Protocol SAKK 18/ 25 Overcoming Resistance to Immunotherapy Combining Gemcitabine With Ivonescimab in Advanced NSCLC Progressing on Immune Checkpoint Inhibitors: A Multicenter, Single-arm, Open-label Phase II Trial (ORIGIN2)

This Phase II clinical trial (investigates the efficacy of combining gemcitabine, a chemotherapy agent, with ivonescimab, a bispecific PD-1/VEGF antibody, in patients with advanced non-small cell lung cancer (NSCLC) who have experienced disease progression following chemoimmunotherapy (CIT). Lung cancer remains the leading cause of cancer-related death globally, and treatment options after CIT failure are limited. Gemcitabine has demonstrated immunostimulatory properties, including enhanced T-cell infiltration and reduced immunosuppressive cell populations, which may synergize with immune checkpoint inhibitors. Ivonescimab targets both PD-1 and VEGF pathways, potentially enhancing antitumor immune responses and inhibiting tumor angiogenesis. The trial aims to evaluate the objective response rate (ORR) according to RECIST v1.1 criteria. The combination therapy is expected to offer a novel and effective treatment strategy for patients with relapsed NSCLC, addressing a significant unmet medical need.

开始日期2026-03-01

申办/合作机构-

NCT07070466

/ Not yet recruiting临床2期IIT

A Single-Arm, Phase II Study of Ivonescimab in Combination With FOLFOX in Advanced HER2 Negative Gastroesophageal Adenocarcinomas

This is a single arm, open-label, phase II trial investigating the combination of ivonescimab with standard FOLFOX chemotherapy in 1L therapy for HER2- GEA.

开始日期2025-12-12

申办/合作机构

The Massachusetts General Hospital

[+1]

NCT07057791

/ Not yet recruiting临床2期IIT

Phase II Dose Optimization Study of Platinum/Etoposide Plus Ivonescimab (CEI) as First-Line Treatment of Extensive-Stage Small Cell Lung Cancer

Eligible untreated participants with Extensive Stage Small Cell Lung Cancer (ES-SCLC) who are ≥ 18 years of age will be randomized to receive ivonescimab 10 milligrams per kilogram (mg/kg) or ivonescimab 20 mg/kg in combination with carboplatin and etoposide.
Ivonescimab is a type of drug called a bispecific antibody. Antibodies are proteins that specifically recognize and bind to other types of proteins called antigens. Antibodies and antigens can work together to help the immune system fight cancer cells. Bispecific antibody, meaning it targets two different molecules at the same time.
Ivonescimab is a new drug that may help the immune system attack cancer cells and may also block certain pathways that cancer uses to grow and spread. This dual action of ivonescimab aims to help the immune system to fight the cancer and also disrupt tumor growth by blocking blood vessel formation that tumors use to grow.
Participants will receive induction with 4 cycles of ivonescimab (dose determined by randomization) with standard of care carboplatin and etoposide followed by maintenance therapy with ivonescimab at the same dose received during induction. Treatment will continue until disease progression, unacceptable toxicity or participant withdrawal.
The purpose of this study is to determine what dose of ivonescimab works best in combination with carboplatin and etoposide chemotherapy in ES-SCLC. We will also examine the side effects, good and bad, associated with ivonescimab.

开始日期2025-12-01

申办/合作机构

Summit Therapeutics, Inc.

100 项与依沃西单抗相关的临床结果

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100 项与依沃西单抗相关的专利（医药）

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项与依沃西单抗相关的文献（医药）

2025-12-31·mAbs

Antibodies to watch in 2025

Review

作者: Kapoor, Vaishali ; Kaplon, Hélène ; Crescioli, Silvia ; Visweswaraiah, Jyothsna ; Reichert, Janice M. ; Wang, Lin

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025. In particular, we report on 21 antibody therapeutics granted a first approval in at least one country or region during 2024, including bispecific antibodies tarlatamab (IMDELLTRA®), zanidatamab (Ziihera®), zenocutuzumab (BIZENGRI®), odronextamab (Ordspono®), ivonescimab (®), and antibody-drug conjugate (ADC) sacituzumab tirumotecan (®). We also discuss 30 investigational antibody therapeutics for which marketing applications were undergoing review by at least one regulatory agency, as of our last update on December 9, 2024, including ADCs datopotamab deruxtecan, telisotuzumab vedotin, patritumab deruxtecan, trastuzumab botidotin, becotatug vedotin, and trastuzumab rezetecan. Of 178 antibody therapeutics we include in the late-stage pipeline, we summarize key data for 18 for which marketing applications may be submitted by the end of 2025, such as bi- or multispecific antibodies denecimig, sonelokimab, erfonrilimab, and anbenitamab. Key trends in the development and approval of antibody formats such as bispecifics and ADCs, as well as clinical-phase transition and global approval success rates for these antibody formats, are reported.

