H药再登肿瘤学顶级期刊，Cancer Cell刊登H药联合化疗一线治疗鳞状非小细...

北京时间2024年1月5日，复宏汉霖自主研发的抗PD-1单抗H药 汉斯状（斯鲁利单抗）联合化疗一线治疗晚期鳞状非小细胞肺癌（sqNSCLC）的注册性III期临床试验（ASTRUM-004）数据在肿瘤学国际顶级期刊Cancer Cell（影响因子：50.3）正式发表，为H药在肺癌领域的卓越表现再添新证。该研究由上海市肺科医院周彩存教授牵头开展。

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ASTRUM-004总人群最终分析结果于2023年世界肺癌大会（World Conference on Lung Cancer, WCLC）以口头报告形式首次亮相，并于2023欧洲肿瘤学会亚洲分会（ESMO Asia）年会以壁报形式展示该研究亚洲人亚组数据。基于ASTRUM-004研究结果，H药已于2022年正式获得中国国家药品监督管理局（NMPA）批准用于联合化疗一线治疗sqNSCLC，并凭借优异的临床疗效，荣获2023年《CSCO非小细胞肺癌诊疗指南》指南推荐作为晚期sqNSCLC一线治疗I级推荐，为sqNSCLC患者群体带去更多生存获益。

论文通讯作者、ASTRUM-004研究牵头研究者

上海市肺科医院 周彩存教授

ASTRUM-004研究验证了H药联合化疗可以显著改善未经治疗的局部晚期或转移性sqNSCLC患者的生存期，且安全性可控，为sqNSCLC领域的研究和创新再次注入新的活力。目前，斯鲁利单抗联合化疗已成为国内肺鳞癌一线治疗标准方案，也为这一患者群体提供了创新、有效、可靠的治疗选择。

复宏汉霖执行董事、首席执行官兼首席财务官

朱俊先生

一直以来，复宏汉霖都将创新和质量置于公司发展的核心位置。H药多个关键性临床研究在国际知名期刊上接连发表，这是对我们以患者为中心推动高质量研究的不懈努力的高度认可。我们将继续致力于推动科学前沿的落地转化，聚焦解决临床治疗难点和痛点，为全球患者提供更多突破性的治疗选择。

深耕肺癌领域未满足临床需求

肺癌是全球最常见癌症之一，是中国发病率和死亡率最高的恶性肿瘤。根据国家癌症中心发布的最新全国癌症统计数据显示，肺癌新发病例82.8万，总死亡人数65.7万^[1]。NSCLC约占所有肺癌的80%-85%^[2]，约50%的NSCLC患者在诊断时已处于不适合手术切除的局部晚期或已发生转移。而晚期sqNSCLC约占晚期NSCLC的30%，治疗模式多以含铂双药化疗为主，疗效不甚理想，患者的中位生存期较短，很多不超过1年，因此，该领域存在着巨大的未满足的医疗需求。近年来，免疫检查点抑制剂在临床治疗中取得了诸多突破，在NSCLC方面也获得了长足的发展，尤其是抗PD-1单抗联合卡铂+白蛋白紫杉醇治疗晚期或转移性sqNSCLC已获得NCCN、CSCO等国内外权威指南推荐，推动晚期NSCLC进入免疫治疗时代。

