BGB-A445

New data from four priority programs, including the GPC3x4-1BB bispecific antibody, CEA targeting ADC, CDK4 inhibitor, and brain-penetrant PRMT5 inhibitor underscore the depth of BeOne ’ s solid tumor pipeline Multiple TEVIMBRA abstracts reinforce breadth of evidence across lung and gastrointestinal cancers, including data in combination with ZIIHERA in HER2+ gastroesophageal cancer SAN CARLOS, Calif.--(BUSINESS WIRE)-- $ONC #BeOne --BeOne Medicines Ltd. (Nasdaq: ONC; HKEX: 06160; SSE: 688235), a global oncology company, today announced that data from across its rapidly progressing solid tumor portfolio will be presented at the European Society for Medical Oncology (ESMO) Congress 2026 on October 23-27 in Madrid. Presentations will highlight an accelerating pipeline of differentiated targeted therapies, alongside a broad body of evidence for TEVIMBRA ® (tislelizumab), including a late-breaking rapid oral presentation on TEVIMBRA in combination with ZIIHERA ® (zanidatamab) in HER2+ gastroesophageal adenocarcinoma (GEA). Priority pipeline data include an oral proffered paper presentation on BeOne’s GPC3x4-1BB bispecific antibody, currently being studied in hepatocellular carcinoma (HCC) and first-in-human data for two investigational lung cancer assets, a CEA targeting antibody-drug conjugate (ADC), in CEA-expressing non-small cell lung cancer (NSCLC), and a brain-penetrant PRMT5 inhibitor in MTAP-deleted tumors, including NSCLC. A trial-in-progress (TiP) abstract of KANDELA-302 will be presented for the Company’s CDK4 inhibitor, in front-line metastatic HR+/HER2-negative breast cancer (BC). Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeOne, said: “2026 has been an inflection year for our solid tumor portfolio. Across major medical congresses, we have demonstrated proof of concept for five priority programs, while rapidly advancing these assets toward pivotal development. At ESMO, that progress is visible in pipeline data spanning our three strategically focused disease areas, breast, lung, and gastrointestinal cancers, alongside further evidence supporting TEVIMBRA, including updated Phase 3 data in combination with ZIIHERA in HER2+ gastroesophageal adenocarcinoma. Together, the reach of TEVIMBRA and a pipeline advancing at scale position BeOne to change the game in solid tumor oncology.” Pipeline at scale: advancing priority programs with new data at ESMO The latest evidence of the progress of BeOne’s solid tumor pipeline will be presented at ESMO with abstracts being published across four investigational assets, demonstrating the speed and scale of BeOne’s global development superhighway. Priority pipeline presentations at ESMO include: BGB-B2033 (GPC3x4-1BB bispecific