伊匹木单抗(Ipilimumab) - 药物靶点：CTLA4_在研适应症：错配修复缺陷或微高卫星不稳定性结肠癌，不能切除的食管鳞状细胞癌，食管癌_专利_临床

概要

基本信息

药物类型

单克隆抗体

别名

Anti CTLA-4 monoclonal antibody、Anti-CTLA-4 Mab、Ipilimumab (Genetical Recombination)

+ [16]

靶点

CTLA4

作用机制

CTLA4抑制剂(细胞毒性T淋巴细胞相关抗原4抑制剂)

治疗领域

肿瘤消化系统疾病呼吸系统疾病+ [13]

在研适应症

错配修复缺陷或微高卫星不稳定性结肠癌不能切除的食管鳞状细胞癌食管癌+ [306]

非在研适应症

复发性急性淋巴细胞白血病伴有 11q23 异常的急性髓系白血病急性早幼粒细胞白血病+ [90]

原研机构

Bristol Myers Squibb Co.

在研机构

Bristol Myers Squibb Co.

The University of Texas MD Anderson Cancer Center

National Cancer Institute

+ [9]

非在研机构

Checkmate Pharmaceuticals, Inc.National Institutes of Health Clinical Center

The University of Texas Southwestern Medical Center

+ [4]

最高研发阶段批准上市

首次获批日期

美国 (2011-03-25),

黑色素瘤

最高研发阶段(中国)批准上市

特殊审评突破性疗法 (美国)、快速通道 (美国)、加速批准 (美国)、孤儿药 (美国)、优先审评 (中国)、突破性疗法 (中国)、孤儿药 (韩国)、优先审评 (澳大利亚)、附条件批准 (中国)

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结构/序列

Sequence Code 143797L

来源: *****

Sequence Code 9060585H

来源: *****

关联

862

项与伊匹木单抗相关的临床试验

NCT06683755

/ Not yet recruiting临床1/2期IIT

Phase I/IIa Dose Finding Study of Triplet Regimen of Relatlimab Ipilimumab and NIvolumab in First Line Therapy of Metastatic Melanoma (TRINITY)

To determine the recommended Phase IIa dose (RP2D) of the triplet combination.
To determine the safety and efficacy of the combination at the RP2D.

开始日期2025-05-01

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT06708949

/ Not yet recruiting临床2期IIT

A Randomized Phase 2 Trial of Nivolumab, Relatlimab Plus Ipilimumab vs. Nivolumab Plus Ipilimumab in First-line Advanced Renal Cell Carcinoma (RCC)

This is a phase 2 stratified, randomized, multicenter, study investigating the efficacy of a triplet arm treating with nivolumab 480 mg every 4 weeks (Q4W), relatlimab 160 mg Q4W and ipilimumab 1 mg/kg every 8 weeks (Q8W) intravenous (IV) versus a doublet arm treating with nivolumab 480 mg Q3W and ipilimumab 1mg/kg Q3W IV in first-line advanced RCC.

开始日期2025-05-01

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

NCT06364917

/ Not yet recruiting临床2期IIT

DISCERN: Dual Immune Strategy Versus Single Checkpoint Inhibition Efficacy Response in PDL-1 Negative Non-Small Cell Lung Cancer (NSCLC)

The purpose of this study, known as DISCERN, is to compare two different treatments for a type of lung cancer called non-small cell lung cancer (NSCLC) that does not show a marker known as PD-L1. This study will help us understand if using two types of immune therapy together with chemotherapy is better than using one type of immune therapy with chemotherapy. We're doing this by looking at changes in the subject's cancer's DNA in the blood after starting treatment.

开始日期2025-03-31

申办/合作机构

The University of Alabama at Birmingham

100 项与伊匹木单抗相关的临床结果

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100 项与伊匹木单抗相关的转化医学

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100 项与伊匹木单抗相关的专利（医药）

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5,479

项与伊匹木单抗相关的文献（医药）

2025-12-31·OncoImmunology

Circulating cytokine associations with clinical outcomes in melanoma patients treated with combination nivolumab plus ipilimumab

Article

作者: Baginska, Joanna ; Rodig, Scott J. ; Severgnini, Mariano ; Hodi, F. Stephen ; Chen, Jiajia ; Brennick, Ryan ; Manuszak, Claire ; Weirather, Jason L. ; Manos, Michael ; Ranasinghe, Srinika ; Liu, David ; Huang, Amy Y. ; Holovatska, Marta ; Hathaway, Emma ; Nazzaro, Matthew ; Giobbie-Hurder, Anita ; Tarantino, Giuseppe ; Russell, Janice D. ; Pfaff, Kathleen L.

Nivolumab plus ipilimumab (aCTLA-4/aPD-1) combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. We hypothesized that circulating cytokines and peripheral white blood cells may predict response to therapy and evaluated 15 cytokines and complete blood counts (CBC with differentials) from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. Clinical endpoints evaluated included durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). A parsimonious predictive model was developed to identify cytokines predictors of response to combination therapy. In this study, we found that pre-treatment, patients with DCB had higher IL-23, lower CXCL6, and lower IL-10 levels. Lower NLR one month after starting therapy predicted better PFS and OS, primarily driven by an increase in absolute lymphocytes. A multivariate model demonstrated that baseline CXCL6, IL-10, IL-23 were independent predictors of therapy response, and the combined model has reached an area under the curve (AUC) of 0.79 in prediction of response to combination therapy. Our study identified baseline CXCL6, IL-23, and IL-10 as predictors of response to aCTLA4/aPD1 combination therapy among patients with metastatic melanoma. This study also provides a framework for identifying patients who are likely to respond to combination ICB, as well as a subset of patients with high risk of developing resistance and are thus in need of alternative therapeutic options, such as clinical trials.

