Trastuzumab-PKRB(Celltrion)

- Revenue up 45% and operating profit up 86.3% YoY, with a 32.4% operating margin demonstrating solid growth. - High-margin new products grew 76% YoY, accounting for 65% of total biologics revenue. - COGS ratio improved by 5.4 percentage points YoY, reflecting continued improvement in profitability. - Operating margin above 30% was achieved despite continued investment in R&D for future growth. - The company aims to exceed its annual guidance, supported by major market tenders and continued expansion of newly launched products in the second half. INCHEON, South Korea – Celltrion today announced that it recorded consolidated revenue of KRW 1.3937 trillion and operating profit of KRW 451.8 billion for the second quarter of 2026. The results represent year-over-year (YoY) increases of 45% in revenue and 86.3% in operating profit. Following a record quarterly revenue performance in the first quarter, the company also achieved its highest-ever quarterly revenue in the second quarter. Operating margin improved by 7.2 percentage points from a year earlier to 32.4%, demonstrating both strong top-line growth and enhanced profitability. Compared with the preliminary earnings announced on July 3, revenue increased by KRW 93.7 billion and operating profit rose by KRW 21.8 billion. The latest results reflect more than just revenue growth, highlighting qualitative growth driven by a portfolio shift toward new products and improved manufacturing efficiency. Stable sales of key products, strong global sales growth of newly launched high-margin products, and faster-than-expected cost structure improvements contributed to the performance. The results also demonstrated a virtuous business cycle in which profits from commercialized products provide stable financial support for research and development investments to fuel future growth. ▲ High-Margin New Products Continue Strong Growth Across Major Markets, Accounting for 65% of Biologics Revenue Second-quarter growth was driven by the rapid expansion of high-margin new products[1], while key products including Remsima, Truxima, and Herzuma maintained solid market positions. Truxima ranked No. 1 in market share in the United States, supported by expanded long-term supply agreements, while Remsima maintained its leading position across key markets. Herzuma achieved a record-high market share of 78% in Japan and exceeded 30% market share in Europe. Revenue from new products increased 76% YoY, expanding their contribution to total biologics revenue to 65%. By product, Remsima SC surpassed a 32% market share across the EU5[2] markets, while Zymfentra, the U.S. brand of Remsima SC, has continued to see steady uptake since launch. Yuflyma maintained its leading position in the European adalimumab market and continued to gain market share in the United States through expanded