2025-08-01·Nature Reviews Clinical Oncology

The next generation of immunotherapies for lung cancers

Review

作者: Yang, Weiwei ; Zhang, Li ; Zhao, Hongyun ; Zhao, Shen

Immunotherapies, specifically immune-checkpoint inhibitors (ICIs) targeting PD-(L)1 or CTLA4, have revolutionized the treatment of lung cancer; however, many patients do not have a response to ICIs and most of those with an initial tumour response eventually have disease progression owing to acquired resistance. Over the past few years, numerous therapeutic strategies have been explored to address the problems of intrinsic and acquired resistance to ICIs. In 2024, regulatory approvals of the bispecific PD-1 × VEGF antibody ivonescimab for the treatment of non-small-cell lung cancer in China and the bispecific DLL3 × CD3 T cell engager tarlatamab for patients with small cell lung cancer in the USA provided clinical proof-of-concept for overcoming the challenge of ICI resistance using novel immunotherapeutic agents, thereby increasing enthusiasm for the exploration of next-generation immunotherapies for lung cancer. A large variety of immunotherapies with diverse targets and mechanisms of action are currently being tested in clinical trials involving patients with lung cancer. In this Review, we provide an overview of these emerging immunotherapies in clinical development for non-small-cell lung cancer and/or small cell lung cancer, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic cancer vaccines. We describe the designs of these agents and the mechanisms by which they might overcome resistance to the current generation of ICIs. We also discuss hurdles impeding the clinical translation of each immunotherapeutic modality and potential strategies to address these challenges, using representative examples of agents that have entered the later phases of clinical testing.

2025-06-12·Antibody therapeutics

A novel bispecific antibody CVL006 superior to AK112 for dual targeting of PD-L1 and VEGF in cancer therapy

Article

作者: Shen, Xiaokun ; Huang, Hao ; Wu, Ziai ; Cao, Liang ; Pan, Junfang ; Li, Zhongyuan ; Song, Zeng ; Chen, XiaoBing ; Wang, Chunyan ; Huang, Jinwen

Abstract:

Background:

Preclinical and clinical studies highlight the enhanced anticancer efficacy of combining anti-VEGF/VEGFR drugs with immune checkpoint inhibitors (ICIs). PD-L1/VEGF bispecific antibodies outperform monotherapy or combined PD-L1 inhibitors and anti-VEGF antibodies by simultaneously blocking the PD-1/PD-L1 immune pathway and VEGF-driven angiogenesis, providing a dual mechanism for superior antitumor activity.

Methods:

We developed CVL006, a novel bispecific antibody, by fusing an anti-PD-L1 VHH domain with a humanized IgG1 anti-VEGF monoclonal antibody. CVL006 retains antibody-dependent cellular cytotoxicity (ADCC) functionality. Preclinical evaluations included binding affinity and specificity assessments, dual-pathway blockade testing, and in vivo efficacy comparisons to atezolizumab and PD-1/VEGF bispecific antibody AK112 (ivonescimab).

Results:

CVL006 demonstrated high affinity and specificity for human PD-L1 and VEGF. It effectively inhibited VEGF/VEGFR signaling and the PD-L1/PD-1 axis, suppressing VEGF-induced angiogenesis and reactivating T cells. This reactivation led to increased cytokine secretion critical for immune response. In vivo studies revealed CVL006’s superior antitumor efficacy, achieving greater tumor growth inhibition and angiogenesis suppression than atezolizumab. CVL006 also outperformed AK112 in preclinical models, showcasing robust antitumor activity.

Conclusions:

CVL006 integrates immune checkpoint inhibition and tumor vascularization disruption, offering a comprehensive anticancer strategy. Its superior preclinical performance compared to atezolizumab and AK112 underscores its therapeutic potential, paving the way for further development and clinical translation.

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项与依沃西单抗相关的新闻（医药）

2025-09-10

·PRNewswire

Cadonilimab(PD-1/CTLA-4) plus Pulocimab (VEGFR-2) Combination Therapy Shows Promising Results in IO-Resistant Non-Small Cell Lung Cancer in Oral Presentation at the 2025 WCLC