ASTRUM-004是一项随机、双盲、国际多中心Ⅲ期研究，旨在研究斯鲁利单抗对比安慰剂分别联合化疗在既往未接受治疗的晚期sqNSCLC患者中的疗效和安全性。截至2023年1月31日，537例患者以2∶1的比例随机分组，两组患者分别接受静脉输注斯鲁利单抗4.5 mg/kg或安慰剂（最多35个周期）联合化疗（卡铂和白蛋白紫杉醇，4-6个周期），每三周为一个周期。无进展生存期（PFS）的更新分析显示，中位随访时长为16.9个月时，斯鲁利单抗-化疗组相对于安慰剂-化疗组在中位PFS上持续获益【IRRC评估的中位PFS，8.3 vs. 5.7个月；风险比（HR）0.53，95% CI 0.42-0.67】。在预设的各亚组分析中，斯鲁利单抗-化疗组在PFS的HR值上均展现出优势。总生存期（OS）的最终分析显示，中位随访时长为31.1个月时，治疗方案中添加斯鲁利单抗显著延长了中位OS（22.7 vs. 18.2个月；HR 0.73，95% CI 0.58-0.93；P=0.010，达到了显著性阈值0.046）。截至最终分析时，已有97名（54.2%）安慰剂-化疗组患者转为接受斯鲁利单抗治疗。经两阶段模型调整后的安慰剂-化疗组中位OS为11.5个月（95% CI 9.6-13.5），斯鲁利单抗-化疗组相对于安慰剂-化疗组的HR为 0.49（95% CI 0.37-0.64）。安全性方面，斯鲁利单抗联合化疗的安全性良好。与单纯化疗相比，在未经治疗的局部晚期或转移性sqNSCLC患者中，斯鲁利单抗显著改善了生存期，且安全性可控。对于这一患者人群，斯鲁利单抗联合化疗将是一种非常有前景的治疗方案。

斯鲁利单抗-化疗组中位PFS持续改善

H药（斯鲁利单抗）显著延长中位OS

屡获海内外学术及行业认可

H药 汉斯状（斯鲁利单抗）是复宏汉霖首个自主研制的创新型单抗药。自2022年3月获批上市以来，H药已在中国获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、sqNSCLC、广泛期小细胞肺癌（ES-SCLC）和食管鳞状细胞癌（ESCC），惠及逾51,000名患者。2023年12月，H药正式获得印度尼西亚药品管理局批准用于ES-SCLC的治疗。H药用于治疗ES-SCLC和非鳞状非小细胞肺癌（nsNSCLC）的上市申请也已分别获得欧盟EMA和中国NMPA受理。以H药为基础，公司在全球开展多元化的肿瘤免疫联合疗法，并充分运用自有管线覆盖肿瘤特异性靶点、抗血管生成靶点和肿瘤免疫靶点等，助力H药与单抗、化疗等治疗手段开展联合治疗。以临床需求为导向，公司就H药在消化道肿瘤和肺癌领域进行了差异化、多维度布局，适应症广泛覆盖肺癌、食管鳞癌、头颈鳞癌和胃癌等高发大癌种，在全球范围内累计入组逾3600名受试者。

在肺癌领域，除ASTRUM-004之外，H药针对ES-SCLC适应症的关键性临床研究ASTRUM-005已在全球四大顶级医学期刊之一的《美国医学会杂志》（JAMA）发表，成为全球首个登上JAMA主刊的小细胞肺癌免疫治疗临床研究。而在消化道领域，H药MSI-H实体瘤适应症和食管鳞状细胞癌（ESCC）两项关键临床研究结果则分别发表于国际知名期刊British Journal of Cancer和《自然-医学》（Nature Medicine）。H药多项关键性临床研究结果在国际知名期刊的接连发表，在全球范围内展现了中国医药企业自主研制PD-1单抗的创新水平和研发实力，体现了国际学术舞台对H药质量的充分认可。此外，H药还荣获《CSCO 小细胞肺癌诊疗指南》、《CSCO非小细胞肺癌诊疗指南》、《CSCO 食管癌诊疗指南》、《CSCO结直肠癌诊疗指南》、《CSCO免疫检查点抑制剂临床应用指南》和《中国食管癌放射治疗指南》等多部权威指南推荐，为肿瘤临床诊疗提供重要参考。

未来，复宏汉霖将持续加码创新，以临床需求为先导，继续高效地为全球患者提供更多可负担、疗效更好的治疗方案。

【参考文献】

[1] Rongshou Zheng, Siwei Zhang, Hongmei Zeng, et al. Cancer incidence and mortality in China, 2016. Journal of the National Cancer Center, 2022, ISSN 2667-0054, dio:10.1016/j.jncc.2022.02.002

[2] About Lung Cancer. American Cancer Society. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. Version 3.2023

关于Cancer Cell

Cancer Cell是Cell Press旗下专注癌症发现科学、转化和临床肿瘤学领域的顶级刊物，其期刊影响因子为50.3。作为在发表开创性癌症研究和肿瘤学论文方面的先驱，该刊在坚持严谨的基础研究的同时，致力于弥合前沿发现与临床实践之间的鸿沟，并关注癌症的整体视角。