antibody): An oral proffered paper presentation with updated Phase 1 dose-escalation and first dose-optimization results in previously treated patients with advanced HCC. BG-C477 (CEA targeting ADC): First-in-human Phase 1 data in heavily pretreated, locally advanced NSCLC, with further analysis provided in patients with CEA-high expressing tumors. BGB-58067 (PRMT5 inhibitor): First-in-human data evaluating BeOne’s brain-penetrant, MTA-cooperative PRMT5 inhibitor in MTAP-deficient advanced tumors. BGB-43395 (CDK4 inhibitor): Trial-in-progress presentation of KANDELA-302, a global Phase 3 study evaluating BGB-43395 plus letrozole compared with investigator’s choice of a CDK4/6 inhibitor plus letrozole as first-line treatment for advanced or metastatic HR+/HER2-negative BC. Strengthening evidence base for TEVIMBRA in lung and gastrointestinal cancers In addition to pipeline data, seven abstracts at ESMO will further characterize TEVIMBRA across lung and gastrointestinal cancers, including a late-breaking, rapid oral presentation with new data from the Phase 3 HERIZON-GEA-01 trial in HER2+ gastroesophageal adenocarcinoma. Key TEVIMBRA presentations include: HERIZON-GEA-01: Second interim analysis of the Phase 3 trial of ZIIHERA plus chemotherapy, with and without TEVIMBRA, in first-line HER2-positive locally advanced or metastatic GEA. RATIONALE-312: Exploratory analysis evaluating the effect of TEVIMBRA plus platinum-etoposide on brain disease progression in first-line extensive stage small-cell lung cancer (ES-SCLC). RATIONALE-315: Analysis of clinical outcomes by adjuvant treatment cycles with perioperative TEVIMBRA plus chemotherapy in patients with resectable NSCLC. RATIONALE-305 and RATIONALE-302: New analyses further evaluating outcomes with TEVIMBRA in gastric/gastroesophageal junction (GEJ) adenocarcinoma and esophageal squamous cell carcinoma (ESCC), respectively. Full list of BeOne’s presentations at ESMO: Pipeline data Abstract Title Presentation Details (CET) Lead Author Phase 1 study of BGB-B2033 monotherapy: First disclosure of dose optimization and dose escalation update in advanced HCC Proffered paper 1679O ; Gastrointestinal tumour, upper digestive; Oct. 24, 10:15-11:45AM Hong Jae Chon First-in-human study of BG-C477, a novel CEA-targeting ADC, in advanced solid tumors: initial results in NSCLC Poster: 2567P ; NSCLC, locally advanced; Oct. 26, 12:00-12:45 Matthew Lee First-in-human trial of BGB-58067, an MTA-cooperative PRMT5 inhibitor, in MTAP-deficient advanced tumors Poster: 1043P ; Translational Research and Biomarkers; Oct. 23, 3:15-4:00 PM Jordi Rodon KANDELA-302: A Phase 3, global, open-label, randomized study of the selective CDK4 inhibitor BGB-43395 + letrozole