XELOX相比，斯鲁利单抗联合HLX04和XELOX明显延长了PFS，改善了其他疗效终点，且安全性可控。斯鲁利单抗联合HLX04和XELOX是一种有前景的转移性CRC患者一线治疗方案，值得进一步研究。
摘要标题：
HLX22联合HLX02和XELOX一线治疗HER2阳性局部晚期或转移性胃/胃食管交界部癌：一项随机、双盲、多中心II期研究
试验设计：
本研究在最后一例患者入组3个月后揭盲。入组的患者为既往未接受过系统性抗肿瘤治疗的局部晚期或转移性HER2阳性胃/胃食管交界部（G/GEJ）癌患者。研究分为两个部分，本报告将侧重于介绍第一部分。在第一部分中，患者按1:1:1的比例随机分组，分别接受HLX22（创新型抗HER2单抗）25 mg/kg + HLX02（曲妥珠单抗）+ XELOX（A组）、HLX22 15 mg/kg + HLX02 + XELOX（B组）或安慰剂 + HLX02 + XELOX（C组）治疗，每3周为一个周期。主要终点是由IRRC根据RECIST v1.1评估的PFS和ORR。次要终点包括其他疗效指标和安全性。
结果：
截至2023年7月30日（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14.3个月。44（83.0%）例患者为男性。主要疗效结果见表1。表1中报告的肿瘤评估由IRRC进行。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5（27.8%）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。
结论：
在HLX02 + XELOX的基础上加入HLX22可提高HER2阳性G/GEJ癌患者一线治疗的生存期和抗肿瘤反应，且安全性可控。
表1. 疗效结果
*对A组和C组之间以及B组和C组之间的风险比（HR）进行估算。
NE，不可评估；NR，未达到。
【参考文献】
[1] Sung H. et al. CA Cancer J Clin 2021;71(3):209-49.
[2] Iwasa, S. et al. Cancer Commun (Lond) 43, 519-522 (2023).
[3] Hurwitz, H. et al. N Engl J Med 350, 2335-2342 (2004).
[4] Benson, A. B. et al. J Natl Compr Canc Netw 20, 1139-1167 (2022).
[5] Ajani JA. et al. J Natl Compr Canc Netw 2022;20(2):167-92.
[6] Alsina M. et al. Nat Rev Gastroenterol Hepatol 2023;20(3):155-70.
[7] Gravalos C. et al. Ann Oncol 2008;19(9):1523-9.
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，在国际上市2款产品，19项适应症获批，3个上市申请分别获中国药监局、美国FDA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，上海徐汇基地和松江基地（一）均已获得中国和欧盟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20多种创新单克隆抗体，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）、中国首个自主研发的中欧双批单抗药物汉曲优®（曲妥珠单抗，欧洲商品名：Zercepac®，澳大利亚商品名：Tuzucip®和Trastucip®）、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。
Results from Clinical Trials of Two Henlius’ Novel Products Released at ASCO GI 2024
Recently, the latest clinical data of two Henlius products were released online and will be presented in poster sessions at the 2024 ASCO Gastrointestinal Cancers Symposium (ASCO GI), namely, the phase 2/3 study (HLX10-015-CRC301) of Henlius’ NMPA approved anti-PD-1 monoclonal antibody (mAb) HANSIZHUANG (serplulimab) in metastatic colorectal cancer (mCRC) with Professor Rui-Hua Xu of Sun Yat-Sen University Cancer Center as the leading principal investigator, and the phase 2 study (HLX22-GC-201) of Henlius’ novel anti-HER2 mAb, HLX22, combined with HANQUYOU (trastuzumab for injection, HLX02, trade name in Europe: Zercepac®; trade names in Australia: Tuzucip® and Trastucip®) and chemotherapy for the first-line treatment of HER2-positive gastric/gastroesophageal junction (G/GEJ) cancer with Professor Jin Li of Shanghai East Hospital, School of Medicine, Tongji University as the leading principal investigator of this study.
HLX10-015-CRC301
Colorectal cancer (CRC) is one of the most common malignancies globally. Over 1.9 million newly diagnosed cases and more than 900,000 deaths were estimated in 2020[1]. The standard of care for metastatic CRC (mCRC) involves the combination of vascular endothelial growth factor (VEGF) inhibitor, such as bevacizumab, and systemic chemotherapy[2-4]. Previously, HANSIZHUANG was approved in China for the treatment of MSI-H solid tumours in March 2022 based on its excellent efficacy data, and then was recommended by the CSCO Guidelines for Colorectal Cancer and the CSCO Clinical Practice Guidelines on Immune Checkpoint Inhibitor. The company is continuing to explore immuno-oncology therapy for this arena, with the goal of delivering more effective treatment for a broader population of patients. The results of this study demonstrated that serplulimab plus HLX04 (a bevacizumab biosimilar) and XELOX markedly prolonged PFS compared to placebo plus bevacizumab and XELOX, with a manageable safety profile.
HLX22-GC-201
Gastric/gastroesophageal junction (G/GEJ) cancer represents a global healthcare challenge with more than 1 million new cases estimated in 2020[1]. G/GEJ cancer is often diagnosed at the advanced stage, and the prognosis of advanced G/GEJ cancer is poor, with a 5-year relative survival rate of only 6%[5,6]. And the prognosis for patients with HER2-positive disease used to be even worse than those with HER2-negative disease[5-7]. HLX22 is an innovative anti-HER2 mAb that was introduced from AbClon, Inc. and further researched 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. The pre-clinical studies showed that the combination therapy of HLX22 and trastuzumab would inhibit the cell proliferation induced by epidermal growth factor (EGF) and Histidine-Rich Glycoprotein 1 (HRG1) and enhance the antitumor activity in vitro and in vivo. The phase 1 clinical trial of HLX22 demonstrates that HLX22 is well tolerated and has good safety profiles. As of now, no similar dual HER2 blockade therapy for the treatment of HER2-positive gastric cancer has received approval for commercialization globally.