HONG KONG, Sept. 9, 2025 /PRNewswire/ -- Akeso Inc. (9926.HK) announced that data from a Phase Ib/II clinical study evaluating the combination of cadonilimab and pulocimab (an anti-VEGFR-2 antibody) in patients with immunotherapy (IO)-resistant NSCLC were presented in a Mini Oral session at the 2025 World Conference on Lung Cancer (WCLC). This marks the first clinical data release for cadonilimab in IO-resistant lung cancer. The cadonilimab combination therapy for advanced squamous non-small cell lung cancer (NSCLC) progressing after PD-(L)1 inhibitor treatment, has previously received Breakthrough Therapy Designation from the NMPA. The combination of cadonilimab and pulocimab also offers a potentially chemo-free option for advanced IO resistant NSCLC patients. The data presented at the 2025 WCLC demonstrated that the cadonilimab plus pulocimab regimen shows encouraging efficacy and broad clinical potential in patients with advanced or metastatic NSCLC who progressed after first-line standard immunotherapy-based treatment, offering a promising effective and safe therapeutic option for IO-resistant lung cancer patients: As of January 13, 2025, with a median follow-up of 16.7 months, the cadonilimab-based combination achieved a median overall survival (mOS) of 15.6 months and a median progression-free survival (mPFS) of 5.8 months in IO-resistant NSCLC. In the squamous NSCLC (sqNSCLC) subgroup, mOS was 16.7 months, mPFS was 7.1 months, the disease control rate (DCR) reached 96.2%, and the objective response rate (ORR) was 11.5%. In the non-squamous NSCLC (nsq-NSCLC) subgroup, mOS was 12.8 months, mPFS was 5.5 months, DCR was 95.2%, and ORR was 14.3%. Based on the promising clinical efficacy and safety data, preparation is underway for a Phase III clinical study evaluating the combination of cadonilimab and pulocimab for IO-resistant lung cancer. Additionally, ivonescimab (PD-1/VEGF), another novel bispecific antibody developed by Akeso, has shown unique efficacy and significant expansion potential in the IO-resistant NSCLC population. A registrational Phase III trial for ivonescimab has already been initiated. As first-in-class bispecific antibodies, both cadonilimab and ivonescimab are showing increasing advantages across a broadening range of disease areas. By leveraging dual-targets with synergistic mechanisms, they both address critical clinical challenges, such as limited efficacy or resistance to single-target agents like PD-1 inhibitors. This positions the bispecific antibodies as superior treatment options for patients worldwide. In recent years, immunotherapy has made significant progress in lung cancer treatment. PD-1/L1 inhibitors, either alone or with platinum-based chemotherapy, are the first-line treatment for driver-negative advanced NSCLC. However, 60%–70% of patients experience disease progression within a year. Docetaxel is the standard therapy for IO-resistant patients, but its effectiveness is limited. Improving outcomes for NSCLC patients after IO resistance remains a critical unmet need. Previous Phase III trials for IO-resistant lung cancer, including those with PD-1 inhibitors and ADCs, have not demonstrated meaningful clinical benefits. There is currently no approved standard treatment for NSCLC after resistance to IO therapies. The combination of cadonilimab and pulocimab has shown strong clinical potential in IO-resistant lung cancer, notably extending patient survival. The cadonilimab and pulocimab combination has also shown promising clinical data in other treatment-resistant cancers, including IO-resistant hepatocellular carcinoma and gastric cancer. Cadonilimab's proven efficacy for patients across all levels of PD-L1 expression, positions it as a key solution for IO-resistant cancers. This breakthrough offers a potentially new option for NSCLC patients that currently have limited treatment options after resistance to cancer immunotherapies. Forward-Looking Statement of Akeso, Inc. This announcement by Akeso, Inc. (9926.HK, "Akeso") contains "forward-looking statements". These statements reflect the current beliefs and expectations of Akeso's management and are subject to significant risks and uncertainties. These statements are not intended to form the basis of any investment decision or any decision to purchase securities of Akeso. There can be no assurance that the drug candidate(s) indicated in this announcement or Akeso's other pipeline candidates will obtain the required regulatory approvals or achieve commercial success. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in P.R.China, the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Akeso's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the Akeso's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. Akeso does not undertake any obligation to publicly revise these forward-looking statements to reflect events or circumstances after the date hereof, except as required by law. About Akeso Akeso (HKEX: 9926.HK) is a leading biopharmaceutical company committed to the research, development, manufacturing and commercialization of the world's first or best-in-class innovative biological medicines. Founded in 2012, the company has created a unique integrated R&D innovation system with the comprehensive end-to-end drug development platform (ACE Platform) and bi-specific antibody drug development technology (Tetrabody) as the core, a GMP-compliant manufacturing system and a commercialization system with an advanced operation mode, and has gradually developed into a globally competitive biopharmaceutical company focused on innovative solutions. With fully integrated multi-functional platform, Akeso is internally working on a robust pipeline of over 50 innovative assets in the fields of cancer, autoimmune disease, inflammation, metabolic disease and other major diseases. Among them, 24 candidates have entered clinical trials (including 15 bispecific/multispecific antibodies and bispecific ADCs. Additionally, 7 new drugs are commercially available. Through efficient and breakthrough R&D innovation, Akeso always integrates superior global resources, develops the first-in-class and best-in-class new drugs, provides affordable therapeutic antibodies for patients worldwide, and continuously creates more commercial and social values to become a global leading biopharmaceutical enterprise. For more information, please visit and follow us on Linkedin. SOURCE Akeso, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期免疫疗法突破性疗法临床结果