2025-12-31·mAbs

Engineered ipilimumab variants that bind human and mouse CTLA-4

Article

作者: Barman, Ishita ; Lee, Peter S. ; Diong, SJ ; Bee, Christine ; Rajpal, Arvind ; Kumar, Anusha ; West, Sean ; Chau, Bryant ; Robison, Brett ; Strop, Pavel ; Chang, Olin ; Moon, Thomas M. ; Korman, Alan J.

Testing of candidate monoclonal antibody therapeutics in preclinical models is an essential step in drug development. Identification of antibody therapeutic candidates that bind their human targets and cross-react to mouse orthologs is often challenging, especially for targets with low sequence homology. In such cases, surrogate antibodies that bind mouse orthologs must be used. The antibody 9D9, which binds mouse CTLA-4, is a commonly used surrogate for CTLA-4 checkpoint blockade studies in mouse cancer models. In this work, we reveal that 9D9 has significant biophysical dissimilarities to therapeutic CTLA-4 antibodies. The 9D9-mCTLA4 complex crystal structure was determined and shows that the surrogate antibody binds an epitope distinct from ipilimumab and tremelimumab. In addition, while ipilimumab has pH-independent binding to hCTLA-4, 9D9 loses binding to mCTLA-4 at physiologically relevant acidic pH ranges. We used phage and yeast display to engineer ipilimumab to bind mouse CTLA-4 with single-digit nM affinity from an initial state with no apparent binding. The engineered variants showed pH-independent and cross-reactive binding to both mouse and human CTLA-4. Crystal structures of a variant in complex with both mouse and human CTLA-4 confirmed that it targets an equivalent epitope as ipilimumab. These cross-reactive ipilimumab variants may facilitate improved translatability and future mechanism-of-action studies for anti-CTLA-4 targeting in murine models.

2025-12-31·OncoImmunology

Plasma protein dynamics during ipilimumab treatment in metastatic melanoma: associations with tumor response, adverse events and survival

Article

作者: Kyte, Jon Amund ; Lereim, Ragnhild Reehorst ; Chauhan, Sudhir Kumar ; Dunn, Claire ; Straume, Oddbjørn ; Aamdal, Elin ; Guren, Tormod Kyrre

The immune checkpoint inhibitor ipilimumab provides long term survival in some metastatic melanoma patients, but the majority has no benefit, and may experience serious side effects. Here, we investigated the dynamics of plasma cytokine concentrations and their potential utility for predicting treatment response, adverse events and overall survival (OS) in patients with metastatic melanoma undergoing ipilimumab monotherapy. A cohort of 148 patients was examined, with plasma samples collected prior to treatment initiation and at the end of the first and second treatment cycles. Concentrations of 48 plasma proteins were measured using a multiplex immunoassay. The results revealed a general increase in cytokine levels following the first ipilimumab dose, consistent with immune activation. Patients not responding to treatment exhibited significantly elevated baseline levels of G-CSF, IL-2RA, MIP-1a, and SCF, compared to tumor responders (p < 0.05). Furthermore, high levels of IL-2RA, IFNγ, PDGF-bb and MIG were linked to inferior OS, while high concentrations of MIF and RANTES were associated with improved OS (p < 0.05). A multivariate model containing CRP, LDH, ECOG, IL-2RA and PDGF-bb identified a subgroup of patients with poor OS. Patients who experienced severe immune-related adverse events within three months of treatment initiation had higher baseline concentrations of several cytokines, indicating a potential association between preexisting inflammation and adverse events. These findings indicate that the first dose of ipilimumab induces a systemic response with increased levels of circulating cytokines and suggest candidate biomarkers for clinical response, immune-mediated toxicity and survival. Further studies in independent patient cohorts are required to confirm the findings.

1,588

项与伊匹木单抗相关的新闻（医药）

2025-01-28

·PMLiVE

BMS presents promising data for immunotherapy combination in phase 3 colorectal cancer trial