vs CDK4/6 inhibitors + letrozole for first-line treatment of advanced or metastatic HR+/HER2− breast cancer Poster: 1885TiP ; HR+ Breast Cancer; Oct. 24, 12:00-12:45 Sara M. Tolaney TEVIMBRA data Abstract Title Presentation Details (CET) Lead Author Zanidatamab + chemotherapy ± tislelizumab for first-line HER2+ advanced/metastatic GEA: second interim analysis from HERIZON-GEA-01 Rapid oral: LBA79; Gastrointestinal tumour, upper digestive Oct 23, 4:15-5:45 PM Kohei Shitara Phase 1b/2 trial of BGB-A445 (OX40 agonist) with or without tislelizumab in urothelial carcinoma, renal cell carcinoma, and melanoma Poster: 1980P ; Investigational Immunotherapy; Oct. 24, 12:00-12:45 Bin Lian Impact of progressive disease patterns on post-progression overall survival in ESCC: A post hoc analysis of RATIONALE-302 Poster: 2950P ; Oesophagogastric cancer; Oct. 25, 12:00-12:45 Jhe-Cyuan Guo RATIONALE-305: Post-treatment immuno-oncology adjustment analysis to assess tislelizumab treatment effect vs placebo Poster: 2931P ; Oesophagogastric cancer; Oct. 25, 12:00-12:45 Markus Moehler RATIONALE-312: Exploratory analysis of tislelizumab plus platinum-etoposide on brain disease progression in first-line ES-SCLC Poster: 3839P ; SCLC; Oct. 26, 12:00-12:45 Francesco Passiglia RATIONALE-315: Clinical outcomes by adjuvant treatment cycles in perioperative tislelizumab plus chemotherapy in resectable NSCLC Poster: 2594P ; NSCLC, locally advanced; Oct. 26, 12:00-12:45 Ernest Nadal Exposure-adjusted analyses of safety patterns in HERIZON-GEA-01: Zanidatamab with and without tislelizumab and chemotherapy in 1L HER2+ metastatic GEA Poster: 2946P ; Oesophagogastric cancer; Oct. 25, 12:00-12:45 Sun Young Rha About ZIIHERA (zanidatamab-hrii) ZIIHERA (zanidatamab-hrii) is a bispecific human epidermal growth factor receptor 2, or HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab with HER2 results in internalization leading to a reduction in HER2 expression of the receptor on the tumor cell surface. Zanidatamab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo. 1 Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is approved in China for the treatment of patients who have unresectable, locally advanced, or metastatic HER2-high expression (IHC 3+) biliary tract cancer (BTC) and who have received prior systemic therapy. ZIIHERA has also been granted accelerated approval in the U.S. and conditional marketing authorization in the European Union for eligible BTC patients. Zanidatamab is being developed by Jazz and BeOne under license agreements from Zymeworks, which first developed the molecule. BeOne has licensed zanidatamab from Zymeworks in Asia (excluding India and Japan), Australia and New Zealand. Jazz