2025-09-09

·梅斯医学

WCLC 2025|专访Federico Cappuzzo教授：EGFR突变NSCLC诊疗革新，从精准治疗到动态监测的突破之路

2025年世界肺癌大会（WCLC）在西班牙巴塞罗盛大召开。作为全球规模最大的肿瘤领域学术会议之一，WCLC大会吸引了来自全球专家学者的目光，共同探讨肺癌和其他胸部恶性肿瘤的前沿诊疗进展。会议期间，梅斯医学有幸采访到国际知名专家意大利AUSL della Romagna-Ravenna医院肿瘤内科主任Federico Cappuzzo教授。面对非小细胞肺癌（NSCLC）领域日新月异的突破，Cappuzzo教授深入剖析了EGFR突变NSCLC未来诊疗格局，就靶向治疗、免疫治疗及液体活检等关键议题分享了前沿洞见。从单药到联合，迈向精准化新时代随着第三代EGFR-TKI（如奥希替尼）的广泛应用，以及新型抗体药物偶联物（ADC）和双特异性抗体等创新疗法的相继问世，EGFR突变NSCLC的治疗格局正经历深刻变革。 “过去1年，EGFR突变NSCLC的治疗图景发生了显著变化。”Cappuzzo教授指出，“一方面，以ADC为代表的创新药物为患者提供了更多治疗选择；另一方面，一线治疗策略也在持续优化，朝着更高效、更个体化的方向发展。对于高耐药风险患者，我们正在积极探索将EGFR-TKI与化疗联合，或引入埃万妥单抗（amivantamab）等靶向EGFR/c-MET的双特异性抗体，以延缓耐药发生、提高治疗深度。这些探索为制定个体化治疗方案开辟了全新路径。” “本次大会公布的埃万妥单抗研究数据令人鼓舞，埃万妥单抗联合化疗对比单纯化疗用于EGFR突变晚期NSCLC一线治疗，显著延长了无进展生存期，并显示出总生存期的获益趋势。这标志着EGFR突变NSCLC的治疗已迈入‘多元化’的新时代。未来的关键在于‘精准匹配’，为每一位患者选择最合适的治疗组合。”Cappuzzo教授总结道。免疫治疗的边界与突破：谁真正受益？尽管免疫检查点抑制剂在驱动基因阴性NSCLC中取得了巨大成功，但在EGFR或ALK阳性患者中的应用仍面临严峻挑战。目前，免疫治疗并未被推荐用于EGFR/ALK阳性NSCLC患者，尤其在老年群体中，缺乏充分证据支持其有效性和安全性。 Cappuzzo教授强调，“尽管多项研究表明，在EGFR突变患者中，单独使用PD-1/PD-L1抑制剂不仅疗效有限，还可能增加免疫相关不良事件的风险，甚至出现超进展现象，但是希望并未消失。目前显示出临床潜力的是依沃西单抗（Ivonescimab），一种同时靶向PD-1与LAG-3的双特异性抗体。最新临床数据显示，该药联合化疗在第三代EGFR-TKI耐药患者中展现出良好的抗肿瘤活性，客观缓解率和疾病控制率。” “目前尚无充分临床证据支持免疫治疗与靶向治疗或放疗联合或序贯应用的安全性与有效性，且存在免疫相关不良事件与治疗毒性叠加的风险，临床应用需谨慎。在局部晚期EGFR突变NSCLC中，奥希替尼作为第三代TKI，已被III期LAURA研究证实可显著改善无进展生存期，成为当前标准治疗选择。”Cappuzzo教授表示。液体活检：照亮耐药迷雾的“分子探针” 随着精准医疗的快速发展，肺癌的诊疗正逐步从传统的“以组织为中心”向“以分子动态为导向”的模式转变。在这一进程中，液体活检作为一种微创、可重复、实时监测肿瘤分子演变的前沿技术，正在深刻重塑NSCLC的临床管理路径。与传统的组织活检相比，液体活检通过检测外周血中的循环肿瘤DNA（ctDNA）、循环肿瘤细胞或外泌体等生物标志物，能够在不依赖侵入性操作的前提下，动态捕捉肿瘤的基因变异谱及其演化过程。这一优势使其在治疗监测、耐药机制识别和个体化干预策略制定中展现出巨大潜力。 Cappuzzo教授指出，“液体活检的核心价值在于其‘动态监测’能力。它能够实时追踪EGFR T790M、C797S突变、MET扩增、HER2扩增、RET融合乃至小细胞转化等关键耐药机制的出现，帮助临床医生在影像学进展之前就识别出分子层面的变化，从而提前调整治疗方案。” 总之，随着液体活检技术的不断成熟，我们正逐步实现对肿瘤分子动态的“实时可视化”监测。通过无创方式追踪ctDNA变化，临床医生能够在疾病进展前识别T790M丢失、MET扩增、HER2突变或组织学转化等耐药机制，从而提前制定个体化干预策略。这一技术正成为连接诊断与治疗的桥梁，推动肺癌管理向“动态监测—精准识别—及时调整治疗”的闭环模式演进。未来的肺癌治疗，绝不再是‘一刀切’的标准化流程，而是基于患者独特的分子分型、耐药演化轨迹、肿瘤微环境特征以及身体状况等多维度信息，构建高度个体化、动态调整的整合治疗策略。撰文 | 梅斯医学编辑 | 木白 ●维生素B+绿茶让大脑“返老还童”？多项研究：联用显著延缓神经衰老，经常补充不仅痴呆风险骤降超60%，还能有效降血压 ●寒心！家属潜入医生办公室，将红包偷塞进白大褂，反手却举报医生受贿！医院纪委：已查明，是诬告！医生呼吁：关好办公室的门，难防坏人 ● 睡前运动越猛，睡眠越崩？多项研究：睡前2小时高强度运动，入睡延迟36分钟，睡眠蒸发超20分钟；但3分钟抗阻运动反提升睡眠质量版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」立刻下载梅斯医学APP！