关于H药 汉斯状

H药 汉斯状为重组人源化抗PD-1单抗注射液（通用名：斯鲁利单抗注射液），是全球首个获批一线治疗小细胞肺癌的抗PD-1单抗，已在中国和印度尼西亚获批上市。截至目前，H药已有4项适应症获批上市，2项适应症上市申请分别在中国和欧盟获受理，10余项临床试验同步在全球开展。

2022年3月，H药正式于中国获批上市，目前可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（sqNSCLC）、广泛期小细胞肺癌（ES-SCLC）及食管鳞状细胞癌（ESCC）。H药联合化疗一线治疗非鳞状非小细胞肺癌（nsNSCLC）和一线治疗广泛期小细胞肺癌（ES-SCLC）的上市申请也分别获得中国NMPA和欧盟EMA受理。聚焦肺癌和消化道肿瘤，复宏汉霖积极推进H药与公司其他产品的协同以及与创新疗法的联合，在全球同步开展10余项肿瘤免疫联合疗法临床试验，于中国、美国、土耳其、波兰、格鲁吉亚等国家和地区累计入组超3600人。H药的4项关键性临床研究结果分别发表于知名期刊《美国医学会杂志》（JAMA）、《自然-医学》（Nature Medicine）、Cancer Cell和British Journal of Cancer。此外，H药还荣获《CSCO 小细胞肺癌诊疗指南》、《CSCO非小细胞肺癌诊疗指南》、《CSCO 食管癌诊疗指南》、《CSCO结直肠癌诊疗指南》、《CSCO免疫检查点抑制剂临床应用指南》和《中国食管癌放射治疗指南》等多部权威指南推荐，为肿瘤临床诊疗提供重要参考。海外方面，H药治疗SCLC也已获得美国FDA和欧盟EC的孤儿药资格认定，并在美国启动了一项H药对比一线标准治疗阿替利珠单抗的头对头桥接试验。

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。

Cancer Cell Published the Results of ASTRUM-004: HANSIZHUANG Combined with Chemotherapy for the First-line Treatment of sqNSCLC

Shanghai, China, January 5^th, 2024 – Shanghai Henlius Biotech, Inc. (2696.HK) announced that ASTRUM-004, Henlius’ pivotal phase 3 clinical study of anti-PD-1 mAb HANSIZHUANG (serplulimab) plus chemotherapy as first-line treatment for previously untreated locally advanced or metastatic squamous non-small-cell lung cancer (sqNSCLC), was published in Cancer Cell, a highly regarded oncology journal with an impact factor of 50.3. This publication serves as further evidence of the exceptional performance of HANSIZHUANG in the field of lung cancer. The study was led by Professor Caicun Zhou from Shanghai Pulmonary Hospital.

Results of the overall population ASTRUM-004 were initially presented at the IASLC 2023 World Conference on Lung Cancer (WCLC 2023) in the form of oral presentation. Additionally, the data from its Asian subgroup were showcased in a poster session at the European Society of Medical Oncology Asia (ESMO Asia) Congress 2023. Previously in 2022, the new drug application (NDA) of serplulimab for the treatment of sqNSCLC has been approved by the National Medical Products Administration (NMPA) based on the results of ASTRUM-004. Furthermore, HANSIZHUANG has been recommended as Grade I by the 2023 CSCO Guidelines for Non-Small Cell Lung Cancer for the first-line treatment of advanced sqNSCLC due to its outstanding clinical effectiveness and survival advantages for sqNSCLC patients.

Prof. Caicun Zhou, the corresponding author, as well as the leading principal investigator of the study, said, “The ASTRUM-004 study validated in the final analysis that serplulimab in combination with chemotherapy significantly improved survival with a manageable safety profile in previously untreated locally advanced or metastatic sqNSCLC patients. These findings re-energize research and innovation in the field of sqNSCLC. Serplulimab has become the first-line treatment of sqNSCLC in China and offers a novel, effective, and reliable therapy option for this patient population.”

