An open-label, Phase I/Ib study investigating the safety and efficacy of tiragolumab + atezolizumab + RadScopal™ XRT in patients with metastatic solid malignancies.

开始日期2025-06-30

申办/合作机构-

NCT06328036

/ Withdrawn临床2期IIT

Phase 2 and Biomarker Trial of Anti-TIGIT and Anti-PDL1 in Patients With Recurrent Glioblastoma

This phase II trial compares the safety, side effects and effectiveness of atezolizumab with tiragolumab to atezolizumab alone in treating patients with glioblastoma that has come back after a period of improvement (recurrent). Glioblastoma is the most common primary brain cancer in adults and despite aggressive treatment, it is nearly always fatal. Currently, there are limited effective treatment options in patients that have recurrence. Immunotherapy has been shown to be effective in other types of cancer and may be an appealing potential treatment option for recurrent glioblastoma. Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Study doctors also want to learn if a tumor infiltrating T lymphocyte (TIL) response is helpful to determine the benefit of the combination of study drugs compared to the usual approach. TILs are a type of immune cell that has moved from the blood into a tumor. TILs can recognize and kill tumor cells. Giving atezolizumab with tiragolumab may be safe, tolerable and/or effective compared to atezolizumab alone in treating patients with recurrent glioblastoma.

开始日期2025-04-30

申办/合作机构

National Cancer Institute

NCT06603818

/ Not yet recruiting临床2期IIT

A Phase II Study of Immunotherapies (Tiragolumab and Atezolizumab) in Combination With Stereotactic Body Radiation Radiotherapy in Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)

Background:
Metastatic colorectal cancer (mCRC) is cancer that has spread beyond the colon and rectum. Most people with mCRC die within 5 years. New immune-based treatments are making progress with some types of colon cancer. But these treatments do little for people with a type of cancer that is microsatellite stable (MSS). MSS is a specific cancer biomarker. Better treatments are needed.
Objective:
To test 2 drugs (tiragolumab and atezolizumab) combined with radiation therapy in people with MSS mCRC.
Eligibility:
People aged 18 years and older with MSS mCRC.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have imaging scans and a test of their heart function. They will provide a tissue sample from their tumor; if one is not already available, a new sample will be taken. Their ability to perform normal tasks will be assessed.
Tiragolumab and atezolizumab are both administered through a tube attached to a needle inserted into a vein. Participants will receive both drugs on day 1 of 3-week treatment cycles. Each study visit should last about 8 hours.
Participants will receive radiation therapy on days 1, 3, and 5 of cycle 1 only.
Blood samples and rectal swabs will be collected on day 1 of every cycle.
Imaging scans will be repeated every 9 weeks. Additional tumor samples may be taken during treatment.
Treatment will continue for up to 2 years.
Participants will have a follow-up visit 1 month after treatment ends. Follow-up visits will continue every 3 months for 1 more year.

开始日期2025-04-24

申办/合作机构

National Cancer Institute

100 项与替瑞利尤单抗相关的临床结果

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100 项与替瑞利尤单抗相关的转化医学

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100 项与替瑞利尤单抗相关的专利（医药）

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项与替瑞利尤单抗相关的文献（医药）

2025-05-01·CLINICAL PHARMACOLOGY & THERAPEUTICS

Model‐Informed Selection of the Recommended Phase 2 Dosage for Anti‐TIGIT Immunotherapy Leveraging co‐Expressed PD‐1 Inhibitor Target Engagement

Article

作者: Hu, Ping ; Venkatakrishnan, Karthik ; Gao, Wei ; Kareva, Irina ; Victor, Anja ; Kitzing, Thomas ; Richter, Emilia ; Pierre, Vadryn ; Zutshi, Anup

Refining dose projections requires a deep understanding of drug‐target relationships at the site of action, which is often challenging to achieve. Here we present a case study of how one can refine dose projections for a TIGIT‐targeted immunotherapy by leveraging information from the well‐studied PD‐1 pathway since the co‐expression of PD‐1 and TIGIT on immune cells provides a unique opportunity to extrapolate data from one target to inform the dosing strategy for the other. We develop a fit‐for‐purpose mathematical model that captures the experimentally observed relationship between the concentration of a mouse PD‐1 antagonist in the plasma and PD‐1 target engagement within the tumor microenvironment (TME). We then assess the applicability of this PD‐1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti‐TIGIT antibody, across various doses. This analysis aims to refine our understanding of the dose–response relationship for targeting TIGIT, a critical step in optimizing therapeutic efficacy, without conducting additional experiments. The approach is then extended to project efficacious doses for M6223, another anti‐TIGIT antibody, using the established PD‐1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug‐target relationship at the site of action by leveraging established drug‐target relationships. Through extrapolating information from a well‐characterized pathway, we offer a method to inform dose optimization strategies with limited data using model‐informed drug development.

2025-03-01·BMJ Open

NeoTRACK trial: Neoadjuvant TiRagolumab, Atezolizumab and Chemotherapy – dissection of IO- efficacy in NSCLC by longitudinal tracKing – protocol of a non-randomised, open-label, single-arm, phase II study

Article

作者: Kirchner, Marietta ; Doerr, Fabian ; Cvetkovic, Jelena ; Christopoulos, Petros ; Bölükbas, Servet ; Thomas, Michael ; Wiesweg, Marcel ; Stenzinger, Albrecht ; Eichhorn, Martin E ; Winter, Hauke ; Hegedüs, Balazs ; Schnorbach, Johannes ; Klotz, Laura V ; Schneider, Marc ; Allgaeuer, Michael ; Schramm, Alexander ; Eichhorn, Florian ; Bozorgmehr, Farastuk ; Schuler, Martin ; Griffo, Raffaella ; Roesch, Romina M

Background:

Immunotherapies targeting the programmed death receptor-1/programmed death ligand-1(PD-1/PD-L1) checkpoint have a major impact on the treatment of both resectable and advanced non-small cell lung cancer (NSCLC). Additional blockade of the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT)-receptor may synergistically foster the immune-related response. Several trials are currently investigating the combination of neoadjuvant platinum-based chemotherapy and dual checkpoint inhibition prior to curative surgery. The investigator-initiated NeoTRACK trial (EU CT number: 2022-501322-38-00; ClinicalTrials.gov identifier:NCT05825625; IKF056) aims to evaluate the feasibility and safety of perioperative anti-PD-L1 (by atezolizumab) and anti-TIGIT (by tiragolumab) treatment in combination with chemotherapy in patients with early stage NSCLC.