2025-09-09

·同写意

数据向好，康方跌倒？

9月17日-18日，同写意将联合益诺思、清大浦恒、基锘威生物等机构在上海举办“上海未来细胞疗法决策者峰会”，敬请期待！被视作PD-1/VEGF双抗标杆的ivonescimab（依沃西），再次迎来重磅数据更新。 9月7日，康方生物海外合作方Summit Therapeutics，在2025年世界肺癌大会上披露HARMONi研究最新成果，中位随访时间延长至13.7个月后，西方患者数据成熟度提升，OS的HR缩小至0.78（p=0.0332）。与5月公布的数据相比，此次更新显示OS获益有所改善，但仍未达到研究预设的统计学显著性阈值（p≤0.0448）。在PFS方面，依沃西组显著降低疾病进展或死亡风险达48%（HR=0.52，p<0.00001），已达到研究的主要终点。康方生物表示，HARMONi研究根据FDA的要求，随机纳入了约38%的北美和欧洲的患者。最新分析表明，西方和亚洲患者包括OS和PFS在内的临床研究终点获益“高度一致”。然而，一场本应属于胜利者的庆典，骤然变成质疑与交锋的战场。一边，资本市场上演了截然不同的剧情。9月8日港股开盘，康方生物股价不涨反跌，跌幅一度接近10%。次日，股价继续下探0.84%——这多少折射出投资者的态度分化。另一边，华尔街的分析师们提出了尖锐质疑：为什么在长期随访中，西方患者的PFS改善率（33%）明显低于中国患者（45%）？如果东西方患者数据真的“高度一致”，为何试验会如此迅速地触达OS最终分析点，以至于西方人群的随访时间仅有9.2个月，远短于中国患者的32.7个月？更核心的问题是：在一个强调“OS为王”的监管时代，仅凭强大的PFS数据和OS趋势，能否真正说服FDA？基于前述种种质疑，同写意采访了Biotech创始人、药企数据统计部门高管、FDA前审评官员等业内人士，尝试从不同的观测维度，梳理出一些理解这款潜在“药王”的脉络。事实上，围绕依沃西这款药物数据的争论，也远超出一个药物、一家公司的命运本身。它触及了中国创新药出海的核心痛点：国际多中心临床试验的设计如何经得起推敲？当遇到东西方人群差异时，该如何证明数据的一致性？与Summit这样的美国Biotech合作，是否不如跟MNC的联姻来得稳妥？站在数据与监管的十字路口，依沃西的遭遇正在成为整个行业的试金石——中国创新药的出海之路，究竟需要怎样的科学严谨性、国际临床能力和战略耐心？所有人都在等待FDA的最终判决，而这场判决的意义，早已超出了一款药物的范畴。 TONACEA 01 对OS的困惑 “强烈谴责公司在明明Hamoni试验已经进行最终的OS分析且没有达到统计学显著性的情况下，不明确披露海外OS已经进行OS最终分析且没达到统计学显著性。”雪球上，一位用户言辞激烈地指责。在HARMONi试验中，尽管PFS达到了预定目标，但依沃西在另一个主要终点OS方面的表现，未能满足市场的高期待。礼邦制药首席科学官肖申解释说，早在5月进行初步分析时，依沃西的mOS是16.8个月，对照组为14个月，HR为0.79。“这个结果应该算有临床意义的差异，但P=0.057，高于预设阈值（0.0448），所以没有达到统计学上的显著性。” 作为合作方的Summit，当时也提及相关数据。不过，最初的对外沟通措辞，给许多投资者和分析师留下了这样的初步印象：HARMONi未来仍有机会在OS方面达到统计学显著水平。 8月，康方生物在发布的半年业绩报告中表示，“依沃西展现出良好的OS获益趋势”。此次世界肺癌大会的报告证实，HARMONi在最终分析中，OS获益进一步提升。但是，有两个问题需要回应。首先，HARMONi研究“4月DCO锁库了，9月数据还能用吗”？一篇文章解释说，DCO并非“终点线”，它更像是“快照”，只要统计分析计划里写清事件驱动规则，就能按预设事件继续随访下去。简而言之，对于HARMONi研究，261例是方案写定的“终点线”，以事件为终点。由于4月尚未到事件终点，所以9月更新的数据是可被考虑的。其次，虽然随着随访时间延长，患者OS获益持续改善，却也改变不了“未能达到OS临床终点”的事实。这与Summit此前披露的结果一致：依沃西联合化疗组的死亡风险为21%，p值为0.057，而统计学显著性标准设定是0.0448。来自Leerink Partners的分析师说，这意味着，Summit哪怕重新审视OS，也无法就探索性分析宣称具有统计学意义，因为该分析并未被前瞻性地纳入正式的统计计划中。最终的OS分析是由于438人试验中261例死亡而触发的。当时，依沃西联合化疗组有122例患者（56%）死亡，化疗组有140例患者（64%）死亡；mOS分别为16.8个月和14个月。缺少足够坚实的OS数据，对依沃西来说尤其糟糕，因为FDA已告知Summit，需要有统计学上显著的OS获益，才能支持其在二线EGFR突变NSCLC治疗中的批准——至少这项适应症如此。不过，一位临床专家向同写意表示，“OS statistically significant不如clinicall meaningful重要”，OS HR落在0.75-0.80之间，就已经是有临床获益的好药。石药集团CMO黑永疆也觉得，从综合数据考虑，依沃西呈现的价值定位是应该整体导向的，不能因为OS没有达到统计学上的显著差异就一棒子打死。在这种语境下，PFS达到临床终点、OS持续改善，仍有较大机会进入美国市场。 TONACEA 02 “一致性”问题 Summit对新的数据感到鼓舞，康方生物也声称西方和亚洲患者包括OS和PFS在内的临床研究终点获益高度一致，尽管如此，数据结果却仍然引发困惑。如果Summit使用HARMONi-A作为基准来设计HARMONi，同时假设依沃西在中国和西方患者中的表现相似，那么，HARMONi是怎样如此迅速地达到最终OS分析的触发点，以至于对于FDA最重要的西方人群的9个月随访显然太短了？一种可能的解释是，在依沃西能够证明其治疗效果的最初几个月里，西方人群的死亡速度比预期要快。 Summit首席商业和战略官Dave Gancarz否认了这种猜测。他透露，当试验达到预设的死亡事件数量时，在西方人群的死亡事件比预期要少。对OS曲线的Fierce分析显示，两项试验之间存在一些早期差异。 HARMONi研究中，依沃西获益在9个月后开始显现。而根据2024年公布的中位随访期17.6个月的数据，HARMONi-A研究的试验组和对照组的生存曲线分离耗时约一半，即在第5个月之前。到第9个月，依沃西联合化疗组在患者生存概率方面已较单纯化疗组高出4.4个百分点的绝对优势。 HARMONi-A进行首次中期OS分析时，数据截止时间为2023年6月，中位随访期为10.2个月，结果与此类似。2023年5月，Summit正式启动HARMONi试验。国内一位统计学背景的审评专家向同写意表示，西方人群的入组时间短，导致随访时间偏少，有可能在事件数达标时依沃西的疗效还未得到展现，从而稀释了最终的获益，造成阴性结果结果。对于数据的“一致性”，Summit临床开发负责人Jack West回应说，“中国患者与北美患者并不完全相同”，其中包括约14%的HARMONi-A患者仅接受了上一代EGFR抑制剂治疗，而不是HARMONi研究中的第三代药物。至于西方人群的随访时间较短，West指出，HARMONi的招募速度较慢，部分原因是COVID-19过后试验活动尚未恢复正常。 