The data released at ASCO GI 2024 are as follows:
Title
First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: a phase 2/3 study
Study design
This was a randomized, double-blind, multicenter phase 2/3 study; current report will focus on the phase 2 part. Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomized 1:1 to receive serplulimab (300 mg, Q3W IV) plus HLX04 (a bevacizumab biosimilar, 7.5 mg/kg, Q3W IV) and XELOX (group A) or placebo plus bevacizumab and XELOX (group B). Randomization was stratified by PD-L1 expression level (CPS <1 vs. 1≤ CPS <50 vs. CPS ≥50), ECOG PS score (0 vs. 1), and primary tumor site (left- vs. right-sided). The primary endpoint was IRRC-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments.
Results
Between July 16, 2021 and January 20, 2022, 114 patients were enrolled and randomly assigned to group A (n = 57) and group B (n = 57). 83 (72.8%) patients were male. All patients had stage IV colorectal cancer (CRC), and 90 out of the 94 (95.7%) with available MSI status were MSS. Current report will focus on efficacy and safety findings in the modified intention-to-treat population, which included only patients who received study treatment (group A, n = 55; group B, n = 57). As of June 1, 2023 (data cutoff), median follow-up duration was 17.7 months. IRRC-assessed median PFS was longer in group A than in group B (17.2 vs. 10.7 months; stratified HR 0.60, 95% CI 0.31–1.14). Median OS was not reached in either group (stratified HR 0.77, 95% CI 0.41–1.45). 36 (65.5%) patients in group A and 32 (56.1%) in group B had grade ≥3 treatment-related adverse events (AEs), most commonly neutrophil count decreased (21.8% vs. 10.5%) and platelet count decreased (16.4% vs. 10.5%). Grade ≥3 immune-related AEs were reported for 5 (9.1%) patients in group A and 1 (1.8%) in group B. Treatment-related deaths occurred in 4 (7.3%) patients in group A and 3 (5.3%) in group B.
Conclusion
Serplulimab plus HLX04 and XELOX prolonged PFS compared to placebo plus bevacizumab and XELOX. Improvements in other efficacy endpoints were also observed with a manageable safety profile in patients with metastatic CRC. Serplulimab plus HLX04 and XELOX is a promising first-line treatment option for metastatic CRC patients that warrants further investigation.
Title
HLX22 plus HLX02 and XELOX for first-line treatment of HER2-positive locally advanced or metastatic gastric/gastroesophageal junction cancer: a randomized, double-blind, multicenter phase 2 study
Study design
The study was unblinded 3 months after the last patient was enrolled. Patients with locally advanced or metastatic HER2-positive gastric/gastroesophageal junction (G/GEJ) cancer and had not received prior systemic antitumor therapy were enrolled. The study consisted of 2 parts; current report will focus on part 1. In part 1, patients were randomized 1:1:1 to receive HLX22 (a novel anti-HER2 monoclonal antibody) 25 mg/kg + HLX02 (a trastuzumab biosimilar) + XELOX (group A), HLX22 15 mg/kg + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were PFS and ORR assessed by IRRC per RECIST v1.1. Secondary endpoints included other efficacy measures and safety.
Results
As of July 30, 2023 (data cutoff), 53 patients were randomized to group A (n = 18), B (n = 17), and C (n = 18), and were followed up for a median of 14.3 months. 44 (83.0%) patients were male. Main efficacy results are presented in Table 1. Tumor assessments reported in Table 1 were performed by IRRC. Treatment-related adverse events (TRAEs) occurred in 18 (100.0%), 16 (94.1%), and 17 (94.4%) patients in the respective groups. Serious TRAEs were observed in 5 (27.8%) patients in group A, 1 (5.9%) in group B, and 1 (5.6%) in group C. Only 1 (5.6%) patient in group C had a grade 5 TRAE.
Conclusion
Adding HLX22 to HLX02 + XELOX improved survival and antitumor response in patients with HER2-positive G/GEJ cancer in the first-line setting, with a manageable safety profile.
Table 1. Efficacy results
*Hazard ratio (HR) was estimated between group A and C, as well as between group B and C.
NE, not evaluable; NR, not reached.
【References】
[1] Sung H. et al. CA Cancer J Clin 2021;71(3):209-49.
[2] Iwasa, S. et al. Cancer Commun (Lond) 43, 519-522 (2023).
[3] Hurwitz, H. et al. N Engl J Med 350, 2335-2342 (2004).
[4] Benson, A. B. et al. J Natl Compr Canc Netw 20, 1139-1167 (2022).
[5] Ajani JA. et al. J Natl Compr Canc Netw 2022;20(2):167-92.
[6] Alsina M. et al. Nat Rev Gastroenterol Hepatol 2023;20(3):155-70.
[7] Gravalos C. et al. Ann Oncol 2008;19(9):1523-9.
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, 2 has been approved for marketing in overseas markets, 19 indications are approved worldwide, and 3 marketing applications have been accepted for review in China, the U.S., 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 centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Facility and Songjiang First Plant, both certificated by China and the EU GMP.
Henlius has pro-actively built a diversified and high-quality product pipeline covering over 20 innovative monoclonal antibodies (mAbs) 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 for injection, trade name in Europe: Zercepac®; trade names in Australia: Tuzucip® and Trastucip®), the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, 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.