Methods and analysis:

NeoTRACK is an open-label, single-arm, prospective, bicentric phase II trial. Patients with NSCLC in clinical stages II, IIIA and IIIB (only T3N2) will receive two cycles of standard platinum-based chemotherapy in combination with the anti-TIGIT antibody tiragolumab and the anti-PD-L1 antibody atezolizumab, followed by curative surgery. After surgery, patients without pathological complete response (pCR) will receive another two cycles of chemotherapy in combination with tiragolumab and atezolizumab, followed by tiragolumab/atezolizumab maintenance for up to 1 year (maximum 16 cycles). Patients with pCR will only receive dual immunotherapy. All patients will be followed-up for 30 months after the last study treatment. The clinical study will be aligned with a translational research programme to investigate treatment-naïve tumour tissues, surgical specimens and longitudinally collected blood samples. 35 patients are planned for enrolment. Patient recruitment started in August 2023, and treatment of the last patient is estimated to start 2.5 years thereafter.

Discussion:

The NeoTRACK trial aims to assess the feasibility and efficacy of combining tiragolumab and atezolizumab as both neoadjuvant and adjuvant therapies in patients with resectable NSCLC. The concept of treatment personalisation based on postoperative pCR is of great clinical interest.

Ethics and dissemination:

The trial obtained ethical and regulatory approval in Germany through the Clinical Trials Information System (CTIS, ID: 2022-501322-38-00) and the Paul Ehrlich Institute (PEI, competent authority for approval of clinical trials using medicinal products for human use in Germany, process number: PB00148) on 30 March 2023. A data safety and monitoring board will meet regularly to review ongoing treatment in terms of safety.Study results will be published in peer-reviewed journals, presented at conferences and in the public registry of CTIS, following trial completion.

Trial registration number:

NCT05825625.

2025-02-01·LANCET ONCOLOGY

Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b–2, study

Article

作者: Yu, Nancy ; Wang, Yulei ; Hack, Stephen P ; Ryoo, Baek-Yeol ; Mahrus, Sami ; Burgoyne, Adam M ; Secrest, Matthew H ; Li, Daneng ; Yin, Anqi ; Edubilli, Tirupathi Rao ; Gane, Ed ; Finn, Richard S ; Badhrinarayanan, Shreya ; Shemesh, Colby S ; Cotter, Christopher ; Cha, Edward ; Hsu, Chih-Hung

BACKGROUND:

PD-L1 and VEGF blockade with atezolizumab plus bevacizumab has been shown to improve survival in unresectable hepatocellular carcinoma. TIGIT is an immune checkpoint regulator implicated in many cancers, including unresectable hepatocellular carcinoma. Here, we evaluate the clinical activity and safety of the addition of tiragolumab, an anti-TIGIT monoclonal antibody, to atezolizumab plus bevacizumab.

METHODS:

This randomised, open-label, phase 1b-2 umbrella study was conducted at 26 centres across China, France, Israel, New Zealand, South Korea, Taiwan, and the USA. Eligible patients were adults aged 18 years old or older with previously untreated locally advanced unresectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A disease, and a life expectancy of at least 3 months. Eligible patients were randomly assigned (2:1) using permuted block randomisation to receive either tiragolumab 600 mg plus atezolizumab 1200 mg plus bevacizumab 15 mg/kg or atezolizumab 1200 mg plus bevacizumab 15 mg/kg, administered via intravenous infusion every 3 weeks on day 1 of each 21-day cycle. Patients received treatment until unacceptable toxic effects or loss of clinical benefit, whichever occurred first. The primary endpoint was objective response rate. Analysis of clinical activity was done in the efficacy-evaluable population (all patients who received at least one dose of each drug for their assigned treatment regimen) and safety was assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT04524871, and is ongoing.

FINDINGS:

Between Aug 20, 2020, and Feb 10, 2022, we assessed 154 patients for eligibility and 59 eligible patients were randomly assigned to receive tiragolumab plus atezolizumab plus bevacizumab (n=41) or atezolizumab plus bevacizumab (n=18); one patient in the tiragolumab plus atezolizumab plus bevacizumab group experienced an adverse event before receiving any treatment and withdrew from the study. Median age was 65·0 years (IQR 61·0-73·0). 46 (79%) of 58 patients were male and 12 (21%) were female. Most patients were Asian (23 [40%]) or White (21 [36%]). At the time of clinical cutoff (Aug 21, 2023), median follow-up was 20·6 months (IQR 10·6-28·0) in the tiragolumab plus atezolizumab plus bevacizumab group and 14·0 months (4·2-18·5) in the atezolizumab plus bevacizumab group. The confirmed objective response rate was 43% (95% CI 27-59, n=17) in the tiragolumab plus atezolizumab plus bevacizumab group and 11% (1-35, n=2) in the atezolizumab plus bevacizumab group. All patients in both groups experienced an adverse event. The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1-2. The most common grade 3-4 adverse events were hypertension (six [15%] of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group vs two [11%] of 18 patients in the atezolizumab plus bevacizumab group), aspartate aminotransferase increased (three [8%] of 40 patients vs one [6%] of 18 patients), and proteinuria (two [5%] of 40 patients vs two [11%] of 18 patients). Serious adverse events occurred in 21 (53%) of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group and in ten (56%) of 18 patients in the atezolizumab plus bevacizumab group. Treatment-related deaths occurred in one patient in the tiragolumab plus atezolizumab plus bevacizumab group (due to cholestasis) and two patients in the atezolizumab plus bevacizumab group (due to oesophageal varices haemorrhage and upper gastrointestinal haemorrhage). The addition of tiragolumab to atezolizumab plus bevacizumab did not appear to result in a substantial worsening of treatment-related or immune-mediated adverse events, and no new safety signals were identified.