Mr. Jason Zhu, Executive Director, CEO, and CFO of Henlius said, “Henlius has always prioritized innovation and quality in our company's development, and the publication of multiple pivotal studies of HANSIZHUANG in internationally known journals is testimony of our unwavering commitment revolves around a patient-centric approach. We will remain devoted to promoting scientific frontier translation, focusing on clinical treatment challenges and pain points, and providing more breakthrough therapeutic solutions for patients worldwide.”

Addressing unmet medical needs in lung cancer

Lung cancer is one of the most common cancers in the world, and it is the malignant tumour with the highest morbidity and mortality in China. According to the latest national cancer statistics released by the National Cancer Center, there are 828,000 new cases of lung cancer, with a total death toll of 657,000 ^[1], in which NSCLC accounts for about 80% - 85% of all lung cancers ^[2], and about 50% of NSCLC patients are in locally advanced stage that is not suitable for surgical resection or have metastasis at the time of diagnosis. Treatment of advanced sqNSCLC, making up about 30% of the advanced NSCLC, is given first place to a platinum-based doublet chemotherapy, which has limited efficacy, and the median survival time is quite short, many of which are less than 1 year. Therefore, there are huge unmet medical needs. In recent years, immune checkpoint inhibitors have made breakthroughs in NSCLC treatment, especially, the anti-PD-1 mAb combined with carboplatin and albumin-bound paclitaxel which has been recommended by domestic and international authoritative guidelines for the treatment of advanced or metastatic sqNSCLC, pushing forward the treatment of the advanced NSCLC into the era of immunotherapy.

ASTRUM-004 is a randomized, double-blind, international multicentre phase 3 study to compare the clinical efficacy and safety of serplulimab plus chemotherapy versus chemotherapy in patients with locally advanced or metastatic sqNSCLC who have not previously received systemic treatment. As of January 31, 2023, a total of 537 patients were randomized 2:1 to receive intravenous serplulimab 4.5 mg/kg or placebo (up to 35 cycles) in combination with chemotherapy (carboplatin and nab-paclitaxel, 4-6 cycles) in 3-week cycles. Updated analysis of progression-free survival (PFS) showed that with a median follow-up of 16.9 months, the PFS benefit of serplulimab-chemotherapy vs. placebo-chemotherapy was maintained (IRRC-assessed, median, 8.3 vs. 5.7 months; hazard ratio [HR] 0.53, 95% CI 0.42-0.67). The HR for PFS consistently favoured serplulimab-chemotherapy group across the prespecified subgroups. Final analysis of overall survival (OS) demonstrated that with a median follow-up of 31.1 months, OS was significantly prolonged with the addition of serplulimab (median, 22.7 vs. 18.2 months; HR 0.73, 95% CI 0.58-0.93; p=0.010, crossing the significance boundary of 0.046). By the time of the final analysis, 97 (54.2%) patients in the placebo-chemotherapy group had crossed over to serplulimab monotherapy. The median OS in the placebo-chemotherapy group adjusted by the two-stage model was 11.5 months (95% CI 9.6–13.5), resulting in an adjusted HR of 0.49 (95% CI 0.37–0.64). The safety profile of serplulimab plus chemotherapy was manageable. In conclusion, serplulimab plus chemotherapy could be a promising treatment option for this patient population.

Recognized by academic communities and industry

HANSIZHUANG (serplulimab) is the first innovative mAb developed by Henlius. Since launched in March 2022, HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, sqNSCLC, extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), benefiting more than 51,000 patients. In December 2023, HANSIZHUANG was approved in Indonesia for the treatment of ES-SCLC. The marketing applications of the first-line treatment for non-squamous non-small cell lung cancer (nsNSCLC) and ES-SCLC are under review by the NMPA and the European Medicines Agency (EMA), respectively. Henlius actively promotes HANSIZHUANG in conjunction with in-house products of the company such as tumour-specific target, angiogenesis target, immunotherapeutic target, etc. and chemotherapy drugs to conduct immune combination therapies. Underpinned by the patient-centric strategy, Henlius has carried out a differentiated and multi-dimensional layout in the field of gastrointestinal cancer and lung cancer, covering a wide variety of indications, such as lung cancer, ESCC, head and neck squamous cell carcinoma and gastric cancer, etc. To date, more than 3,600 subjects have been enrolled worldwide for HANSIZHUANG clinical trials.