Pharmaceuticals has rights in all other regions. ZIIHERA is a registered trademark of Zymeworks BC Inc. About TEVIMBRA (tislelizumab) TEVIMBRA is a uniquely designed humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. TEVIMBRA is the cornerstone asset of BeOne’s solid tumor portfolio and has shown potential across multiple tumor types and disease settings. The global TEVIMBRA clinical development program includes almost 15,000 patients enrolled to date in 30+ countries and regions across 71 trials, including 21 registration-enabling studies. TEVIMBRA is approved for various solid tumors (see prescribing information) in over 50 countries, and more than 2.2 million patients have been treated globally. Important Safety Information The current European Summary of Product Characteristics (SmPC) for TEVIMBRA is available from the European Medicines Agency . The information in this press release is intended for a global audience. Product indications vary by region. About BeOne BeOne Medicines is a global oncology company that is discovering and developing innovative treatments for cancer patients worldwide. With a portfolio spanning hematology and solid tumors, BeOne is expediting development of its diverse pipeline of novel therapeutics through its internal capabilities and collaborations. The Company has a growing global team spanning six continents who are driven by scientific excellence and exceptional speed to reach more patients than ever before. To learn more about BeOne, please visit and follow us on LinkedIn , X , Facebook and Instagram . Forward-Looking Statement This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the advancement of BeOne’s solid tumor pipeline toward pivotal development; the potential of TEVIMBRA across multiple tumor types and disease settings; and BeOne’s plans, commitments, aspirations, and goals under the heading “About BeOne.” Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeOne’s ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing, and progress of clinical trials and marketing approval; BeOne’s ability to achieve commercial success for its marketed medicines and drug candidates, if approved; BeOne’s ability to obtain and maintain protection of intellectual property for its medicines and technology; BeOne’s reliance on third parties to conduct drug development, manufacturing, commercialization, and other services; BeOne’s limited experience in obtaining regulatory approvals and commercializing pharmaceutical products and its ability to obtain additional funding for operations and to complete the development of its drug candidates and achieve and maintain profitability; and those risks more fully discussed in the section entitled “Risk Factors” in