INTERPRETATION:

This signal-seeking study suggests that the addition of tiragolumab to atezolizumab and bevacizumab might be more clinically active than atezolizumab plus bevacizumab alone in unresectable hepatocellular carcinoma. Based on these data, further study of combination tiragolumab plus atezolizumab plus bevacizumab is warranted.

FUNDING:

F Hoffmann-La Roche and Genentech.

289

项与替瑞利尤单抗相关的新闻（医药）

2025-04-11

·微信

21亿研发费用“打水漂”，百济神州7年“烧光”591亿

因试验数据不佳，清明前百济神州投入近21亿元的项目折戟。4月3日，百济神州在官网宣布停止TIGIT抗体欧司珀利单抗（ Ociperlimab）作为肺癌潜在治疗方法的临床开发计划。公告显示，依据预先计划的无效性分析结果，独立数据监查委员会建议终止正在进行的3期AdvanTIG-302试验（NCTO4746924）。试验的总体有效性和安全性数据评估表明，该研究或难以达到总生存期主要终点。但同时，未发现新的安全信号。经慎重考虑，百济神州决定终止该试验。来源：百济神州官网值得注意的是，2023 年 7 月 10 日，百济神州方面与诺华制药集团签署了针对 Ociperlimab 的共同终止和释放协议，终止了双方在 2021 年 12 月签署的选择权、合作和许可协议。但此后，百济神州选择继续推进 Ociperlimab 的临床研究。截至2024年上半年末，百济神州已在欧司珀利单抗项目累计投入 20.9亿元。▍TIGIT靶点研发困境TIGIT作为一种免疫检查点蛋白，通过抑制T细胞和NK细胞的活性，帮助肿瘤逃避免疫系统的攻击。理论上，阻断TIGIT通路可以增强免疫细胞的抗肿瘤活性。然而，TIGIT与PD-1/PD-L1通路在免疫调节中的作用机制存在显著差异，这使得联合疗法在实际应用中面临更多的不确定性。作为免疫治疗领域的热门靶点，TIGIT曾吸引了多家大药企的投入。此次项目终止是TIGIT靶点研发困境的缩影。2024年5月，默沙东因毒性相关退出率过高，终止了其抗TIGIT抗体 Vibostolimab 在高危黑色素瘤患者中的 III 期试验；几个月后，默沙东又根据独立数据审查委员会的建议，终止了 Vibostolimab 联合 Keytruda 治疗 NSCLC 的另一项 III 期试验。2024年 7 月，罗氏（Roche）也因生存期数据令人失望，终止了其抗 TIGIT 药物 Tiragolumab 在 NSCLC 中的 II/III 期试验。尽管在肺癌领域屡遭挫折，并不意味着TIGIT靶点的彻底失败。不仅罗氏仍在肝癌上开发该类药物，阿斯利康今年也刚刚启动PD-1/TIGIT双抗的3期临床试验，百济神州在欧司珀利单抗开发计划中，还有关于DLBCL，头颈癌，胃癌等早期研究。此外，还有吉利德与Arcus Biosciences合作开发的Domvanalimab（一种Fc沉默型抗TIGIT单克隆抗体），该药在II期显示积极数据。▍7年，百济研发费用679亿元百济神州以“高举高打”策略闻名，其研发投入长期位居国内首位。年报显示，2024年百济神州全年研发费用高达19.53亿美元（约合人民币142.79亿元），同比增长9.8%，占营收比例约52%。百济神州2021年上市后，一举成为行业研发支出的领头羊。2018年至2024年，其研发费用分别为45.97亿元、65.88亿元、89.43亿元、95.38亿元和111.52亿元、128.13亿元、142.79亿元。从2022年起，百济神州研发费用首次超过百亿，高出恒瑞医药近一倍。近7年，百济神州研发费用合计达679亿元，且在科创板33家医药企业中，也仅有这一家年度研发支出超过100亿元。在创新药领域，高研发投入并不一定会保证未来一定是高利润，因为创新药的研发存在极高的风险和不确定性。但是创新药要想在未来市场中找到一席之地，研发投入也是必不可少的。虽然百济神州在研发上投入大量资金，但新药研发是漫长复杂的过程，其中涉及到临床前研究、临床试验、生产、销售以及相关服务等多个环节，每个环节确实都会存在着失败的可能性。也就是说，做研发不一定有出路，但是不做研发一定没有出路。张毅表示，这种大量投入研发的模式是否能够持久，和公司财务状况、融资能力以及市场需求和走势，以及研发方向是否正确，都有非常密切的关系。不管如何，构建门槛都一定是在研发上下工夫。结语：创新药的战场从未温情。百济神州的TIGIT故事，既是对科学不确定性的敬畏，也是对坚持者的致敬。当一家企业敢于在单一项目上押注数年、耗资数十亿，即便失败，其积累的临床数据、国际化经验与人才团队，也将成为下一代药物研发的基石。喜欢我们文章的朋友点个“在看”和“赞”吧，不然微信推送规则改变，有可能每天都会错过我们哦~免责声明“汇聚南药”公众号所转载文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请在留言栏及时告知，我们会在24小时内删除相关信息。信息来源：野马财经、一度医药新浪医药往期推荐本平台不对转载文章的观点负责，文章所包含内容的准确性、可靠性或完整性提供任何明示暗示的保证。