As for the first-line lung cancer treatment, in addition to ASTRUM-004, a pivotal phase 3 clinical study of HANSIZHUANG for the first-line treatment of ES-SCLC, ASTRUM-005, has been published in the Journal of the American Medical Association (JAMA), one of the top four medical journals, and became the world's first clinical study on SCLC immunotherapy in JAMA. In the field of gastrointestinal cancer, the results of 2 pivotal trials of HANSIZHUANG in MSI-H solid tumours and ESCC were published in the British Journal of Cancer and Nature Medicine, respectively. Furthermore, HANSIZHUANG was respectively recommended by the CSCO Guidelines for Small Cell Lung Cancer, the CSCO Guidelines for Non-Small Cell Lung Cancer, the CSCO Guidelines for Esophageal Cancer, the CSCO Guidelines for Colorectal Cancer, the CSCO Clinical Practice Guidelines on Immune Checkpoint Inhibitor, the China Guidelines for Radiotherapy of Esophageal Cancer, and other definitive guides, providing valuable references for clinical diagnosis and treatment of tumours.

Looking forward, Henlius will actively improve efficiency through innovations, focusing on unmet medical needs to bring more high-quality and affordable therapies to patients worldwide.  

About Cancer Cell

Cancer Cell is a Cell press journal which provides a high-profile forum to promote major advances in cancer discovery, translational research and oncology, with a journal impact factor of 50.3. As a pioneer in publishing innovative cancer research and oncology, the journal aims to bridge the gap between cutting-edge discoveries and clinical applications. It upholds high standards for fundamental research and emphasizes a comprehensive perspective on cancer.

About HANSIZHUANG

HANSIZHUANG (recombinant humanized anti-PD-1 monoclonal antibody injection, generic name: serplulimab injection) is the first anti-PD-1 mAb for the first-line treatment of SCLC and has been approved in China and Indonesia. Up to date, 4 indications are approved for marketing, 2 marketing applications are under review in China and the EU, and more than 10 clinical trials are ongoing across the world.

HANSIZHUANG was approved in China in March 2022 and has been approved by the National Medicinal Products Administration (NMPA) for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC). The marketing applications of the first-line treatment for non-squamous non-small cell lung cancer (nsNSCLC) and ES-SCLC are under review by the NMPA and the European Medicines Agency (EMA), respectively. Focusing on lung and gastrointestinal cancer, the synergy of HANSIZHUANG with in-house products of the company and innovative therapies are being actively promoted. The company has initiated more than 10 clinical trials on immuno-oncology combination therapies in a wide variety of indications with more than 3,600 subjects enrolled in China, the U.S., Turkey, Poland, Georgia and other countries and regions. The results of 4 pivotal trials of HANSIZHUANG were published in the Journal of the American Medical Association (JAMA), Nature Medicine, Cancer Cell, and British Journal of Cancer, respectively. Furthermore, HANSIZHUANG was respectively recommended by the CSCO Guidelines for Small Cell Lung Cancer, the CSCO Guidelines for Non-Small Cell Lung Cancer, the CSCO Guidelines for Esophageal Cancer, the CSCO Guidelines for Colorectal Cancer, the CSCO Clinical Practice Guidelines on Immune Checkpoint Inhibitor, the China Guidelines for Radiotherapy of Esophageal Cancer, and other definitive guides, providing valuable references for clinical diagnosis and treatment of tumours. On the other hand, serplulimab was granted orphan drug designations by the U.S. FDA and the EC for the treatment of SCLC, and its bridging head-to-head trial in the United States to compare HANSIZHUANG to standard of care atezolizumab (anti-PD-L1 mAb) for the first-line treatment of ES-SCLC is well under way.

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, 1 has been approved for marketing in overseas markets, 18 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 Plant certificated by China and the EU GMP and Songjiang First Plant certificated by China 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), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. Its NDA for the treatment of esophageal squamous cell carcinoma (ESCC) is under review. What's more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

(复星医药)