supply capabilities and distribution networks. Vegzelma maintained its leadership position in Europe and strengthened its U.S. growth foundation through formulary listings by two major pharmacy benefit managers (PBMs). Combined quarterly revenue from five newly launched products — Eydenzelt, Avtozma, Omlyclo, Stoboclo and Osenvelt, and Steqeyma — whose global rollout accelerated last year, exceeded KRW 300 billion, up 49% from the previous quarter. Celltrion plans to increase the share of biologics revenue generated by new products to approximately 70% in the second half of the year by continuing to expand launches into additional markets and broaden approved indications. ▲ COGS Ratio Improves to 38%; Product Mix and Manufacturing Efficiency Accelerate Profit Growth The cost of sales ratio improved to 38%, down 5.4 percentage points YoY and 2.1 percentage points from the previous quarter. The improvement was driven by a more favorable product mix resulting from the growing contribution of high-margin new products, as well as enhanced cost competitiveness through the depletion of high-cost inventory, higher production yields, and process optimization. This led to the emergence of operating leverage, with operating profit growth significantly exceeding revenue growth. The company expects profitability improvement to accelerate further in the second half as continued top-line growth generates greater economies of scale, alongside more efficient SG&A spending. The profitability improvement reflects a structural change driven by a shift in revenue mix toward new products and enhanced manufacturing competitiveness, rather than one-off factors. As the contribution of new products continues to increase, the foundation for stable earnings growth is expected to strengthen further. ▲ Operating Margin Exceeds 30% After Recognizing R&D Expenses for Future Growth Celltrion's second-quarter performance was particularly noteworthy compared with previous quarters, as the company achieved a 32.4% operating margin despite recognizing R&D expenses related to future growth. Celltrion continues to invest in R&D—from the discovery of follow-on biosimilars and novel drug candidates to preclinical and clinical studies, regulatory approval, and commercialization—and recognizes the related costs in current-period earnings. Unlike manufacturing-focused business models, this structure entails maintaining the profitability of current products while simultaneously bearing the investment burden required for future pipeline development. Yet Celltrion delivered an operating margin exceeding 30%, demonstrating that the cash-generating capability and the competitiveness of its business provide strong support for continued R&D investment. Celltrion continues to strengthen a business model in which commercial success supports investment in the development of