临床3期免疫疗法临床结果临床2期临床失败

2025-04-10

·CPHI制药在线

TIGIT靶点折戟：百济神州20亿学费的背后

关注并星标CPHI制药在线2025年4月3日，中国创新药企百济神州宣布终止其抗TIGIT抗体欧司珀利单抗（BGB-A1217）在非小细胞肺癌（NSCLC）的3期临床试验AdvanTIG-302。这一决定基于独立数据监查委员会（IDMC）的无效性分析结果：研究难以达到总生存期（OS）这一主要终点。尽管未发现新的安全性风险，但这一项目仍以累计投入超20.9亿元、入组2000余例患者的代价宣告失败。TIGIT曾被誉为“下一个PD-1”，如今却因临床试验接连失败陷入集体性迷茫，这场耗资数百亿美元的研发马拉松，究竟暴露了哪些问题？烧了20亿，明星药咋就凉了？作为百济神州管线中的明星项目，欧司珀利单抗一度承载着突破肺癌治疗瓶颈的厚望。AdvanTIG-302试验的设计堪称雄心勃勃：通过将欧司珀利单抗与自家PD-1抑制剂替雷利珠单抗（Tevimbra）联用，直接挑战默沙东的Keytruda（帕博利珠单抗）在PD-L1高表达晚期非小细胞肺癌患者中的霸主地位。这一策略的逻辑看似完美——TIGIT与PD-1分别作用于免疫系统的不同环节，双管齐下本应产生协同效应。然而现实却给了理想一记重击。中期分析显示，联合疗法在延长患者总生存期上不仅未能超越Keytruda，甚至可能劣于对照组。这迫使百济神州在累计投入20.9亿元后选择止损，而这一数字尚未计入诺华2021年支付的3亿美元首付款。当年诺华重金押注的豪赌，最终因“风险收益比不理想”于2023年提前退场，如今看来更像是一次精准的风险预判。这场败局背后，是肿瘤免疫疗法研发的典型困境。即便坐拥替雷利珠单抗这一年销28亿美元的PD-1王牌，百济仍难以复刻PD-1单药的成功路径。当Keytruda、Opdivo等药物将PD-1/PD-L1抑制剂的单药疗效逼近天花板后，行业普遍将突破希望寄托于联合疗法。但问题在于，疗效的叠加往往伴随毒性的指数级增长。欧司珀利单抗虽未出现新的安全信号，但其与替雷利珠单抗联用时的3级以上不良反应发生率高达52%，远超Keytruda单药的17%。这种“杀敌一千自损八百”的窘境，让联合疗法的临床价值变得愈发微妙。TIGIT靶点：一场集体幻觉？TIGIT靶点发现于2009年的免疫检查点蛋白，曾因双重机制被视为“天选之子”：既能抑制杀伤性T细胞的活性，又能增强调节性T细胞（Tregs）的免疫抑制作用。理论上，阻断TIGIT可以同时解除两道免疫刹车，释放更强大的抗肿瘤效应。然而正是这种机制复杂性，埋下了今日困局的伏笔。早期临床数据就敲响了警钟。无论是罗氏的Tiragolumab、默沙东的Vibostolimab，还是百济的欧司珀利单抗，单药治疗的客观缓解率（ORR）普遍不足15%，远低于PD-1抑制剂20%-40%的水平。这迫使药企转向联合疗法，但疗效与毒性的平衡难题随即浮现。以罗氏2024年失败的SKYSCRAPER-01试验为例，Tiragolumab联合PD-L1抑制剂阿替利珠单抗虽将ORR从对照组的38%提升至55%，但患者总生存期却未显示统计学差异。更讽刺的是，联合组中位无进展生存期（PFS）反而比对照组缩短了0.8个月。此类矛盾数据提示，TIGIT可能在某些患者亚群中起反作用——比如通过过度激活免疫系统导致耗竭，或意外增强Tregs的免疫抑制功能。全球药企为此付出的代价堪称惨烈。过去四年间，TIGIT领域累计烧掉超过200亿美元研发资金，但进入Ⅲ期的药物仅存2款，40%项目已终止。罗氏在肺癌领域连折三阵后，仅剩肝癌适应症苦苦支撑；默沙东的Vibostolimab因疗效不足提前终止Ⅲ期试验；吉利德与Arcus合作的Domvanalimab在非小细胞肺癌失利后，转战消化道肿瘤也前景未明。这场集体溃败不仅动摇了资本市场的信心，更暴露出肿瘤免疫疗法研发的系统性风险——临床前模型的预测性与人体试验结果之间存在难以逾越的鸿沟。肿瘤免疫疗法的生死劫TIGIT靶点的困境，本质上是整个肿瘤免疫疗法领域的缩影。自PD-1/PD-L1抑制剂开启癌症治疗新时代以来，行业始终在重复一个魔咒：每一个“下一个PD-1”的豪言，最终都沦为资本狂欢后的泡沫。从CTLA-4、LAG-3到TIM-3，热门靶点的更迭速度越来越快，但临床转化成功率却持续走低。据统计，肿瘤免疫疗法的临床成功率仅为5.3%，远低于行业平均的10.4%。这种反差背后，是科学探索与商业逻辑的激烈碰撞。PD-1/PD-L1抑制剂创造的商业神话——Keytruda年销售额突破250亿美元，Opdivo、Tecentriq等产品紧随其后——催生了“靶点内卷”的畸形生态。当跨国药企的专利悬崖逼近，寻找“接班产品”的压力迫使行业将资源疯狂投向少数明星靶点。TIGIT正是这种焦虑的产物：顶峰时期全球同时推进的临床试验超过60项，但其中80%集中在肺癌、肝癌等成熟赛道，真正探索创新适应症的研究不足10%。这种“扎堆内耗”不仅造成资源浪费，更阻碍了对靶点机制的深度理解。百济神州首席医学官Mark Lanasa在宣布终止试验时坦言：“我们必须学会区分科学上的可能性和临床上的可行性。”这句话直指行业痛点——当资本裹挟科学，当KPI绑架创新，原本需要十年磨一剑的基础研究被压缩成急功近利的“流水线作业”。以TIGIT为例，其作用机制至今仍存在争议：究竟是独立信号通路，还是PD-1的辅助调节器？在不同肿瘤微环境中是否具有功能异质性？这些问题尚未得到充分解答，上百项临床试验就已仓促上马。这种“蒙眼狂奔”的研发模式，注定要付出高昂学费。我们又能从中吸取什么？百济神州的TIGIT挫败，对中国创新药企具有特殊警示意义。作为最早布局该靶点的国内企业之一，百济曾凭借欧司珀利单抗的授权交易站上国际舞台，但最终仍难逃“跟风式创新”的陷阱。当前国内仍有康方生物、君实生物等十余家药企布局TIGIT，但90%以上的项目集中在肺癌、食管癌等红海领域，且临床设计高度同质化，这种“扎堆内卷”不仅消耗宝贵资源，更凸显出原始创新能力的匮乏。同时，百济在终止欧司珀利单抗后，迅速将资源转向BCL-2抑制剂、TROP2 ADC等差异化管线，这种“壮士断腕”的果断值得我们学习。结语TIGIT靶点的集体溃败，或许正是肿瘤免疫疗法走向理性的转折点。在这场耗资数百亿美元的全球实验中，双抗、细胞疗法、表观遗传调控等新武器的出现，正在重写游戏规则。而TIGIT的故事也远未终结，它可能不会成为下一个PD-1，但在某些特定场景下，或许仍是拼图中不可或缺的一块。参考资料：　　［1］百济神州公告［2］Novartis retreats from TIGIT, handing $300M candidate back to BeiGene.［3］Nurix Licenses a Drug Discovery Program to Sanofi Targeting a Novel Transcription Factor for Autoimmune Diseases. Retrieved April 3, 2025END2025金笔奖征文活动开启，来投稿吧！领取CPHI & PMEC China 2025展会门票智药研习社课程预告来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