9月8日的电话会上，Summit CEO Robert Duggan进一步补充道，2023年1月FDA曾破例允许其将中国单区域研究扩展为多区域试验，但北美医生对PD-1/VEGF双抗和中国数据的保守态度，客观上延迟了入组进度。除了OS，长期随访中，HARMONi和HARMONi-A试验组患者的PFS差异为12个百分点。在部分业内人士看来，5个百分点以内的差距很容易判断，而5到10个百分点的差距，则会引起一些争论。支持者认为，HARMONi延续了PFS强阳性结果。一位国际药企统计数据部门前全球领导人告诉同写意，根据目前公开资料，“PFS应该是positive的”。所以，“这个study从统计意义上应该实现相应预设目的”。简言之，HARMONi研究得到的33% PFS获益本身就相当可观，在肿瘤试验里可视为具有临床意义。5月初步分析记录的48% PFS获益，则意味着该试验确实达到两个主要终点之一。然而，一些西方分析师觉得，鉴于既往在中国看到的其他III期临床试验结果表现，它们在中国以外有多大的适用性，需要打上一个问号。 West在最新的电话会上回应说，PFS分析显示亚洲与西方的HR高度一致（从0.52变为0.57），mPFS在各区域差异≤0.1个月，北美亚组OS HR是0.70，mOS未达（对照组14.0个月）。这些结果的置信区间高度重叠。 TONACEA 03 获批概率几何？如果按照现有资料，FDA会批准依沃西吗？ Summit对中国以外人群进行了一项更长期的OS分析，依沃西试验组的死亡风险降低率已扩大至22%，名义p值改善为0.0332。北美和欧洲患者的死亡风险降低率是16%，北美患者为30%，中国患者为24%。然而，前述数据均不具有统计学意义。相比起来，康方生物不久前的半年报报告披露，中国开展的HARMONi-A在最终分析中取得具有临床意义和统计学显著性的OS获益。由于HARMONi的中国受试者——占整个试验人群的62%——直接来自HARMONi-A研究，这些受试者此前曾接受第三代EGFR抑制剂治疗失败，故而，此次更长的随访期仅针对西方人群。北美和欧洲患者的中位随访期在更新后为13.7个月，而最终OS分析时为9.2个月。中国患者的中位随访期为32.7个月。在获批概率上，专家的意见呈现出不小的分歧。例如，黑永疆就认为，总体上来看数据并没有变差，加上西方人的数据趋势向好，FDA允许其上市的可能性更大些。 “从正面看，PFS达到预设，OS也有改善。从反面看，PFS相差是2.4个月，FDA此前很少批过比差小于3个月的药物，除非OS结果足够好。”不过FDA前审评官，诺思格首席统计师何崑告诉同写意，他仍觉得批准的概率略大于一半。而按照岸脉生物CMO朱永红的观点，历史上EGFR适应症在欧美的获批基于强PFS结果的并不少见，所以获批不是完全不可能。只不过，目前的大环境是，FDA刚刚强调过OS作为主要终点的重要性。 “个人感觉要看康方和Summit的totality of data package，包括其他试验的初步结果。”朱永红补充说。 8月，FDA发布的《癌症临床试验中总生存期评估新指南草案》明确要求，在可行情况下，OS应作为临床试验的主要终点。即使OS不作为主要终点，药企也必须收集并提交生存数据，以支持药物安全性和疗效的最终评价。包括依沃西在内的PD-1/VEGF双抗，被认为在FDA此番改革中首当其冲。这类双靶药物理论上可协同提升疗效，然而其临床数据呈现一个尴尬的悖论：PFS数据耀眼，OS尚未“撞线”。 “FDA已经把政策收紧了，强调临床获益的金指标是OS。”烨辉医药创始人华烨分析，“从这次结果来看，OS数据没有达到显著性差别，所以想要获批的难度不小。” 和黄医药CMO石明则认为，临床试验西方人太少，应做全西方人3GTKI，获批希望小于一半。另外，针对依沃西在北美人群的生存获益数据突出，华烨还提及，注册法规上通常只是将亚组数据作为支持性的次要证据，整体数据质量才是对批准结果影响更重要的砝码。肖申也对此表示复议。FDA主要看全人群预设分析，而不是事后挑出的亚组。如果整体数据还没达到预设p值门槛，FDA态度会非常谨慎。他指出：“公告中名义p值是0.032，它是否按预先统计计划做了多重性、期中分析校正？如果与方案阈值一致，或经校正仍小于0.0448，那就获批就没问题。” 若是只有北美亚组显著，但整体人群还是边缘显著，肖申分析，FDA可能会要求补充数据，进行长期的随访，或要求做confirmatory trial（可能是上市后III期确认性研究）。部分情况下，尤其获得优先审评或突破性疗法指定，FDA也可能选择有条件批准。不确定之处在于，FDA一般要求亚组分析必须在统计计划中预先定义，否则很难作为批准的主要依据。而倘若“HR=0.78”来自于后续随访数据，属于事后分析，结果不太会作为批准依据。由于此次更新的数据截取时间非常近，Summit称，正在与FDA协商最优申报路径，从而确定最终的具体时间表。 TONACEA 04 出海的“if线” 2022年，康方生物与Summit达成最高总计50亿美元的“联姻”，刷新了当时的创新药出海记录，让业界看到了中国Biotech的风光可能。但是，随着依沃西去年以来的数次III期临床数据更新，尤其是此番2025年世界肺癌大会上披露的全球HARMONi结果——OS未达到统计学上的显著水平——业界对这段佳话逐渐出现更多不同的解读。国内一位Biotech CEO对同写意感慨，HARMONi直接纳入国内开展的HARMONi-A研究人群，这样的设计有些过于取巧。通常要开展一项多中心的国际临床试验，入组、对照等条件是统一的，桥接的做法势必带来临床数据的差异波动。在业界看来，Summit以激进的战略著称，这多少解释了为什么北美受试者的占比为何如此少。结果就是，尽管在金标准OS上进一步得到提升，却并未达到监管惯例所需要的显著性。 “这提醒我们，在国际临床试验设计上，对于统计分析方案要提前考虑好欧美人群的比重、入组和随访时间，减少回顾性分析存在的假阳性质疑。”前述国内统计学背景审评专家说。倘若康方生物最初不是选择Summit，而是MNC，结果也许会大不相同。持有这种观点的人，从科伦博泰与默沙东、百利天恒与BMS的合作里找到背书。如此对比并不严谨，但业界的共识却是，MNC国际临床管理能力普遍更高，数据更扎实。当然，目前为依沃西的国际化之路下定论，似乎还为时尚早。 Duggan透过9月8日的电话会告诉投资者，Summit的核心战略保持不变：持续推进对应市场份额更大的HARMONi-3/7研究，未来数月还会新增两项III期研究，对有利于药物开发的合作持开放态度。而随着今年以来的MNC涌入，包括辉瑞、默沙东分别从三生制药、礼新医药引进PD-1/VEGF双抗，相信不久的将来，我们可以得到关于本土创新出海更完整的道路图景。请您预测！参考资料： 1.HARMONi研究更新数据：OS HR=0.78（P=0.0332），依沃西全球一致性获益数据在WCLC发布 2.Summit's global PD-1xVEGF data challenge regional consistency claims but show new promising survival trend 3.HARMONi 4月DCO了, 9月数据还能用? FDA认哪个? 4.FDA重拳出击：OS为王！ 5.数据与决策的十字路口：Summit Post-WCLC 电话会十问十答 6.康方又一关