Bristol Myers Squibb (BMS) has shared promising results from a late-stage study of its dual immunotherapy combination in metastatic colorectal cancer (CRC). The ongoing phase 3 CheckMate-8HW trial has been evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) against Opdivo alone across all lines of therapy, including the front-line, in patients with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) metastatic CRC. Results presented at this year’s American Society of Clinical Oncology Gastrointestinal Cancers Symposium showed that Opdivo plus Yervoy was associated with a statistically significant and clinically meaningful 38% reduction in the risk of disease progression or death compared to Opdivo monotherapy at a median follow up of 47 months. Overall response rate was also significantly higher with Opdivo plus Yervoy compared to Opdivo alone, at 71% versus 58%, and the safety of the combination was consistent with previously reported data. More than 154,000 cases of CRC, which develops in the colon or the rectum, are expected to be diagnosed in the US in 2025. Up to 7% of patients with metastatic disease have dMMR or MSI-H tumours and, as a result, are less likely to benefit from conventional chemotherapy and typically face a poor prognosis. Opdivo plus Yervoy-based combinations already hold approvals for a range of indications, including for patients with MSI-H/dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan. Previous results reported from CheckMate-8HW showed that Opdivo plus Yervoy reduced the risk of disease progression or death by 79% compared to investigator’s choice of chemotherapy. Commenting on the latest results for the combination, Dana Walker, vice president, global programme lead, late development, oncology, BMS, said: “The benefit of dual inhibition of PD-1 and CTLA-4 has been well established in phase 3 trials of Opdivo plus Yervoy across a broad range of tumour types, including in MSI-H/dMMR metastatic CRC compared to chemotherapy. “The results from this analysis of the CheckMate-8HW trial answer affirmatively an important question about whether dual immunotherapy with Opdivo plus Yervoy can also improve outcomes for patients with MSI-H/dMMR metastatic CRC compared with Opdivo alone.”