免疫疗法临床3期引进/卖出临床结果

2025-04-09

·VIP说

肿瘤免疫治疗策略2.0

# 本篇笔记仅基于公开资料和信息撰写、为个人观点、供学术交流所用、不构成任何建议 #我用了差不多一个月的时间，看了几十家代表公司的产品线、几千篇研报和点评、几万个注册临床试验，想要看清楚肿瘤免疫治疗棋局的现状和未来。这不符合我的本性，我是宁可去无人区探险，也不想投入毫厘铢锱不能差错的极致内卷中。但是，现实就是，现在和未来很长一段时间内，免疫检查点抑制剂都会是肿瘤治疗的基石，即使MNC们早就已经布局于免疫检查点抑制剂之外甚至肿瘤治疗之外，国内大多数药企还有一段国产替代的长路要走。既然不能提前退休，只能强忍着非常严重的内卷PTSD看棋局，这种不适感压制了我的段子手级别语言天赋，所以这篇笔记会写的非常......直白。我个人给免疫治疗策略1.0的定义，就是大家手里都有个PD-(L)1抑制剂产品。全球已经有32个/国内已经有24个PD-(L)1抑制剂产品上市。图片引用来自“IO笔记”。至于免疫治疗策略2.0，就是如何进一步迭代和升级。PD-(L)1抑制剂产品本身的迭代和升级，目前大家的策略非常一致，改良单抗本身没能创造出什么奇迹，就开发双抗/多抗和复方，以及皮下注射、口服小分子、ADC等新剂型。双抗/多抗和复方本质类似于联合给药方案，所以放到后面再说。开发皮下注射剂型看上去是个捷径，不过如果大家的目标是国际市场，可能会有专利侵权风险：阿斯利康7.5亿美元引进Alteogen透明质酸酶技术，后者深陷侵权风险口服小分子PD-(L)1抑制剂，我是没有“小药说药”那么关注，而且似乎已经冷却：靶向PD-1/PD-L1小分子药物的研究进展至于PD-(L)1 ADC，反正已经热闹起来：靶向PD-L1 ADC：辉瑞首次国内申报临床！复宏汉霖、映恩生物“勇攀高峰”此外，国内外很多家药企已经想开了，不搞什么伪创新药，帕博利珠单抗核心专利将于2028年到期，直接开发生物类似药。国内外我已经数出来10个帕博利珠单抗类似药在做注册临床试验了，还有3个纳武利尤单抗生物类似药。更广谱的迭代和升级策略，就是以PD-(L)1抑制剂产品为基石，开发各种联合给药方案。汇总信息还是医药魔方做得最漂亮（反正我下载了PPT）：PD-1/PD-L1抑制剂中美获批及全球注册性临床试验15年动态趋势医药魔方PPT中部分内容截图：类似的汇总信息报告和点评很多，都能让大家一眼看清楚肿瘤免疫治疗棋局已经内卷到什么地步，看完不但没有思路，反而更加焦虑了。所以我们还是采用最简单高效的fast follow的老办法，看看几十家代表公司的肿瘤免疫治疗产品线，看看follow谁家的具体策略最适合自家。1. 默沙东/默克帕博利珠单抗(PD-1单抗)，长期被群殴和围攻的药王，王冠太重。在肿瘤领域，默沙东/默克不断探索和拓展其各种联合给药方案，并且积极布局复方和皮下等新剂型，双抗等新产品，以求夯实其在肿瘤领域的领先地位。复方主要是MK-1308A(PD-1+CTLA-4，Pembrolizumab+Quavonlimab)，MK-7684A(PD-1+TIGHT，Pembrolizumab+Vibostolimab)，MK-4280A(PD-1+LAG-3，Pembrolizumab+favezelimab)，2024年12月宣布终止开发后两个，目前只有MK-1308A还在推进。皮下剂型MK-3475A的III期临床试验刚官宣成功。近年来，默沙东/默克的肿瘤产品线重点已经布局于免疫检查点抑制剂之外，但免疫检查点抑制剂还是肿瘤治疗的基石，肿瘤领域且没有禁忌症，什么新产品都尝试联联看，就像吃什么菜都要配一碗白米饭。看帕博利珠单抗适应症布局是一项极其艰巨的工作，我差不多用了半个月时间，剩下几十个产品用了剩下的半个月时间。太多了。不仅因为默沙东/默克财大气粗，有把握的III期试验开几百个，没把握的I-II期试验和IIT开几千个，更因为帕博利珠单抗是基石中的基石，米饭中的白米饭，其他药企开发联合给药方案也是首选帕博利珠单抗。即使默沙东/默克没有布局，其他药企也会填空，所有瘤种所有适应症，完全没有空缺。最后得去翻默沙东/默克官网的PPT，才能找出他家真正的主线。如果布局图里出现了个别空缺，那也是某些III期临床试验失败导致的，绝不是没人尝试过填空。