细胞疗法临床结果

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批准上市

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适应症	国家/地区	公司	日期
PD-L1阳性非小细胞肺癌	中国	康方赛诺医药有限公司	2025-04-22
EGFR阳性非鳞状非小细胞肺癌	中国	康方赛诺医药有限公司	2024-05-21

未上市

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适应症	最高研发状态	国家/地区	公司	日期
晚期鳞状非小细胞肺癌	申请上市	中国	康方药业有限公司	2025-07-25
晚期鳞状非小细胞肺癌	申请上市	中国	康方赛诺医药有限公司	2025-07-25
非小细胞肺癌	临床3期	中国	中山康方生物医药有限公司	2025-06-30
晚期非小细胞肺癌	临床3期	-	中山康方生物医药有限公司	2025-06-01
小细胞肺癌	临床3期	中国	中山康方生物医药有限公司	2025-05-29
局限期小细胞肺癌	临床3期	中国	中山康方生物医药有限公司	2025-05-29
转移性胰腺癌	临床3期	中国	中山康方生物医药有限公司	2025-05-14
大肠腺癌	临床3期	中国	中山康方生物医药有限公司	2025-05-09
转移性结直肠癌	临床3期	中国	中山康方生物医药有限公司	2025-05-09
PD-L1阴性三阴性乳腺癌	临床3期	中国	中山康方生物医药有限公司	2025-02-07