follow-on biosimilars and novel drug candidates, driving new product launches and revenue growth. This has led to growing recognition that the company's value should be assessed not only on its current profitability, but also on the value of its pipeline and long-term growth prospects supported by sustained R&D investment. ▲ Expanding Biosimilar and Novel Drug Pipeline to Strengthen Future Growth Drivers Building on the launch of 11 biosimilars globally as of last year, Celltrion is accelerating development of its next-generation pipeline. The company plans to build a portfolio of 18 products by 2030, including biosimilars referencing autoimmune disease treatments such as Ocrevus, Cosentyx, and Taltz, as well as oncology therapies such as Keytruda and Darzalex. Supported by the ongoing trend toward relaxed clinical requirements among regulatory authorities, certain follow-on products are expected to benefit from reduced patient enrollment requirements, shorter development timelines, and lower R&D costs. In novel drug development, the company continues to expand its novel drug portfolio through both in-house R&D and open innovation initiatives, with programs spanning antibody-drug conjugates (ADCs), multispecific antibodies, and obesity treatments. Leveraging the stable cash flows generated by its biosimilar business, Celltrion aims to accelerate its transformation into a global biopharmaceutical company by delivering tangible R&D outcomes from its novel drug pipeline. ▲ Stronger Second-Half Growth Expected; Company Aims to Exceed Full-Year Guidance Celltrion expects second-half growth to exceed first-half performance as supplies under major tender contracts increase and newly launched products continue to gain market share across key markets. Driven by new product expansion into additional markets, U.S. PBM formulary coverage, deliveries under European public tenders, and year-end inventory stocking by distributors, the company aims to exceed its full-year targets of KRW 5.3 trillion in revenue and KRW 1.8 trillion in operating profit. A Celltrion official said, “Our second-quarter results demonstrated Celltrion’s cash-generating capability and business competitiveness, as we achieved an operating margin exceeding 30% while continuing to invest in R&D for future growth.” The official added, “We will continue to reinvest the stable cash flows generated by our biosimilar business into follow-on products and novel drug development, with the goal of exceeding our full-year performance targets and enhancing long-term corporate value.” [1] New products: Remsima SC (marketed as Zymfentra in the U.S.), Yuflyma, Vegzelma, Steqeyma, Stoboclo·Osenvelt, Avtozma, Omlyclo, and Eydenzelt [2] EU5: Germany, Spain, the United Kingdom, Italy, France