比如大家都吃过瓜的LEAP系列。但是有三个瘤种，即著名的冷肿瘤们，卵巢癌、胰腺癌、前列腺癌，所有药企都是屡战屡败+屡败屡战。先驱栽坑里那是代价，后来者再盲目跳坑，我可能忍不住嘲笑了，如果不是颠覆性作用机制的新药，建议不要再尝试将免疫治疗用于这几个瘤种。2. BMS纳武利尤单抗(PD-1单抗)，没能问鼎药王，所以在此基础上早早开发出皮下注射剂型，与伊匹木单抗(Ipilimumab, CTLA-4)联合方案，与Relatlimab(LAG-3单抗)联合方案，甚至开发了复方OPDUALAG(Nivolumab+Relatlimab)，均已成功获批多个适应症。也曾在TIGHT、IDO等靶点药物联合方案上栽过跟头，最新产品是复方BMS-986489(PD-1+fucosyl-GM1, Nivolumab+BMS-986012)。近年来，BMS的肿瘤产品线重点也已经布局于免疫检查点抑制剂之外。但免疫检查点抑制剂还是肿瘤治疗的基石，主动或被动开发联合方案也非常多。3. 罗氏阿替利珠单抗(PD-L1单抗)，其实已经算差异化开发了，靶点从PD-1换成了PD-L1。阿替利珠单抗是早早成功开发了皮下注射剂型。之后开发双抗时换回PD-1单抗，包括Tobemstomig(RO7247669, PD-1/LAG-3)，Lomvastomig(PD-1/TIM-3, RO7121661)。罗氏在肿瘤免疫治疗方面不算成功，主要是因为阿替利珠单抗与Tiragolumab(TIGHT单抗)的联合方案投入太大，受伤太深。但是深挖一下新技术平台，还能翻出来PD1-IL2v，PDL1 LNA等产品。值得注意的是，阿替利珠单抗用于三阴性乳腺癌非常波折，各种姿势的III期临床试验失败和撤回适应症，鉴于特瑞普利单抗在同一适应症里取得过成功，咱们不能说三阴性乳腺癌不适合免疫治疗，但PD-1单抗似乎比PD-L1单抗强一些。肾癌、尿路上皮癌、头颈癌、宫颈癌里也有类似情况，建议谨慎选择PD-L1单抗。4. 阿斯利康度伐利尤单抗(PD-L1单抗)，早期策略和BMS类似，开发皮下注射剂型，还有和替西木单抗(Tremelimumab, CTLA-4)的联合给药方案。后来者的好处就是可以避开先驱们栽过的坑，适应症开发都比较顺利。现在已经不做复方了，直接换双抗，Volrustomig(PD-1/CTLA-4)，Sabestomig(PD-1/TIM-3)，Rilvegostomig (PD-1/TIGHT)。发起IO+ADC潮流的应该就是他家，而且他家明显艺高人胆大，最偏爱Rilvegostomig (PD-1/TIGHT)，这是要死磕TIGHT靶点的节奏。5. 辉瑞、吉列德、再生元、GSK、Incyte、BIOCAD可以说，辉瑞几乎错了肿瘤免疫治疗浪潮。Avelumab(PD-L1单抗)开发顺位非常靠后，所以从超级冷门小适应症下手—皮肤默克尔细胞癌，弯道超车获批上市后，目前仅在膀胱癌领域取得成功（联合阿昔替尼用于肾癌一线是基于PFS成功附条件获批，但是OS失败，现在很尴尬；用于非小细胞肺癌、头颈癌和胃癌都是全面失败）。后来一度想悄悄开发PD-1单抗皮下注射剂型Sasanlimab（未获批上市），最终还是抢跑PF-08046054(PD-1 ADC)。后来者后来到辉瑞这个地步，如果还不愿赌服输，就得这么另辟蹊径。但是Sasanlimab有点过，首个适应症居然选择联合BCG用于非肌层浸润性膀胱癌，之前帕博利珠单抗和纳武利尤单抗都挑战失败的适应症，全球均未有免疫检查点抑制剂类产品获批。吉列德也是后来者，但是通过收购Arcus获得了赛帕利单抗(Zimberelimab，PD-1单抗)，果然顺产没有顺手快。在国内，赛帕利单抗用于经典型霍奇金淋巴瘤和晚期宫颈癌已获批上市。但是他家的联合给药方案，目前以Domvanalimab(TIGHT单抗)为主，又是一个死磕TIGHT靶点的。再生元不算后来者，Cemiplimab(PD-1单抗)虽然不算先驱，但是通过小适应症—皮肤鳞状细胞癌和皮肤基底细胞癌，早早弯道超车获批上市。他家毕竟是资深肿瘤免疫疗法biotech，联合给药方案非常多，目前以联合Fianlimab(LAG-3单抗)为主。