临床结果ASCO会议临床3期免疫疗法

2025-01-27

·药渡

带你深入了解PD-1

前言程序性死亡受体-1（PD-1）的基因于1992年由日本科学家Honjo在小鼠中分离、鉴定，在经历细胞死亡的T细胞杂交瘤中发现，因此得名。PD-1与CTLA-4、CD28和KIRs的结构具有相似性，人们因此猜测PD-1的配体可能是B7或MHC I家族成员。在2000年和2001年，Honjo和Freeman先后发现了PD-1与PD-L1（CD274；B7-H1）和PD-L2（CD273；B7-DC）相互作用的证据，共同阐述了PD-1/PD-L1对人体T细胞的调控作用，从而确定了PD-1途径。 2002年，耶鲁大学的华人教授陈列平发表的文章中指出大多数的肿瘤细胞通过表达PD-L1实现免疫逃逸，这为后面PD-1/PD-L1抗肿瘤药物的研发提供了重要的理论依据。2014年7月全球首个PD-1药物Opdivo在日本上市，同年12月，第二个PD-1药物Keytruda在美国上市，2016年首个PD-L1抑制剂上市。随后默克公司与辉瑞的Bavencio，阿斯利康PD-L1单抗Imfinzi在2017年上市，2018年Libtayo上市，全球目前已有多个PD-1/PD-L1抑制剂药物上市，而处于临床前或临床阶段的PD-1/PD-L1抑制剂玩家多达上百个。此外，PD-1抑制剂也已成为多种联合治疗的基石。因此，进一步了解PD-1抑制剂作为单一药物如何发挥作用以及在这些不同类型的联合治疗中的作用变得越来越重要。 PD-1的信号通路 PD-1受体是I型跨膜糖蛋白，属于CD28受体超家族成员。但与CD28不同，它在细胞表面是单体。在结构上，PD-1由细胞外免疫球蛋白可变结构域、跨膜结构域和负责信号和骨架分子结合的细胞质尾部组成。PD-1的细胞质尾部包含两个酪氨酸基序，一个ITIM（VDY223GEL）和一个ITSM（TEY248ATI）。两个结构域在PD-1配体结合时通过Lck的酪氨酸激酶活性磷酸化。 PD-1在活化的T细胞和B细胞、自然杀伤（NK）细胞、单核细胞、树突状细胞和癌细胞如黑色素瘤上表达。PD-1通过与PD-L1结合而被激活，并且与PD-L2具有更高的亲和力。两者的表达都是干扰素/细胞因子诱导的，但具有特定的表达模式：PD-L1在造血细胞和非造血细胞中广泛表达，而PD-L2主要在APC上表达。在免疫细胞中，PD-1信号依赖于酪氨酸磷酸酶SHP-2。PD-1/SHP-2信号轴的破坏是肿瘤环境中对PD-1抗体产生临床反应的部分原因。配体结合后，SHP-2被招募到PD-1的磷酸化ITSM， ITSM的磷酸化诱导SHP-2向活性构象的转换。对重建的免疫突触的显微镜观察表明，在PD-L1的存在下，PD-1和CD28在TCR富集区中央发生关联。其中PD-1招募SHP-2，促进CD3ζ和CD28磷酸化的降低，并对TCR信号强度产生负面影响。PD-1促进的CD28去磷酸化深刻影响TCR信号体的PI3K募集，降低PI3K/AKT途径活性及其转录靶点，如Bcl-xL。此外，SHP-2被认为不仅负责阻断CD28共刺激信号，而且还负责抑制TCR介导的ZAP70磷酸化及其与CD3ζ的关联，这些信号会导致PKCθ和ERK激活以及下游IL-2的产生和扩增。 PD-1及其配体的作用方式 PD-1配体PD-L1和PD-L2的表达模式不同。PD-L1广泛表达于造血细胞和非造血细胞。而PD-L2的表达比PD-L1更为有限，主要局限于造血细胞。PD-L1也在多种肿瘤类型的肿瘤细胞表达；尽管比PD-L1更为有限，PD-L2也在肿瘤细胞（如食管腺癌）上被观察到。虽然PD-L1和PD-L2都与PD-1结合，但它们都有第二个不同的相互作用蛋白。PD-L1还可以结合B7-1（CD80），而PD-L2也可以结合排斥导向分子b（RGMb）。B7-1主要由造血细胞和抗原呈递细胞表达，而RGMb则表达于巨噬细胞、肺泡上皮细胞、神经组织和各种器官。 PD-1与PD-L1的顺式作用典型的PD-1途径相互作用发生在活化T细胞上表达的PD-1与肿瘤、抗原呈递细胞（APC）或非造血细胞上的PD-L1之间的反式相互作用，并导致T细胞活化的抑制。如果PD-1和PD-L1都表达在同一细胞表面，那么PD-1和PD-L1之间也可以发生顺式作用，并且这种相互作用与反式相互作用具有相似的亲和力。在非小细胞肺癌等肿瘤中，PD-1可与PD-L1在肿瘤浸润巨噬细胞、MDSCs、树突状细胞以及一些肿瘤细胞亚群上共同表达。顺式相互作用与反式相互作用竞争，导致抑制PD-1信号的PD-L1更少。考虑到PD-L1在一些肿瘤浸润淋巴细胞（TIL）上的表达，PD-L1和PD-1在T细胞表面也可能发生顺式相互作用。反式与顺式PD-1/PD-L1相互作用的相对重要性可能取决于它们在相同或不同细胞表面的相对丰度，需要进一步仔细评估。 PD-L1与B7-1的相互作用 PD-L1可与B7-1结合，亲和力为1.4μM，约为B7-1对CD28（4μM）亲和力的3倍，但弱于PD-L1与PD-1（0.77μM）或B7-1与CTLA-4（0.2μM）的亲和力。 PD-L1与B7-1的相互作用只发生在同一细胞表面的顺式结构中。竞争结合研究和突变分析表明，PD-1和B7-1竞争PD-L1上的重叠结合区域。因此，B7-1与PD-L1的结合阻止了PD-L1与PD-1的相互作用，从而减少了PD-1抑制信号。令人惊讶的是，B7-1与PD-L1的结合不会干扰B7-1与CD28的结合；因此，它们可以形成三聚体复合物，与CD28共刺激信号结合。PD-L1与B7-1结合对CTLA-4与B7-1结合的影响更为微妙。CTLA-4同型二聚体可以以高亲和力与B7-1同型二聚体结合，导致B7-1被Treg反式内吞。PD-L1与B7-1的结合将CTLA-4相互作用降低为单价，从而显著降低亲和力。这可以防止B7-1的去除，并减少任何T细胞固有的CTLA-4信号。大多数PD-L1单抗都同时阻断PD-L1/PD-1和PD-L1/B7-1相互作用。在肿瘤免疫治疗中，这种类型的PD-L1单抗通过增强CTLA-4介导的同型二聚体B7-1的去除，导致APC上B7-1表达水平降低。这为PD-L1和CTLA-4联合阻断的临床试验提供了良好的理论基础。 PD-L2与RGMb的相互作用 PD-L2与T细胞上的PD-1结合抑制T细胞活化，PD-L2/PD-1的亲和力是PD-L1/PD-1的三倍。它们与PD-1的结合区域类似，因此，PD-L2和PD-L1竞争与PD-1的结合。虽然PD-L2的亲和力高于PD-L1，但其较低的表达水平为PD-L1/PD-1提供了竞争优势。 PD-L2的第二个结合蛋白是RGMb，它具有类似于PD-L2/PD-1的亲和力。RGMb是一种糖基磷脂酰肌醇（GPI）锚定蛋白，PD-L2可能与RGMb超复合物反式结合，以调节下游通路。PD-L2在该超复合物中的功能作用及其影响尚需进一步研究。 PD-1的功能 PD-1对TCR激活阈值的调节决定了T细胞对信号强度的反应范围，从而决定了它们的分化命运，包括耗竭和记忆形成。