雷紫璇, 桑蝶, 兰波, 等. 曲妥珠单抗生物类似药HLX02与原研药联合帕妥珠单抗及化疗在HER-2阳性乳腺癌患者新辅助治疗中的疗效安全性及成本效益比较[J]. 中华肿瘤杂志, 2025, 47(6): 517-524. DOI: 10.3760/cma.j.cn112152-20241115-00503.  摘   要  目的 比较曲妥珠单抗生物类似药（HLX02）与原研药（HST）联合帕妥珠单抗及化疗在人表皮生长因子受体2（HER-2）阳性乳腺癌患者中作为新辅助治疗的疗效、安全性和成本效益。 方法 研究采用回顾性队列研究设计，纳入2020年10月至2024年1月于中国医学科学院肿瘤医院接受新辅助治疗并完成根治性手术治疗的175例HER-2阳性乳腺癌患者。根据所用曲妥珠单抗的不同，将患者分为HST治疗组（89例）和HLX02治疗组（86例），比较两组患者的新辅助治疗的有效性、安全性和曲妥珠单抗成本效益，并采用logistic回归模型分析影响总体病理完全缓解（tpCR）率的因素。 结果 HST组和HLX02组患者临床T分期、手术方式差异有统计学意义（均P＜0.05），其他临床病理特征如年龄、组织学分级等差异均无统计学意义（均P＞0.05），大部分基线临床病理特征均衡（均P＞0.05）。HST组与HLX02组患者的tpCR率分别为55.1%（49/89）和54.7%（47/86，P=0.957），术后病理Miller-Payne分级中G5的比率分别为55.1%（49/89）及55.8%（48/86，P=0.991），差异无统计学意义。单因素和多因素回归分析显示，激素受体状态是影响pCR率的独立危险因素（OR=0.31，95% CI：0.16～0.61，P＜0.001）。HST组与HLX02组患者在新辅助治疗期间的不良事件发生情况类似，均未出现曲妥珠单抗相关的心脏不良反应。成本效益分析显示，HLX02方案的成本-效果比为586.48，低于HST方案的604.96，并且比较平均费用成本，HLX02组在新辅助治疗期间曲妥珠单抗治疗费用低于HST组［tpCR患者：（31 208.37±2 191.00）元和（33 224.49±2 741.00）元，非tpCR患者：（33 030.05±5 787.00）元和（33 412.50±4 203.00）元，均P＜0.05］。 结论 在HER-2阳性早期乳腺癌的新辅助治疗中，曲妥珠单抗类似药HLX02联合帕妥珠单抗及化疗的疗效与安全性与原研药相似，成本效益更高。 【关键词】乳腺肿瘤；人表皮生长因子受体2阳性；曲妥珠单抗；生物类似药；新辅助 2022年全球恶性肿瘤统计报告显示，乳腺癌跃居为全球女性发病率与死亡率首位的恶性肿瘤。约15%～20%的乳腺癌表现为人类表皮生长因子受体2（human epidermal growth factor receptor 2， HER-2）过表达或基因扩增，这类肿瘤通常恶性程度高、转移复发早、预后差。在HER-2阳性乳腺癌的治疗中，新辅助治疗具有重要的临床意义，曲妥珠单抗联合帕妥珠单抗双重HER-2阻断加化疗的新辅助治疗方案能够更显著提高病理完全缓解（pathological complete response， pCR）率，与患者的长期生存密切相关。对于早期HER-2阳性乳腺癌患者，国内外权威指南推荐首选基于曲妥珠单抗和帕妥珠单抗联合化疗的新辅助治疗方案。HLX02（中国商品名：汉曲优，欧洲商品名：Zercepac）是于2020年上市的曲妥珠单抗生物类似药，既往研究证明了HLX02在HER-2阳性乳腺癌的早期新辅助治疗及复发转移阶段治疗的疗效与原研药等效，且不良事件发生率无显著差异，但两者在真实世界诊疗场景中的对比数据仍然有限，仍需要较大样本的真实世界研究验证，且其成本效益差异尚未明确。 因此，本研究采用真实世界回顾性队列研究方法，收集新辅助抗HER-2治疗后接受手术的HER-2阳性乳腺癌患者，分析比较曲妥珠单抗原研药（HST）治疗组及曲妥珠单抗生物类似药（HLX02）治疗组间的疗效、安全性及成本效益，旨在为HER-2 阳性乳腺癌患者的临床治疗决策提供更多选择。 资料与方法 1. 研究对象：回顾性收集2020年10月至2024年1月于中国医学科学院肿瘤医院经HST或HLX02联合帕妥珠单抗和化疗新辅助治疗，并完成手术的乳腺癌患者的临床资料。纳入标准：（1）年龄≥18岁的女性；（2）经粗针穿刺活检病理确诊的HER-2阳性乳腺癌；（3）新辅助治疗≥4个周期；（4）有完整的术后病理资料；（5）美国东部肿瘤协作组（Eastern Cooperative Oncology Group， ECOG）功能状态评分为0～1分。排除标准：（1）妊娠期或哺乳期患者；（2）合并其他恶性肿瘤；（3）有远处转移患者；（4）未行手术治疗；（5）临床资料不完整。共筛选175例患者。本研究经国家癌症中心/中国医学科学院北京协和医学院肿瘤医院伦理委员会批准（立项编号：NCC4639）。 2. 终点评估：（1）疗效指标：主要终点为总体pCR（total pCR， tpCR）率，定义为乳腺原发灶和转移的区域淋巴结均无浸润性癌细胞的组织学证据，或仅存原位癌成分。次要终点为手术切除病灶的病理缓解情况，由病理科医师根据Miller-Payne（MP）分级系统评估。（2）安全性指标：新辅助治疗期间的左室射血分数（left ventricular injection fraction，LVEF）变化及不良事件发生情况。 3. 成本效益评价方法：收集全组患者在围手术治疗期间曲妥珠单抗的使用剂量及实际产生的费用，进行成本效益分析。另通过药物使用支数和药物成本，计算治疗期间的平均费用，以比较曲妥珠单抗原研药与生物类似药HLX02的经济性。 4. 统计学方法：所有数据均使用R软件（版本4.3.2）进行统计学分析，并采用Shapiro-Wilk方法对连续变量进行正态性检验。对于服从正态分布的变量，以±s描述；对于不符合正态分布的变量，以中位数及范围描述。组间差异比较采用χ2检验、Fisher精确检验或独立样本t检验。基于基线特征，进行新辅助治疗疗效的亚组分析，并采用单因素和多因素logistic回归模型探讨影响tpCR的因素。检验水准α=0.05。 结  果 一、患者的基线资料 纳入分析的175例患者基线特征见表1。HST组共89例，HLX02组共86例，两组患者仅临床T分期、手术方式差异有统计学意义（均P＜0.05，表1）。HST组患者年龄为（48.93±10.76）岁，HLX02组患者年龄为（46.29±10.26）岁，差异无统计学意义（t=-1.66，P=0.099）；HST组患者治疗周期为6个（4，8个），HLX02组为6个（4，8个），差异无统计学意义（Z=3 785.50，P=0.835）；HST组患者首次新辅助用药到手术的时间为5.03个月（3.47，11.60个月），HLX02组为4.85个月（1.43，19.60个月），差异无统计学意义（Z=2 983.00，P=0.066）。 