GSK不算后来者也不算先驱，多塔利单抗(Dostarlimab，PD-1单抗) 通过小适应症—dMMR/MSI-H子宫内膜癌，早早弯道超车获批上市，之后仅专注于子宫内膜癌、结直肠癌和头颈癌，坚定的反内卷思维，深得我心。Incyte真不容易，当初为了卡瑞利珠单抗和恒瑞分分合合，最后终于拥有了自己的Retifanlimab(PD-1单抗)。跟辉瑞类似，因为Retifanlimab开发顺位非常靠后，所以从超级冷门小适应症下手—皮肤默克尔细胞癌，弯道超车获批上市。后来居然又被再鼎引入中国继续开发，反正各种不容易。再看Incyte产品线，始终专注于肿瘤免疫疗法，口服PD-L1，PD-1/LAG-3双抗、PD-1/TGF-βRII双抗均有布局。Prolgolimab(PD-1单抗)由俄罗斯药企BIOCAD开发，获得俄罗斯卫生部批准上市，用于治疗转移性黑色素瘤。在两国总理的共同见证下，由上药集团引进入国内共同开发，上药集团不愧是一流国企，非常正确。值得一提的是，Prolgolimab都这么正确了也没有躺平，继续开发复方BCD-217(Prolgolimab+Nurulimab，PD-1+CTLA-4)，还开发了帕博利珠单抗生物类似药。6. 其他外企艾博维：Budigalimab(PD-1单抗)Budigalimab绝对算后来者，我个人高度怀疑艾博维是为了联合其他自家真爱的新产品才被迫开发了基石。到现在最高开发阶段II期临床试验。强生：Cetrelimab(PD-1单抗)也不知道这个产品是不是和辉瑞的Sasanlimab高度类似，首个适应症居然也选择非肌层浸润性膀胱癌，但联合了自家TAR-200，我个人觉得就是为了陪衬TAR-200。2025年1月15日，强生宣布递交TAR-200的上市申请，用于治疗卡介苗（BCG）不应答的高危非肌肉侵袭性膀胱癌（HR-NMIBC）伴原位癌（CIS）患者。此次递交通过实时肿瘤审评（RTOR）项目，允许FDA在完全申请正式递交之前就开始审评以加快进度。 TAR-200为一种膀胱内局部给药的新型递送系统，采用一种双重小片设计，材质为硅聚合物半透小管，吉西他滨在膀胱持续缓慢释放。BI：Ezabenlimab(PD-1单抗)反正我个人高度怀疑BI是为了联合其他自家真爱的新产品才被迫开发了基石。到现在最高开发阶段II期临床试验。安进：Zeluvalimab(PD-1单抗)在安进最新的产品线信息里已经找不到Zeluvalimab了，但是找到了纳武利尤单抗生物类似药，预期2025年获批上市。放弃死磕开发顺位过于滞后的伪创新药，拥抱生物类似药，拥抱效率和利润，毕竟肿瘤免疫治疗也不是安进公司的主线，顶多用来联合其他自家真爱的新产品。Agenus：Botensilimab(PD-1单抗)Agenus还算比较重视Botensilimab，但主要是为了配合新一代产品—Balstilimab(CTLA-4单抗)，声称可以将冷肿瘤转化为热肿瘤。首个适应症选择联合Balstilimab用于non-MSI-H结直肠癌。坚定的反内卷思维，深得我心。BioNTech：BNT327(PD-L1/VEGF双抗)等收购普米斯生物等biotechs，跳过肿瘤免疫治疗1.0时代，直接飞跃至2.0时代潮头，拥有各种最热门双抗和ADC，又是顺产哪有顺手快的成功案例和典型代表。不过最新的消息是BNT311(PD-L1/4-1BB双抗)退回Genmab，这不是一个好消息，真正成功的双抗也不多。BioNTech的策略虽然有抄袭AZ，但非常清晰明确，值得学习。先分析免疫检查点抑制剂单药或既往的联合给药方案，在全球范围内获批过哪些适应症，还有哪些细分人群中有未被满足的临床需求，既往放弃开发或开发失败适应症的困难在哪里。再分析或补充自家产品线里的产品，是否有新颖的作用机制可能攻克之前的困难。最后设计BNT327的临床开发计划：第一步，联合化疗去攻克确定性高、能快速实现高市场价值的适应症；第二步，联合各种新颖作用机制的新产品，填补之前未被满足的临床需求；第三步，探索更多、更新的联合给药方案和适应症。篇幅原因，写完外企部分已经快5000字了，改天再写国内企业部分。信息量过大，CPU干烧到头晕，所有重点点到即止，如有疏漏错误，请大家多包涵。# 本篇笔记仅基于公开资料和信息撰写、为个人观点、供学术交流所用、不构成任何建议 #