BeOne’s most recent quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in BeOne's subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeOne undertakes no duty to update such information unless required by law. To access BeOne media resources, please visit our Newsroom site. 1 ZIIHERA (zanidatamab-hrii) Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc. Contacts Investor Contact Liza Heapes +1 857-302-5663 ir@beonemed.com Media Contact Kyle Blankenship +1 667-351-5176 media@beonemed.com

近期的药物研发进展是意外重重：先是诺和诺德重金买下的 IL-6 用于 ASCVD 一败涂地，再是 Lp(a) 抑制剂未达心血管事件终点，随后诺华 120 亿美金的 AOC 三期“意外”落马（具体亦可参考本公众号前述文章）。好不容易等来一个阳性新闻，却是 OX40 激动剂联合 K 药在头颈癌中意外翻盘。之所以称其意外，是因为 IO 激动剂这一概念在过去数年屡遭滑铁卢。读到新闻标题，颇有“垂死病中惊坐起，笑问客从何处来”之感。不过还是值得仔细分析分析表面数据背后的逻辑和细节。一、OX40 抗肿瘤药物研发总结1.1　OX40：一个“踩油门”的共刺激受体 OX40（CD134，TNFRSF4）是肿瘤坏死因子受体超家族（TNFRSF）成员，主要表达于活化的 CD4⁺/CD8⁺ T 细胞表面，属典型的共刺激受体。与抑制性检查点（如 PD-1/PD-L1）不同，OX40 通路的生理作用在于正向放大 T 细胞应答：其激活可促进 T 细胞增殖、存活与效应分化，诱导记忆 T 细胞生成，并抑制或清除 Foxp3⁺ 调节性 T 细胞（Treg）。因此，早在十余年前，OX40 即被视为 PD-1 之后肿瘤免疫领域的重要靶点。 然而，该靶点的临床转化远较预期困难。OX40 的天然配体 OX40L（CD252，TNFSF4）为同源三聚体，受体激活依赖于高阶聚簇的形成（“三聚体之上的三聚体”/超分子簇），进而募集 TRAF2/3/5 衔接蛋白，激活 NF-κB、PI3K/AKT 与 NFAT 等下游信号通路。针对这一受体超家族，二价抗体存在固有缺陷：仅能介导受体的二聚化，远达不到天然配体所诱导的聚簇程度，单靠 Fab 结合不足以充分激活下游信号。 由此，传统激动型抗体只能依赖 Fc 段与 Fcγ 受体（尤其是 FcγRIIB）的交联，借旁观免疫细胞将抗体–受体复合物进一步聚集；但此类二级交联在体内效率有限、高度依赖微环境，且不稳定。更进一步，该设计面临“条件性激动”的两难：TNFRSF 激动型抗体（含 OX40）的体内激动活性依赖 FcγR 交联，而提供“脚手架”式交联的关键是抑制性受体 FcγRIIB（ITIM 型，仅提供交联、不触发杀伤）；真正介导 ADCC/ADCP 的则是激活性受体 FcγRIIA/IIIA，可能清除本应被激活的 T 细胞（对 OX40 而言，亦有临床前研究提示 Fc 依赖的 Treg 清除反而是其抗肿瘤机制之一）。普通 IgG1 同时结合两类受体，“获得 FcγRIIB 交联”与“避免激活性 FcγR 杀伤”难以兼得——这正是“条件性激动型抗体”（选择性增强 FcγRIIB 结合、削弱激活性 FcγR 结合）工程化设计所要解决的矛盾。1.2　折戟名单：MNC 的集体滑铁卢 下表汇总了主要 OX40 激动剂抗体的临床结局（数据来自 2025 年 Frontiers in Oncology 综述及各公司披露）： 分子 开发方 形式/设计 关键临床结果 结局 PF-04518600                    (ivuxolimab) 辉瑞 IgG2（低 FcγR 亲和） 单药 ORR 约 5.8%（n=142）；剂量爬升仍不见外周 T 细胞激活信号，且提前出现 ≥3 级肝毒性 因缺乏 FcγR 交联、疗效与毒性不匹配而终止 MOXR0916 罗氏/Genentech IgG1（人源化） 单药 ORR 1.2%（n=172）、DCR 66%；瘤内 OX40⁺ T 细胞比例低 2019.11 因 3 级皮疹/腹泻阻断剂量爬升而停止 GSK3174998 GSK IgG1（人源化） 单药 ORR 0%（n=45）；联合帕博利珠 ORR 8%（n=96） 因疗效不足终止开发 MEDI0562 阿斯利康/MedImmune IgG1（人源化） 单药 ORR 4%（n=55）；≥3 级免疫相关不良事件率高达 22% 无客观获益，终止 INCAGN01949 Incyte/Agenus IgG4 + FcγR 增强 单药 ORR 1.5%（n=87），外周/瘤内药效信号微弱，9% 出现 3 级皮疹 2022 年终止 MEDI6469                    (9B12) MedImmune 鼠源 IgG1（新辅助） 头颈鳞癌新辅助（n=17）：3 年 OS 82%、DFS 71%，耐受良好 留下 HNSCC 早期信号，未推进注册 BGB-A445 百济神州 非配体阻断型 IgG1 单药 ORR 4%；联合替雷利珠单抗 ORR 23%（n=30，7 PR） 管线移除 注：PF-04518600、MOXR0916、GSK3174998、MEDI0562、INCAGN01949 等均为传统二价抗体，其单药 ORR 普遍落在 0–5% 区间，与安慰剂无异。1.3　失败原因的共性归纳 综合上述案例，OX40 激动剂的失败可归纳为三点： 药效学信号不足：二价抗体在体内无法形成足够的高阶受体聚簇，T 细胞增殖与激活信号微弱，未能产生可检测的药效学应答； 剂量限制性毒性：为提高激动强度而增大剂量，诱发皮疹、腹泻、肝损伤等免疫相关不良事件（irAE），治疗窗口狭窄； 联合用药缺乏协同且叠加毒性：与 PD-1 抑制剂等联用未见协同获益，反而放大了安全性问题。 