二、疗效评价 HST组和HLX02组患者的tpCR率分别为55.1%（49/89）和54.7%（47/86），差异无统计学意义（P=0.957）。按激素受体（hormone receptor， HR）状态分层分析时，HR阴性（HR-）患者中，HST组和HLX02组的tpCR率分别为70.0%（35/50）和64.9%（24/37，P=0.612）；HR阳性（HR+）患者中，HST组和HLX02组的tpCR率分别为35.9%（14/39）和46.9%（23/49，P=0.297），差异均无统计学意义（图1）。 HST组和HLX02组患者的病理MP分级均未达到统计学差异（P=0.991），HST组和HLX02组分别有55.1%（49/89）和55.8%（48/86）的患者达到G5分级（表2）。 三、tpCR率影响因素分析 单因素和多因素的logistic回归结果如表3所示。单因素分析显示，HER-2+/HR+与较低的tpCR率有关（P＜0.001），而其他基线特征与tpCR率无显著相关性（P＞0.05，表3）。多因素回归分析显示，HER-2+/HR+与较低的tpCR率有关（P＜0.001），表明HR状态是1个独立的预后因素。此外，在单因素和多因素回归分析中，HST组和HLX02组对tpCR率的影响差异无统计学意义（均P＞0.05，表3）。 四、治疗安全性 1. 心脏安全性：HST组和HLX02组患者在接受曲妥珠单抗治疗前后，LVEF均无显著变化（图2）。HST组和HLX02组中所有患者治疗前后LVEF变化的中位值及范围分别为0（-10%～6%）和0 （-13%～11%），差异无统计学意义（P=0.379，P=0.433）。两组患者的LVEF变化均未达到曲妥珠单抗相关心脏不良反应的标准，即LVEF治疗前后绝对数值下降≥16%，或LVEF低于检测中心正常范围（50%～70%）且绝对值下降＞10%。 2. 不良事件发生情况：HST组和HLX02组患者在新辅助治疗治疗期间的不良事件发生情况相似（表4、5）。在血液学不良反应方面（贫血、白细胞减少、中性粒细胞减少和血小板减少），HLX02组3～4级不良事件的发生率在数值上低于HST组。本研究中未观察到5级不良事件的发生。 五、曲妥珠单抗的成本效益分析 在新辅助治疗期间，HLX02方案的成本-效果比为586.48，低于HST方案的604.96，表明HLX02方案在提高1%的tpCR率时所需成本更低，效率更高（表6）。用药成本比较方面，无论tpCR或非tpCR患者曲妥珠单抗治疗期间的平均费用成本，HLX02组均低于HST组，差异有统计学意义（P＜0.001，表7）。 讨  论 本研究是对比曲妥珠单抗生物类似药HLX02与原研药HST在HER-2阳性乳腺癌新辅助疗效及治疗成本的真实世界回顾性研究。曲妥珠单抗作为首个针对HER-2靶点的人源化单克隆抗体，在治疗HER-2阳性乳腺癌中表现出显著疗效。既往曲妥珠单抗生物类似药SB3和CT-P6分别在两项Ⅲ期临床研究显示出新辅助治疗应用的pCR率与应用原研药相当。而HLX02是中国首个自主研发的曲妥珠单抗生物类似药，多项研究已证明其与曲妥珠单抗原研药在疗效和安全性方面的高度相似性。 本回顾性研究结果显示，使用生物类似药HLX02或原研药HST联合帕妥珠单抗进行新辅助治疗后，两组患者的tpCR率分别达到54.7%与55.1%，相较于其他研究，本研究中两组患者达到tpCR的比例均较低，这可能是因为本研究中超过80%的患者存在淋巴结受累的情况，其中N2～3期的患者比例约占54.9%（96/175）。而在其他采用相同新辅助治疗方案的Ⅱ/Ⅲ研究中，基线患者淋巴结阳性的比例约占50%～65%。在两项类似的真实世界研究中，N2～3期的患者比例仅约8%～15%。指南和研究都表明，淋巴结阳性的HER-2阳性患者具有高复发风险，因此本研究可能提示，对于这类高危患者，仅经过标准新辅助治疗，可能难以达到pCR，还需要进一步强化治疗，以降低远期复发风险。通过单因素及多因素logistic回归分析结果显示，HR状态是影响tpCR的独立预后因素，与既往多项研究结果一致，HER-2与HR之间的交叉通路逃逸机制也可能是原因之一。在安全性方面，既往研究中，曲妥珠单抗治疗需要重点关注心脏不良反应的耐受性。本研究结果显示，HST治疗组和HLX02治疗组患者治疗前后的LVEF变化差值均未达到曲妥珠单抗心脏不良反应的判定标准；此外，两组患者3～4级不良事件发生率相当，HLX02组患者3～4级不良事件发生率及血液学不良反应相关不良事件发生率数值略低于HST组，与既往研究结果一致。 生物类似药研发目的是通过降低成本来提高生物制剂的可及性。在疗效与安全性不具有显著差异的基础上，与原研药相比，生物类似药的临床应用是否能为患者减轻药物费用，减低医疗成本成为重要评价因素。本研究成本效果比较显示，HLX02组成本效益比低于HST组（586.48和604.96），表明HLX02组在提高1%的tpCR率时所需成本更低，效益更高。另外，基于临床实践，根据患者在围手术期间曲妥珠单抗的使用剂量及实际产生的费用进行统计分析，发现HLX02组中达到tpCR的患者在新辅助或辅助治疗期间花费的药物平均成本均显著低于HST组，同时HLX02组中未达到tpCR的患者新辅助治疗期间的平均费用成本亦显著低于HST组。 综上所述，曲妥珠单抗原研药HST和其生物类似药HLX02在与帕妥珠单抗联合化疗治疗HER-2阳性早期乳腺癌患者的新辅助治疗中显示出相似的疗效和安全性。激素受体状态是本研究中影响tpCR的独立预后因素。HLX02在经济效益上优于曲妥珠单抗原研药。作为治疗成本更低的替代产品，随着其广泛、合理地应用于临床治疗，可减轻患者个人的治疗费用，提高患者对治疗药物的可及性，极大节省医疗保险预算。 相较于其他同类研究，本研究样本量大，不良事件数据收集较为全面，但也存在一定局限性。由于本研究为回顾性研究，未收集到患者主观表述的不良事件；此外，尚需更多随访信息完善患者的长期生存率和生活质量。 参考文献略。 本刊出版日为每月23日，网站和数据库更新有时间差，欢迎正式出版后下载原文： 1. 机构用户IP：中华医学期刊全文数据库（http://www.yiigle.com/）右上角IP登录，正常检索/查看/下载即可  2. 个人账号：绑定中华医学期刊机构用户后，直接登录本刊官网（http://www.chinjoncol.com/）检索/查看/下载全文（通过万方、中华医学期刊网检索也将跳转至本刊官网）  3. 年卡或单期购买用户：详询中华医学期刊网会员服务 4. 纸质版期刊订阅：中国邮政网上营业厅（https://mall.11185.cn/）检索“中华肿瘤杂志”在出版前订购；或中华医学期刊网-期刊服务-期刊商城订购过刊。 责任编辑 | 殷宝侠 审核发布 | 苏在明 终审 | 代小秋 阅读原文：#乳腺肿瘤# 合集