抗体药物偶联物免疫疗法生物类似药

100 项与替瑞利尤单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11482	-	-	DB16409

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
胃食管交界处癌	临床3期	中国	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	日本	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	比利时	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	加拿大	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	哥斯达黎加	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	法国	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	墨西哥	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	俄罗斯	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	韩国	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	中国台湾	F. Hoffmann-La Roche Ltd.	2025-04-18

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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


NCT04300647 (SKYSCRAPER-04, CTgov)	临床2期	PD-L1阳性宫颈癌	172	atezolizumab (Atezolizumab)	膚鑰鏇積糧積製顧鬱憲 = 獵選廠鹹鏇構遞觸網選網艱餘網鬱鏇願鬱獵齋 (蓋鏇繭壓衊願構鹽衊鬱, 衊醖鏇窪淵築憲顧顧遞 ~ 顧醖鑰糧鏇夢夢顧壓鏇) 更多	-	2025-02-07
				atezolizumab+Tiragolumab (Tiragolumab Plus Atezolizumab)	膚鑰鏇積糧積製顧鬱憲 = 範壓鹽鏇獵廠選構鏇膚網艱餘網鬱鏇願鬱獵齋 (蓋鏇繭壓衊願構鹽衊鬱, 齋簾獵願簾糧衊鏇選鑰 ~ 淵觸網餘壓鹹範獵鏇壓) 更多
NCT04524871 (MORPHEUS-Liver, Pubmed \| Lancet Oncol) 人工标引	临床1/2期	肝细胞癌	58	TiragolumabTiragolumab 600 mg + Atezolizumab 1200 mg + Bevacizumab 15 mg/kgBevacizumab 15 mg/kg	鬱艱憲襯廠憲壓遞廠醖(壓獵繭遞夢糧衊餘壓願) = The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1-2. 顧獵繭憲觸餘製蓋遞遞 (廠鏇憲襯鹽願構糧窪憲 ) 更多	积极	2025-01-21
				Atezolizumab 1200 mg + BevacizumabBevacizumab 15 mg/kg
NCT04619797 (SKYSCRAPER-06, ESMO_IO2024) 人工标引	临床2/3期	晚期肺非鳞状非小细胞癌维持	542	Tiragolumab 600 mg IV + Atezolizumab 1200 mg IV + Carboplatin/Cisplatin + Pemetrexed IV	膚壓夢網廠築鏇願壓艱(鑰壓遞淵鏇淵鑰遞鏇積) = 鹽鑰構遞齋簾憲醖築觸糧遞觸構築鹽壓蓋鬱選 (壓網鏇醖餘鏇鏇鑰襯膚, 15.2 ~ 23.8) 更多	不佳	2024-12-12
				Placebo + Pembrolizumab 200 mg IV + Carboplatin/Cisplatin + Pemetrexed IV	膚壓夢網廠築鏇願壓艱(鑰壓遞淵鏇淵鑰遞鏇積) = 範膚顧鏇淵製顧範齋淵糧遞觸構築鹽壓蓋鬱選 (壓網鏇醖餘鏇鏇鑰襯膚, 20.7 ~ 33.0) 更多
NCT04294810 (SKYSCRAPER-01, GlobeNewswire) 人工标引	临床3期	PD-L1阳性非小细胞肺癌 PD-L1 High Expression	534	tiragolumab + Tecentriq	糧範顧糧鏇製構範鏇醖(製憲選襯範繭鬱衊繭壓) = did not reach the primary endpoint. 繭鬱顧窪鹹願齋糧願糧 (築鏇鬱壓積遞築艱製鬱 ) 未达到更多	不佳	2024-11-26
				Placebo + Tecentriq
NCT05315713 (CTgov)	临床1/2期	滤泡性淋巴瘤 \| 难治性B细胞淋巴瘤	8	Mosunetuzumab SC+tocilizumab+Tiragolumab	繭鏇鏇襯蓋鹹築觸築構 = 選選襯積憲鬱鹽膚齋壓選糧鹹簾製膚蓋製構鹽 (觸鏇憲夢齋構獵鑰齋窪, 襯餘網膚鬱構簾選壓顧 ~ 憲選蓋範壓艱顧膚積鬱) 更多	-	2024-10-04
NCT04619797 (SKYSCRAPER-06, Company_Website) 人工标引	临床2/3期	转移性非鳞状非小细胞肺癌一线	542	tiragolumab+Tecentriq+chemotherapy	鹹鹽鏇鏇齋顧齋鏇鬱淵(糧壓糧蓋夢網齋膚觸積): HR = 1.27 (95% CI, 1.02 ~ 1.57) 未达到更多	不佳	2024-07-03
				Placebo+pembrolizumab+chemotherapy
NCT04300647 (SKYSCRAPER-04, AACR2024)	临床2期	宫颈癌 PD-L1+ \| TIGIT \| TAP ... 更多	171	Tiragolumab plus atezolizumab dual blockade (T+A)	鹽夢餘顧遞築選鹹膚鬱(願餘膚廠鹹鹽範願壓鑰) = 構選蓋壓鹹鑰膚壓鬱觸鹹製膚簾夢鏇顧鏇蓋簾 (襯衊繭築廠願窪壓簾糧 )	积极	2024-03-22
NCT04256421 (SKYSCRAPER-02, Pubmed) 人工标引	临床3期	广泛期小细胞肺癌一线 \| 维持	490	Tiragolumabatezolizumabcarboplatinetoposide	繭鏇簾夢選蓋膚糧醖網(艱淵鬱艱鑰糧糧網鹹襯) = 壓選鑰獵夢膚繭膚蓋範鏇壓鏇膚艱觸壓糧簾衊 (醖鑰構夢範鹽構積觸選 ) 更多	不佳	2024-01-20
				AtezolizAtezolizumabrbocarboplatinetoetoposideE)	繭鏇簾夢選蓋膚糧醖網(艱淵鬱艱鑰糧糧網鹹襯) = 淵襯憲網醖網齋鏇鏇範鏇壓鏇膚艱觸壓糧簾衊 (醖鑰構夢範鹽構積觸選 ) 更多
NCT03281369 (MORPHEUS-EC, ASCO_GI2024) 人工标引	临床1/2期	食管癌一线	152	Cisplatin + 5-FU	齋壓選製觸積鹹窪鑰淵(鏇壓構廠淵齋獵願蓋蓋) = 齋獵廠齋廠膚範蓋鹽襯壓鑰構選繭鹽膚構糧簾 (顧窪餘憲襯顧齋範憲餘, 26.8 ~ 69.4) 更多	积极	2024-01-18
				Atezolizumab + Cisplatin + 5-FU	齋壓選製觸積鹹窪鑰淵(鏇壓構廠淵齋獵願蓋蓋) = 範鏇網積醖鬱糧膚構廠壓鑰構選繭鹽膚構糧簾 (顧窪餘憲襯顧齋範憲餘, 41.0 ~ 66.3) 更多
NCT04540211 (SKYSCRAPER-08, ASCO_GI2024) 人工标引	临床3期	食管鳞状细胞癌一线 PD-L1	461	Tiragolumab 600mg + Atezolizumab 1200mg + Chemotherapy	遞選鬱壓鬱膚製觸夢餘(觸窪醖鹹顧衊願膚構顧) = 範蓋構網淵顧鹹壓觸蓋窪夢蓋醖顧齋顧窪鹹膚 (醖顧夢窪餘窪繭艱襯鏇 ) 更多	积极	2024-01-18
				Placebo + Chemotherapy	遞選鬱壓鬱膚製觸夢餘(觸窪醖鹹顧衊願膚構顧) = 襯顧襯鏇鑰範願簾夢鏇窪夢蓋醖顧齋顧窪鹹膚 (醖顧夢窪餘窪繭艱襯鏇 ) 更多