概言之，OX40 既往的失败源于分子与临床两个层面的叠加：分子层面，二价结构的固有局限决定了受体聚簇与下游信号不足；临床层面，剂量–毒性平衡与联合方案的优化均未实现。二、本次研究分析2.1　HexAgon 研究设计 2026 年 9 月 8 日，Inhibrx 公布 HexAgon 研究 II 期部分的主要终点数据。该研究为随机对照设计，比较六价 OX40 激动剂 INBRX-106 联合帕博利珠单抗与帕博利珠单抗单药，用于初治、PD-L1 阳性（CPS ≥ 20）、转移性或不可切除复发性头颈鳞癌（HNSCC）的一线治疗。研究在美、欧、亚 80 余个中心开展，II 期部分共随机 68 例，其中 63 例可评估主要终点（联合组 29 例，含 HPV⁺ 10 例；对照组 34 例，含 HPV⁺ 9 例），两组基线预后因素基本均衡。 对照组采用帕博利珠单抗单药，为 KEYNOTE-048 所确立的一线 PD-L1 高表达 HNSCC 标准治疗。因此，本研究是对现行标准治疗的直接对照，其证据强度高于既往的单臂探索性研究。2.2　核心数据：ORR 近翻倍，且缓解具备深度与持久性 疗效终点（全人群） INBRX-106 + K药 K药单药 差值 确认客观缓解率 cORR 48.3%（14/29） 26.5%（9/34） ≈ +1.8 倍 完全缓解 CR 13.8%（4 例） 0 — 中位 PFS（中期） 9.6 个月 4.9 个月 +4.7 个月 6 个月 PFS 率 72.4% 42.8% +29.6 pp HPV 阳性亚组（病毒抗原驱动的高免疫原性肿瘤）的数据更为突出： HPV⁺ 亚组 INBRX-106 + K药（n=10） K药单药（n=9） cORR 80.0% 33.3% CR 率 30.0% 0% 6 个月 PFS 率 90.0% 33.0% 中位 PFS 尚未达到 4.6 个月 安全性方面，最常见的治疗相关不良事件为皮疹、疲劳与腹泻，以低级别为主，整体可控，未见治疗相关死亡。据公司管理层披露，其安全性特征与 KEYNOTE-048 中帕博利珠单抗单药组相近。2.3　辅助证据：15 倍 T 细胞扩增（药效学验证） 相较疗效终点，更值得关注的是药效学（PD）数据。2026 年 5 月中期分析显示，联合组患者外周血 CD8⁺/CD4⁺ T 细胞增殖最高达 15 倍、激活最高达 4 倍；对照组（帕博利珠单抗单药）分别仅为 2.5 倍与 1.5 倍。管理层在电话会中指出，既往 OX40 项目在部分患者中的 T 细胞扩增通常仅为 2–5 倍，且未转化为有意义的临床应答。 “药效学与临床应答之间的高度一致，使我们更有信心该信号真实，并具备跨适应症的可复制性。”——Inhibrx CEO Mark Lappe 对于Inhibrx，INBRX-106 首次在人体中实现了高倍率、可定量的 T 细胞扩增，并进一步转化为完全缓解与持久的无进展生存获益。2.4　成功归因的三层分析 ① 分子层面INBRX-106 基于 Inhibrx 专有的单域抗体（sdAb）平台构建，含六个 OX40 结合域，可同时结合多个 OX40 受体，无需 Fc 交联即可诱导受体自主聚簇，实现天然 OX40L 所具备的高阶聚簇，从而强效激活 T 细胞。临床前研究（Holay et al., J Immunother Cancer, DOI 10.1136/jitc-2025-011524）显示，六价分子在受体聚簇、NF-κB 信号、T 细胞增殖与 CD8⁺ 效应功能方面均优于二价激动剂，并在小鼠模型中产生显著的肿瘤消退与生存获益。 ② 适应症层面HPV⁺ 口咽鳞癌由病毒癌蛋白（E6/E7）驱动，属高免疫原性肿瘤：抗原负荷高、T 细胞浸润充分、PD-L1 高表达。这一背景为 OX40 共刺激提供了抗原特异性 T 细胞这一“底物”——只有预先存在抗原特异性 T 细胞，OX40 激动剂方能将其扩增为强效抗肿瘤应答。正如管理层所述：“HPV 阳性肿瘤具有高度免疫原性，当抗原存在时，OX40 共刺激即能真正放大应答。” ③ 联合与终点层面PD-1 阻断解除 T 细胞抑制，OX40 激动提供共刺激信号，二者机制互补；OX40 信号的核心价值在于记忆 T 细胞的诱导，这解释了本研究中完全缓解率（13.8%–30%）与 6 个月 PFS 的显著改善——其优势不仅在于缓解率，更在于缓解深度与持久性。三、核心问题：适应症选择，抑或分子价态？ 到底是适应症选得好，还是分子确实有特色？我觉得可能二者有之，适应症的贡献可能还大一些。3.1　假说一：适应症选择 疗效分化高度集中于 HPV⁺ 亚组（80.0% vs 33.3%），全人群获益在很大程度上由该亚组贡献； 既往唯一显示清晰临床信号的 OX40 试验亦发生于头颈鳞癌（MEDI6469 新辅助，3 年 OS 82%），提示 HNSCC 本身即为 OX40 的适宜适应症； 在低免疫原性肿瘤中，即使分子具备强激动活性，亦可能因缺乏抗原特异性 T 细胞而无从发挥。3.2　假说二：分子价态 该分子画风真的很清奇： 既往二价分子在免疫原性并不低的适应症中亦告失败（GSK3174998 联合帕博利珠单抗 ORR 仅 8%；PF-04518600、MOXR0916、MEDI0562 单药 ORR 0–5%），正常二价抗体的药效学信号确实也是值得怀疑； 根据2026年5披露的信息，临床病人中六价分子联合K药诱导的 T 细胞扩增幅度约为15倍，而K药组是2-3倍扩增；较好的证明了联合后，该分子增加的T细胞活性。当然，这里有个疑问，一般外周T扩增也会带来较强的免疫相关副作用，但似乎昨天透露的信息中，公司管理层对临床的安全性很有信心。 最后，临床前同瘤种、同背景的头对头比较中，六价显著优于二价，表明“价态”本身即为独立变量。 INBRX-106在临床前研究中，展现出较2，3，4价更强的激活信号水平。 外周T细胞激活实验，六价分子也显示更强的激活水平。当然，这些都是体外的验。病人的T细胞变化仅在一些PR中提到，未见到数据。3.3 综合判断：六价聚簇临床前和临床均有证据显示更强的激活水平，但我们也要注意到目前适应症的一些背景；HPV⁺、高 PD-L1 的头颈鳞癌提供了抗原充足、T 细胞浸润、PD-L1 高表达的有利背景，得以显现的放大激活。加之 PD-1 联合与记忆 T 细胞诱导带来的深度、持久获益，三者的共同作用方才促成此次缓解率的近翻倍。 更具体地，可从三个层面理解： 4.分子决定“能否激活”：缺乏六价高阶聚簇，OX40 通路在人体内难以被充分激活，任何适应症均难以弥补——此为历史失败的第一性原因。 