PD-1还在免疫抑制调节性T（Treg）细胞和先天免疫细胞的激活中发挥作用。受PD-1信号影响的这些不同因素决定了癌症免疫治疗反应的持续时间。 PD-1决定T细胞激活阈值 CTL成功激活后，被激活的T细胞的命运就会多样化。一些细胞保持其作为效应T细胞的活性，而另一些细胞由于过度刺激而变得无能、进入耗竭状态或发生凋亡。CTL的PD-1表达提高了激活信号的阈值，并抑制了连续的过度刺激。为了增加癌症免疫治疗的持续时间，通过PD-1阻断降低激活阈值来增加T细胞储备是至关重要的，这可以增加T细胞识别和攻击肿瘤细胞的机会。包括记忆前体在内的活化T细胞的增加也导致长寿命T细胞的增多，这是持久反应的重要因素。 PD1和记忆T细胞生成适应性免疫反应的标志之一是抗原清除后形成免疫记忆。免疫记忆反应使宿主在再次遇到相同抗原时能够更快地作出反应。PD-1信号可通过多种不同机制影响记忆反应。首先，TCR信号的强度与长寿命中央记忆T细胞的形成呈负相关。因此，效应器期PD-1信号的丢失将导致更强的TCR信号，从而导致记忆T细胞反应受损。从机制上讲，最近的研究表明，表达高水平CD62L的记忆前体细胞群和对DNA损伤的反应能力的增强对于长寿记忆群体的形成非常重要，而包括PD-1和淋巴细胞激活基因-3（LAG-3）在内的抑制性受体对于维持这一群体非常重要。其次，PD-1通路在调节原始T细胞向记忆T细胞的分化以及调节现有记忆T细胞群的反应方面具有独特的作用。例如，在CD8+T细胞对流感感染反应的不同阶段使用PD-1抗体的研究表明，在感染后期（从第21天开始）阻断PD-1通路会导致记忆性T细胞数量增加，并产生炎性细胞因子IFN-γ和TNF-α。此外，在鼻内痘苗病毒应答再激发期间阻断PD-1可以克服由于缺乏CD4+T细胞导致的记忆缺陷。最后，PD-1通路影响记忆T细胞的维持和功能能力可能还取决于环境，其机制目前尚不清楚。因此，进一步阐明PD-1通路参与宿主免疫的宿主因素，对于继续改善基于PD-1的患者免疫治疗至关重要。 PD-1抑制Treg细胞功能现在已经认识到PD-1可以调节传统αβT细胞以外的多种细胞类型。Treg细胞是一个特别令人感兴趣的群体，因为这些细胞在免疫调节中起着关键作用。至少有一部分Treg细胞表达PD-1受体水平升高，从而通过调节PD-1通路来调节这一群体。体外研究发现，表达更高水平PD-1的人类Treg细胞倾向于降低抑制能力并增加IFN-γ的产生。在小鼠模型中，来自PD-1缺陷或抗PD-1治疗小鼠的Treg细胞具有更好的抑制能力。在肿瘤中，PD-1阻断导致PD-1+CD8+T细胞功能增强以及PD-1+Treg细胞介导的免疫抑制增强。治疗开始时，PD-1+CD8 T细胞与PD-1+Treg的比率可能会指导最终免疫反应的结果。因此，在检查这些疗法对患者总体预后的影响时，必须考虑PD-1抑制剂对这些对立细胞群（效应细胞与调节细胞）功能的集体影响。 PD-1抑制剂在临床的新用途 2014年，FDA首次批准将阻断PD-1的抗体用于治疗晚期或转移性黑色素瘤。自那时以来，阻断PD-1或PD-L1的抗体已被批准用于20多种晚期癌症。常见实体瘤的总体缓解率（ORR）一般为20-30%。PD-1或PD-L1药物在胶质母细胞瘤、微卫星稳定型结肠癌、胰腺癌或前列腺癌中的疗效有限。鉴于这一成功，人们期望扩大PD-1抑制剂在早期癌症中的应用，包括新辅助和辅助治疗。最初，在一项针对21例可切除早期NSCLC患者的小规模II期试验中，首次评估了新辅助PD-1阻断剂对早期NSCLC的治疗作用。在20名患者中，有9名（45%）患者出现了主要的病理反应，即手术样本中存活的肿瘤细胞少于10%。在9名接受评估的患者中，有8名患者在PD-1抑制后发现肿瘤和血液中T细胞克隆的多样性增加。这些结果促使了许多更大规模的新辅助PD-1抑制剂的研究，包括CheckMate 816、KEYNOTE-671和Impassion030。最近，OpACIN-neo的临床研究结果表明，接受新辅助PD-1或PD-1/CTLA-4联合阻断的局部晚期黑色素瘤患者的病理反应率较高。汇总分析发现，在52%实现pCR或近pCR的患者中，2年无复发生存率为96%，总生存率为100%。这意味着比在辅助治疗中接受PD-1或PD-1/CTLA-4联合阻断的患者60%的2年无复发生存率显著改善。当考虑到III期黑色素瘤的大多数复发发生在手术后的头两年内时，可以进一步认识到这一益处的重要性。此外，OpACIN-neo对三种给药方案进行了测试，发现较低剂量的ipilimumab治疗方案与低irAE发生率相关，同时保持77%的高病理应答率。在一项纳入II期和III期乳腺癌患者的新辅助治疗临床试验中，接受PD-1抑制剂和化疗的三阴性乳腺癌癌患者手术时的pCR率为60%，而仅接受化疗的患者为22%。激素受体阳性癌症患者的pCR发生率为30%，而仅接受化疗的患者为13%。其他试验也有类似的结果，目前正在进行评估早期乳腺癌围手术期治疗中PD-1抑制的其他III期试验。胶质母细胞瘤（GBM）是一种致命的恶性肿瘤，缺乏有效的治疗方法。到目前为止，PD-1抑制剂在复发性胶质母细胞瘤中的试验未能显示生存益处超过标准护理。然而，最近的研究结果表明，在新辅助治疗环境中，PD-1抑制可能有益。在最近的一项II期研究中，接受新辅助PD-1抑制剂的患者中位总生存期显著延长（13.7个月vs 7.5个月，p=0.04），无进展生存期延长（3.3个月vs 2.4个月，p=0.03）。此外，在包括乳腺癌和晚期错配修复缺陷型（MMRd）结直肠癌中，PD-1抑制剂新辅助治疗都显示出明显的临床获益。小结自从30年前PD-1通路首次发现以来，我们在揭示PD-1通路的复杂性方面取得了长足的进步。最近的研究在PD-1及其配体的作用方式，以及PD-1在调节不同分化状态的T细胞方面取得了一些新的见解，有助于深入了解这一重要免疫调节途径的多方面功能。对这些发现的进一步研究将继续影响我们对PD-1途径的理解，以及如何有效和安全地将PD-1调节应用于不同的患者群体。参考文献： 1. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1. Nat Rev Immunol.2023 Apr 25. 2. Emerging concepts in PD-1 checkpoint biology. Semin Immunol. 2021 Feb; 52: 101480. 3.Immune Checkpoint Receptors Signaling in T Cells. Int J Mol Sci.2022 Apr; 23(7): 3529. 药渡媒体商务合作媒体公关 | 新闻&会议发稿张经理：18600036371（微信同号）点击下方“药渡“，关注更多精彩内容免责声明 “药渡”公众号所转载该篇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，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇👇