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05184712 (HARMONi-A, NEWS) 人工标引	临床3期	EGFR突变的非小细胞肺癌 EGFR-mutated	-	ivonescimab + chemotherapy	鹹願淵鑰繭壓淵觸繭鑰(襯觸鑰顧艱襯鬱廠衊願) = the Phase III HARMONi-A trial met its OS goal, showing that ivonescimab. 鹹觸範餘艱簾獵積顧網 (淵鏇膚糧糧獵製選範壓 ) 达到	积极	2025-08-26
				placebo + chemotherapy
NCT06396065 (HARMONi, NEWS 1 \| NEWS 2) 人工标引	临床3期	非鳞状非小细胞肺癌 \| EGFR阳性肿瘤二线 EGFR Mutation	-	ivonescimab +化疗	網餘簾鹹構蓋淵淵膚鏇(繭憲顧遞餘衊鏇餘鬱餘): 0.52 (95.0% CI, 0.41 ~ 0.66), P-Value = <0.00001 更多	积极	2025-05-30
				化疗
NCT05899608 (HARMONi-3, ASCO2025)	临床3期	转移性非小细胞肺癌一线 \| 维持	1,080	Ivonescimab plus chemotherapy	鹹網製廠築願廠繭積膚(膚糧遞顧簾齋鬱艱鏇製) = 鹽壓繭蓋鹹範積齋網鑰網繭製齋獵夢憲鹹鹽積 (夢築鹹醖製艱蓋衊廠構 ) 更多	积极	2025-05-30
				Pembrolizumab plus chemotherapy	鹹網製廠築願廠繭積膚(膚糧遞顧簾齋鬱艱鏇製) = 網艱鏇繭製鏇鹹構醖窪網繭製齋獵夢憲鹹鹽積 (夢築鹹醖製艱蓋衊廠構 ) 更多
NCT06375486 (ASCO2025)	临床2期	不可切除的肝细胞癌一线 HBV infection \| portal vein tumor thrombosis \| extrahepatic spread	27	Ivonescimab + HAIC	憲夢憲齋壓鹽繭壓襯鬱(蓋壓齋願遞構壓膚餘鹹) = 積觸夢選糧夢鹹製醖蓋範淵築繭衊憲簾襯鹽網 (衊鑰選餘淵獵網鹽糧糧 ) 更多	积极	2025-05-30
NCT05840016 (AK112-306 \| HARMONi-6, Company_Website) 人工标引	临床3期	鳞状非小细胞肺癌一线	532	ivonescimab + chemotherapy	鹽願憲憲製膚遞餘鹽窪(鹹築醖鑰醖鏇餘構築遞) = in the intention-to-treat (ITT) population, ivonescimab plus chemotherapy decisively beat tislelizumab plus chemotherapy in terms of progression-free survival (PFS). 餘鬱夢襯廠選膚鬱選襯 (憲選壓壓鏇蓋膚蓋範築 ) 达到更多	优效	2025-04-22
				tislelizumab + chemotherapy
NEWS 人工标引	临床2期	可切除非小细胞肺癌新辅助	-	伊沃西单抗 20 mg/kg (队列1)	構選構餘憲製繭繭襯廠(遞鹹網鬱築壓淵餘鹽鑰) = 艱鬱網壓蓋遞遞鹹齋憲膚廠簾鏇鑰鑰餘鏇築獵 (窪齋願醖築齋膚獵網鹽 ) 更多	积极	2025-01-20
				伊沃西单抗 20 mg/kg或30 mg/kg + 联合化疗 (队列2)	構選構餘憲製繭繭襯廠(遞鹹網鬱築壓淵餘鹽鑰) = 構獵積糧膚鏇製鑰憲淵膚廠簾鏇鑰鑰餘鏇築獵 (窪齋願醖築齋膚獵網鹽 ) 更多
NCT05184712 (HARMONi-A, ESMO_IO2024 \| NEWS) 人工标引	临床3期	EGFR突变的非小细胞肺癌 EGFR Mutation	322	Ivonescimab (Ivo) + Pemetrexed/Carboplatin	遞衊齋鬱獵糧淵窪餘夢(網淵鏇艱鏇襯醖鏇製鑰) = 壓築鑰襯窪遞蓋衊範鹹鹹鹹製鬱餘壓醖構鹽蓋 (鬱餘膚餘觸鏇簾繭夢窪 ) 更多	积极	2024-12-12
				Placebo + Pemetrexed/Carboplatin	遞衊齋鬱獵糧淵窪餘夢(網淵鏇艱鏇襯醖鏇製鑰) = 範膚簾衊襯糧廠淵蓋窪鹹鹹製鬱餘壓醖構鹽蓋 (鬱餘膚餘觸鏇簾繭夢窪 ) 更多
NCT05227664 (SABCS2024) 人工标引	临床2期	三阴性乳腺癌一线	30	Ivonescimab + Paclitaxel/Nab-paclitaxel	壓廠襯鑰築淵構鏇鹽齋(襯構憲築夢製簾鏇鹽顧) = 鬱鏇鹽鏇範憲餘鑰鑰窪範獵觸鹹鹽蓋壓顧餘網 (遞選鬱鬱壓齋膚願選窪 ) 更多	积极	2024-11-26
				Ivonescimab + Paclitaxel/Nab-paclitaxel (PD-L1 CPS ≥10)	壓廠襯鑰築淵構鏇鹽齋(襯構憲築夢製簾鏇鹽顧) = 襯遞艱淵鑰衊糧築襯淵範獵觸鹹鹽蓋壓顧餘網 (遞選鬱鬱壓齋膚願選窪 ) 更多
NCT05227664 (ESMO2024) 人工标引	临床2期	三阴性乳腺癌一线 HER2 Negative \| ER Negative \| PR Negative	30	Ivonescimab 20Paclitaxel + Pnab-paclitaxelg/m2	廠範窪淵獵網衊餘襯繭(糧鏇鏇觸鬱願範鹹遞選) = 鏇窪膚窪餘淵憲廠憲糧鹽鬱膚糧衊鏇繭夢淵憲 (齋顧鏇獵糧淵襯襯觸廠 ) 更多	积极	2024-09-16
				Ivonescimab 20Paclitaxel + Nnab-paclitaxel100 mg/m2	廠範窪淵獵網衊餘襯繭(糧鏇鏇觸鬱願範鹹遞選) = 衊鬱憲選艱蓋糧繭醖鹹鹽鬱膚糧衊鏇繭夢淵憲 (齋顧鏇獵糧淵襯襯觸廠 ) 更多
NCT05382442 (ESMO2024) 人工标引	临床2期	转移性结直肠癌一线 KRAS \| BRAF \| MSS	40	FOLFOXIRI + Ivonescimab	夢夢醖鏇衊齋簾淵壓願(鏇選夢願鹹鹹醖鹹範廠) = 選醖齋築簾積顧夢選餘廠夢簾膚蓋獵窪簾蓋獵 (鬱鬱鏇繭鑰壓繭鬱艱膚 ) 更多	积极	2024-09-14
				FOLFOXIRI + Ivonescimab + Ligufalimab	夢夢醖鏇衊齋簾淵壓願(鏇選夢願鹹鹹醖鹹範廠) = 願積鬱膚遞糧範選壓範廠夢簾膚蓋獵窪簾蓋獵 (鬱鬱鏇繭鑰壓繭鬱艱膚 ) 更多