5.适应症决定“激活的效应大小”：仅在抗原充足、T 细胞浸润的免疫原性肿瘤中，被激活的 T 细胞方有明确的攻击靶点，信号方能放大至统计学显著。 6.联合与终点决定“获益的程度”：PD-1 阻断解除衰竭 T 细胞的抑制，OX40 的记忆诱导属性将缓解转化为持久缓解，直接贡献于 CR 率与 PFS 的改善。 需要说明的是：由于既往二价 OX40 激动剂未曾在一线 HPV⁺ 头颈鳞癌联合 PD-1 的精确场景中进行随机对照，现有数据尚不能完全排除“仅依赖适应症选择与二价分子亦可取得类似效果”的可能性。四、展望与风险4.1　后续开发与商业信号 注册路径：Inhibrx 计划在 II 期部分扩组约 50 例 HPV⁺ 口咽鳞癌（OPSCC，CPS≥1），以支持加速批准；随后启动 HexAgon III 期作为确证性研究，并与 FDA 对齐框架。管理层认为，该数据足以支持基于随机 II 期研究的突破性疗法认定与加速批准。 拓展方向：围手术期非小细胞肺癌（NSCLC）I/II 期（首批数据预计 2027 年中）、一线转移性 NSCLC，以及与治疗性肿瘤疫苗、T 细胞衔接器、CAR-T 的联合。 商业信号：据路透社 4 月报道，默沙东、德国默克、小野制药等对 INBRX-106 表现出兴趣，该资产估值约 80 亿美元；连同四价 DR5 激动剂 ozekibart（INBRX-109，已提交 BLA，PDUFA 日期 2027-04-14），整体交易价值或超 90 亿美元。考虑到帕博利珠单抗 2025 年销售额约 317 亿美元、且 2028 年面临专利悬崖，INBRX-106 具备延长其生命周期、形成组合的潜力。4.2　风险分析 样本量有限：全人群 63 例可评估，HPV⁺ 亚组仅 19 例（联合组 10 例），80% 的 ORR 对应较宽置信区间，该亚组数据应视为强信号而非定论； 数据尚未成熟：中位 PFS（尤其是联合组）仍在随访中，最终数据可能回落； 同类靶点历史：OX40 赛道十余年缺乏临床获益，单次 II 期结果尚不足以完全改变市场判断，仍需 III 期确证；4.3　结语 OX40 这一被多家跨国药企反复验证失败的靶点，首次在随机对照研究中显示出清晰获益。该阳性数据的获得，除了分子的高度差异化之外，也有一定适应症方面的优势。能否拓展到别的适应症，尤其是NSCLC还需要更多的临床研究。但总体给我的感觉，IO激动剂抗体的市场价值和应用场景还是比较有限的。 参考来源 [1]Inhibrx 官方新闻稿（2026-09-08）：INBRX-106 Nearly Doubles Response Rate and Achieves Interim Median PFS of 9.6 months in Phase 2 HNSCC Studyhttps://inhibrxbiosciences.investorroom.com/2026-09-08-Inhibrxs-INBRX-106-Nearly-Doubles-Response-Rate-and-Achieves-Interim-Median-PFS-of-9-6-months-in-Phase-2-HNSCC-Study [2]Fierce Biotech：Inhibrx CEO says progression-free survival data leave 'no question' about OX40 agonist's durabilityhttps://www.fiercebiotech.com/biotech/inhibrxs-profound-dataset-boosts-hopes-accelerated-approval-ox40-agonist [3]微信公众号文章：六价 OX40 激动剂 INBRX-106 联合 K药 II 期数据 [4]Elpiscience（科望医药，ES102 大中华区权益方）中期数据与药效学披露https://www.elpiscience.com/new/interim-phase-2-data-for-hexavalent-ox40-agonist-combination-therapy-in-first-line-hnscc-demonstrate-potential-benefit--over-pd-1-monotherapy.html [5]Holay N, Yadav R, et al. INBRX-106: a hexavalent OX40 agonist that drives superior antitumor responses via optimized receptor clustering. J Immunother Cancer（DOI 10.1136/jitc-2025-011524）https://digitalcommons.providence.org/publications/10496/ [6]Frontiers in Oncology（2025）：OX40/OX40L: a new target for tumor immunotherapy and its clinical research progress（含各失败分子的临床结局表）https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1730620/full [7]网易/药时空（2026-09-09）：II期临床大成功，默沙东欲掷80亿美元收购（含 M&A、K药专利悬崖背景）https://www.163.com/dy/article/L6D0HFD00532CO9S.html [8]AllSci（2026-09-08）：Inhibrx's OX40 agonist nearly doubles response rate（含 KEYNOTE-048、petosemtamab 竞品背景）https://allsci.com/news/clinical-trials/inbrx-106-head-and-neck-cancer-inhibrxs-nearly/ 免责声明：本报告基于公开信源整理与分析，仅供行业研究参考，不构成任何投资建议或诊疗建议。所引数据以原始披露为准；II 期中期数据存在样本量小、随访未成熟等局限，最终结论需待 III 期确证性研究验证。