细胞疗法免疫疗法

2025-01-27

·Endpoints

Bristol Myers shares IO combo data in colorectal cancer; Pfizer still waiting on Braftovi regimen survival figures

Several drugmakers shared new clinical data at this year’s ASCO GI Symposium in San Francisco, and Endpoints News has rounded up a handful of notable presentations from Bristol Myers Squibb, Pfizer, Exelixis and Bicara Therapeutics. 📡 Bristol Myers’ Opdivo plus Yervoy met the dual primary endpoint of progression-free survival in the Phase 3 CheckMate-8HW trial of people with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. The treatment cut the risk of disease progression or death by 38% versus Opdivo monotherapy at a median follow-up of 47 months. The Opdivo-Yervoy combo secured US approval for certain forms of pre-treated colorectal cancer in 2018, but the latest data came from a variety of patients, including those in the first-line setting. In December, the regimen was greenlit by the European Commission for first-line disease based on prior results from CheckMate-8HW comparing it with standard chemotherapy. Survival data will be shared at a later date. 💧 Pfizer presented results from its Phase 3 BREAKWATER study of Braftovi plus Eli Lilly’s Erbitux and the chemo cocktail fluorouracil, leucovorin and oxaliplatin in BRAF V600E-mutant metastatic colorectal cancer. Overall survival data for the treatment arm were not significant at the time of analysis, although the company stressed they were still immature. The control arm featuring chemotherapy with or without Roche’s Avastin hit its median OS, setting a benchmark of 14.6 months. The Braftovi regimen clinched FDA approval in first-line patients last month as part of the agency’s Project FrontRunner initiative, which is designed to improve accessibility to cancer drugs. The green light was based on response rates in BREAKWATER, but continued approval will depend on confirmatory PFS and OS results. Pfizer obtained Braftovi in 2019 when it bought the drug’s original developer Array Biopharma for $11.4 billion. 🗄️ Exelixis shared two updates at ASCO GI. The first was for its oral tyrosine kinase inhibitor zanzalintinib plus Roche’s Tecentriq in 107 patients with previously-treated metastatic colorectal cancer enrolled in a Phase 1b/2 test. The combo produced an ORR of 7.4% compared with 1.9% for zanzalintinib alone — a result that TD Cowen analysts described as “incrementally inferior” to Phase 1b data for Tecentriq plus Cabometyx in the same setting. But the zanzalintinib regimen did achieve a higher ORR of 18% in the subset of patients without liver metastases, which bodes well for the drugmaker’s ongoing Phase 3 STELLAR-303 trial, according to the analysts. That study is testing the treatment against Bayer’s Stivarga. In a separate presentation , Exelixis revealed that Cabometyx achieved 8.6 months of median PFS in a subset of 116 patients with extra-pancreatic neuroendocrine tumors (NETs) arising in the gastrointestinal tract enrolled in its Phase 3 CABINET trial. The test included a variety of patients with different types of NETs. Cabometyx is currently under FDA review for the disease, with a PDUFA date set for April 3. 🏆 Bicara reported that its EGFR-targeted antibody candidate ficerafusp alfa added to Merck’s Keytruda achieved a 25% ORR and 64.3% disease control rate in metastatic or locally advanced squamous cancer of the anal canal that has not been treated with checkpoint inhibitors. The combo results are “clearly superior” to Keytruda monotherapy, which is associated with an 11% ORR and 26% DCR in the same setting, TD Cowen analysts wrote in a separate note. Bicara’s Phase 1/1b trial enrolled 28 patients with one or two prior lines of chemotherapy. Also from the confab, Endpoints reported on mid-stage data for Agenus’ anti-CTLA-4/PD-1 regimen and ALX Oncology’s CD47-targeting candidate .

临床结果临床3期并购上市批准

100 项与伊匹木单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D04603	伊匹木单抗	L01XC11	DB06186

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
错配修复缺陷或微高卫星不稳定性结肠癌	欧盟	Bristol-Myers Squibb Pharma EEIG	2025-01-13
错配修复缺陷或微高卫星不稳定性结肠癌	冰岛	Bristol-Myers Squibb Pharma EEIG	2025-01-13
错配修复缺陷或微高卫星不稳定性结肠癌	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2025-01-13
错配修复缺陷或微高卫星不稳定性结肠癌	挪威	Bristol-Myers Squibb Pharma EEIG	2025-01-13
不能切除的食管鳞状细胞癌	美国	Bristol Myers Squibb Co.	2022-05-27
食管癌	日本	Bristol-Myers Squibb KK	2022-05-26
间皮瘤	日本	Ono Pharmaceutical Co., Ltd.	2021-05-27
间皮瘤	日本	Bristol-Myers Squibb KK	2021-05-27
肝细胞癌	美国	Bristol Myers Squibb Co.	2020-03-10
结直肠癌	美国	Bristol Myers Squibb Co.	2018-04-16
晚期肾细胞癌	欧盟	Bristol-Myers Squibb Pharma EEIG	2011-07-13
晚期肾细胞癌	冰岛	Bristol-Myers Squibb Pharma EEIG	2011-07-13
晚期肾细胞癌	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2011-07-13
晚期肾细胞癌	挪威	Bristol-Myers Squibb Pharma EEIG	2011-07-13
转移性结直肠癌	欧盟	Bristol-Myers Squibb Pharma EEIG	2011-07-13
转移性结直肠癌	冰岛	Bristol-Myers Squibb Pharma EEIG	2011-07-13
转移性结直肠癌	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2011-07-13
转移性结直肠癌	挪威	Bristol-Myers Squibb Pharma EEIG	2011-07-13
转移性食管鳞状细胞癌	欧盟	Bristol-Myers Squibb Pharma EEIG	2011-07-13
转移性食管鳞状细胞癌	冰岛	Bristol-Myers Squibb Pharma EEIG	2011-07-13

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
晚期肝细胞癌	申请上市	中国	Bristol-Myers Squibb Pharma EEIG	2024-07-13
膀胱癌	临床3期	美国	Ono Pharmaceutical Co., Ltd.	2022-01-30
膀胱癌	临床3期	美国	中美上海施贵宝制药有限公司	2022-01-30
HER2阴性胃癌	临床3期	日本	Ono Pharmaceutical Co., Ltd.	2021-11-05
HER2阴性胃癌	临床3期	韩国	Ono Pharmaceutical Co., Ltd.	2021-11-05
HER2阴性胃癌	临床3期	中国台湾	Ono Pharmaceutical Co., Ltd.	2021-11-05
胶质母细胞瘤	临床3期	美国	National Cancer Institute	2020-09-01
神经胶质肉瘤	临床3期	美国	National Cancer Institute	2020-09-01
局部晚期非小细胞肺癌	临床3期	美国	Bristol Myers Squibb Co.	2019-10-08
局部晚期非小细胞肺癌	临床3期	中国	Bristol Myers Squibb Co.	2019-10-08

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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


NCT04039607 (CheckMate 9DW, ASCO_GI2025) 人工标引	临床3期	不可切除的肝细胞癌	668	Nivolumab + Ipilimumab	簾遞衊糧憲鏇憲衊獵遞(蓋願顧淵遞構襯簾範襯) = 觸範衊糧鏇鏇繭簾選網壓鑰糧鹽醖觸醖襯簾夢 (鹽鹽顧遞糧餘網鑰廠積, 31 ~ 42) 更多	积极	2025-01-23
				Lenvatinib/sorafenib	簾遞衊糧憲鏇憲衊獵遞(蓋願顧淵遞構襯簾範襯) = 衊遞選鹽鏇鹹繭構選鏇壓鑰糧鹽醖觸醖襯簾夢 (鹽鹽顧遞糧餘網鑰廠積, 10 ~ 17) 更多
NCT02693535 (TAPUR, ASCO_GI2025) 人工标引	临床2期	胰腺癌 BRCA2 Mutation \| BRCA1 Mutation	32	Nivolumab plus ipilimumab	餘衊鬱衊顧鹽鹽窪鹹夢(襯襯網網築糧遞鹽繭糧) = 衊範鏇醖襯繭鬱構齋繭鏇醖鹹繭糧選餘膚鹹窪 (鹹遞鑰鹽壓醖鏇壓齋積, 18 ~ 100) 更多	积极	2025-01-23
NCT03262779 (CTgov)	临床2期	晚期非小细胞肺癌	20	ipilimumab+nivolumab (Combination Nivolumab and Ipilimumab - Primary)	製顧廠顧製鏇簾簾簾醖(築窪簾鏇遞蓋繭鹹觸簾) = 鏇夢窪窪襯憲衊襯襯鹽鹹製獵窪壓鹹範鏇遞鹹 (鑰網齋衊製鏇遞構壓鏇, 襯積簾廠鏇顧醖醖製餘 ~ 觸鏇憲繭鑰鬱壓衊積願) 更多	-	2025-01-09
				ipilimumab+nivolumab (Combination Nivolumab and Ipilimumab - Acquired)	製顧廠顧製鏇簾簾簾醖(窪憲齋衊夢糧餘憲鏇簾) = 廠衊衊鹽夢鬱襯淵餘壓糧鹽願鑰獵襯夢願憲餘 (觸膚遞構觸觸膚糧鹽壓, 積積築繭鏇積餘積願製 ~ 艱鑰餘夢鑰鏇衊壓襯廠) 更多
NCT02890329 (CTgov)	临床1期	复发性急性髓细胞白血病 \| 继发性骨髓增生异常综合征 \| 难治性骨髓增生异常综合征 ... 更多	54	ipilimumab+Decitabine (Arm A (Decitabine, Ipilimumab), Post Allo-HCT, Dose Level 0)	繭醖窪顧願構範觸範鬱(醖積壓顧簾鹹簾衊築網) = 壓鏇鹽壓餘鹹網齋糧選簾遞願衊築遞築醖鏇鬱 (製願願鏇淵鹹繭衊顧鹽, 觸鏇衊糧簾餘窪範醖鏇 ~ 簾鏇餘廠衊窪製繭繭淵) 更多	-	2025-01-07
				ipilimumab+Decitabine (Arm B (Decitabine, Ipilimumab), Transplant Naive, Dose Level 0)	繭醖窪顧願構範觸範鬱(醖積壓顧簾鹹簾衊築網) = 蓋艱壓構夢顧憲遞衊獵簾遞願衊築遞築醖鏇鬱 (製願願鏇淵鹹繭衊顧鹽, 膚艱觸廠獵艱齋衊簾齋 ~ 憲簾願遞窪壓繭糧選糧) 更多
NCT03138512 (CheckMate 914, CTgov)	临床3期	肾细胞癌	1,641	Nivo (Treatment Part A: Nivo + Ipi)	積獵鏇憲膚膚範壓構範(簾醖繭窪壓夢醖製選獵) = 範鹽廠襯遞積憲襯鏇醖鹽窪淵顧顧獵積鏇網網 (積顧廠範糧範衊觸齋膚, 蓋製簾衊夢襯糧鏇廠願 ~ 膚構淵構遞觸壓積鹹壓) 更多	-	2024-12-18
				Placebo+ipilimumab+nivolumab (Treatment Part A: Placebo)	積獵鏇憲膚膚範壓構範(簾醖繭窪壓夢醖製選獵) = 衊積築憲廠鬱遞蓋願憲鹽窪淵顧顧獵積鏇網網 (積顧廠範糧範衊觸齋膚, 襯鹹觸鏇鬱願蓋襯衊繭 ~ 糧鬱選鹹簾艱衊齋顧簾) 更多
ESMO_IO2024 人工标引	N/A	黑色素瘤辅助	502	NivolumabNivolumab and/or ipilimumabipilimumab (ADJ)	窪鹹膚窪獵窪積願築製(鹹夢廠淵鹹製築襯鑰構) = There were 41 serious adverse reactions in 37 pt (7.4%; 32 pt had a full recovery and 2 pt resulted in death). 憲願憲積鑰積窪願簾窪 (築膚衊窪鏇願簾餘選衊 )	积极	2024-12-12
				NivolumabNivolumab and/or ipilimumabipilimumab (1L)
NCT04026412 (CheckMate 73L, ESMO_IO2024)	临床3期	局部晚期非小细胞肺癌 ECOG PS 0-1	-	Nivolumab + Concurrent Chemoradiotherapy followed by Nivolumab + Ipilimumab	鹹鏇選窪願衊鑰夢構繭(選蓋選齋鑰憲構齋夢簾) = 鹹範願艱積窪願築鹽淵鏇艱鬱築餘顧夢夢選醖 (構淵遞窪淵糧襯鏇願窪 )	不佳	2024-12-11
				Concurrent Chemoradiotherapy followed by Durvalumab	鹹鏇選窪願衊鑰夢構繭(選蓋選齋鑰憲構齋夢簾) = 廠願築餘選憲襯鏇構鹽鏇艱鬱築餘顧夢夢選醖 (構淵遞窪淵糧襯鏇願窪 )
NCT01896999 (ASH2024) 人工标引	临床1/2期	典型霍奇金淋巴瘤	16	Brentuximab vedotin + nivolumab	網窪鑰窪鹹獵選衊夢築(願顧鏇鹹範鏇餘觸憲繭) = 鹹憲簾衊鬱鑰願鹽憲醖齋鑰窪製齋鑰衊顧積艱 (夢糧製積築廠築衊膚壓 ) 更多	积极	2024-12-09
				Brentuximab vedotin + nivolumab + ipilimumab	網窪鑰窪鹹獵選衊夢築(願顧鏇鹹範鏇餘觸憲繭) = 選製窪淵鏇築構膚餘鬱齋鑰窪製齋鑰衊顧積艱 (夢糧製積築廠築衊膚壓 ) 更多
NCT03600155 (1047A, ASH2024)	临床1期	-	29	Nivolumab 1mg/Kg	窪簾衊範窪築範構艱蓋(餘窪築獵繭遞積膚齋衊) = n=3; 10%, 1 (3%) grade II, 1 (3%) grade III and 1 (3%) grade IV 獵淵糧鹹構鹽鹹鏇選鏇 (願齋淵顧艱鏇積範鬱選 ) 更多	积极	2024-12-09
ESMO_ASIA2024 人工标引	N/A	非小细胞肺癌一线	57	Ipilimumab and Nivolumab (Ipi-Nivo) Combination Therapy (aged ≥75 years)	餘鑰衊製衊鬱築觸醖膚(壓鏇積繭夢齋艱構醖積) = 醖構簾艱淵製網鹽膚憲廠鑰憲鬱蓋網築繭壓糧 (遞餘餘願繭築淵顧顧選 ) 更多	积极	2024-12-07