Phase 3, Randomized Study Evaluating the Efficacy and Safety of TAR-210 Erdafitinib Intravesical Delivery System Versus Single Agent Intravesical Chemotherapy in Participants With Intermediate-risk Non-muscle Invasive Bladder Cancer (IR-NMIBC) and Susceptible FGFR Alterations - 42756493BLC3004

开始日期2024-07-24

申办/合作机构-

ISRCTN76448481 / Recruiting临床3期

A phase 3, randomized study evaluating the efficacy and safety of TAR-210 Erdafitinib intravesical delivery system versus single agent intravesical chemotherapy in participants with intermediate-risk non-muscle invasive bladder cancer

开始日期2024-04-29

申办/合作机构

Janssen-Cilag International NV

100 项与厄达替尼相关的临床结果

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100 项与厄达替尼相关的转化医学

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100 项与厄达替尼相关的专利（医药）

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271

项与厄达替尼相关的文献（医药）

2024-12-01·JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes.

Article

作者: Alasmary, Fatmah Ali S ; El-Araby, Moustafa E ; Omar Ebeid, Abdelsattar Mansour ; Abdullah, Dalal A ; Alafeefy, Ahmed M ; Masand, Vijay H ; Ben Bacha, Abir

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC₅₀ = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC₅₀ = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.

2024-11-01·CLINICAL CANCER RESEARCH

Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies

Article

作者: Tselikas, Lambros ; André, Fabrice ; Nobre, Catline ; Loriot, Yohann ; Olaussen, Ken A. ; Combarel, David ; Hollebecque, Antoine ; Facchinetti, Francesco ; Barbé, Rémy ; Friboulet, Luc ; Michiels, Stefan ; Scoazec, Jean-Yves ; Bigot, Ludovic ; Smolenschi, Cristina ; Bahleda, Rastislav ; Besse, Benjamin ; Brayé, Floriane ; Italiano, Antoine ; Vasseur, Damien ; Ponce-Aix, Santiago

Abstract:

Purpose::

Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.

Experimental Design::

We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR–selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies.

Results::

Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated—after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.

Conclusions::

At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.

2024-11-01·BIOMEDICINE & PHARMACOTHERAPY

Enhancing targeted therapy by combining PI3K and AKT inhibitors with or without cisplatin or vincristine in medulloblastoma cell lines in vitro

Article

作者: Lukoseviciute, Monika ; Dalianis, Tina ; Need, Emma ; Kostopoulou, Ourania N. ; Kostopoulou, Ourania N ; Birgersson, Madeleine

AIM:

Despite current intensive therapy, survival rates of medulloblastoma (MB) greatly vary according to molecular subgroup, so new therapies are needed. Recently, we showed that combining phosphoinositide 3-kinase (PI3K), fibroblast growth factor receptor and cyclin-dependent-kinase-4/6 inhibitors (BYL719, JNJ-42756493 and PD-0332991, respectively) or poly (ADP-ribose) polymerase (PARP) and WEE-1 inhibitors (BMN673 and MK1775 respectively) had synergistic effects on MB. Here, in continuation, we investigated the effects of single and combined administrations of PI3K and AKT inhibitors, with/without cisplatin or vincristine on adherent or suspension cultures of different MB subgroups as well as in a spheroid culture of one MB line.

MATERIAL AND METHODS:

MB cell lines DAOY, UW228-3, D425, Med8A, and D283 were treated with single and combined administrations of BYL719, AZD5363, cisplatin or vincristine and followed for viability, cell confluence, cytotoxicity, and cell migration. DAOY was also tested as a spheroid culture.

KEY FINDINGS:

Single BYL719, AZD5363, cisplatin, or vincristine administrations gave dose-dependent responses with regard to inhibition of viability and cell confluence. Combining AZD5363 with BYL719, cisplatin or vincristine resulted in synergistic effects with regard to inhibition of viability in all cell lines, and confluence and migration in all tested cell lines. The administration of single and combined treatments to DAOY spheroids produced largely similar effects.

SIGNIFICANCE:

This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

111

项与厄达替尼相关的新闻（医药）

2024-10-25

·精准药物

胶质瘤NCCN指南更新及分子标志物相关靶免药物总结

导语在过去20多年，胶质瘤治疗领域的突破性进展寥寥无几。然而，今年似乎按了加速器，先后有3款药物：Tovorafenib、伯瑞替尼、Vorasidenib，获得突破性成功，成为对应靶点在胶质瘤中的首款获批药物。这些新药的获批共同开启了脑胶质瘤精准诊疗的新篇章。Vorasidenib也于9月30日纳入NCCN指南。本期就指南更新内容进行介绍，同时对胶质瘤分子标志物相关的靶免药物进行汇总分享，以便读者全面了解。一、NCCN指南更新 2024年8月6日，FDA批准Vorasidenib用于治疗手术后（包括活检、次全切或全切）携带IDH1/2突变的2级星形细胞瘤或少突胶质细胞瘤的12岁及以上患者。2024年9月30日，中枢神经系统癌症NCCN指南从2024V2版更新升级为2024V3版，纳入Vorasidenib并扩大其适应症范围，具体更新内容如下：在GLIO-A 2/9和GLIO-A 4/9页面中的以下4个临床场景中添加靶向IDH1或IDH2突变的Vorasidenib作为治疗选择： 01 作为手术/活检后的辅助治疗方案，用于RT和化疗不是首选、WHO2级、KPS≥60的患者： ►少突胶质细胞瘤（1类），首选 ►IDH突变的星形细胞瘤（1类），首选 ►注脚修改：Vorasidenib是IDH1和IDH2突变的双重抑制剂。在一项Vorasidenib对比安慰剂的3期研究中（Mellinghoff IK, et al.N Engl J Med 2023;389:589-601），在病灶残留或复发的2级IDH突变胶质瘤患者（手术后且未接受治疗）中，与安慰剂相比，Vorasidenib改善了中位PFS（27.7个月vs 11.1个月）。虽然Vorasidenib的FDA批准程序仍在进行中，但符合条件的新诊断的WHO2级疾病患者可以通过扩大准入计划（NCT05592743）获得Vorasidenib。同样适用于GLIO-2A、GLIO-4A页面的脚注k。 02 作为辅助治疗方案，用于KPS <60、WHO2级的患者 ►少突胶质细胞瘤（2A类），在某些情况下适用 ►IDH突变星形细胞瘤（2A类），在某些情况下适用 03 作为RT+化疗后复发或进展性疾病的治疗方案，用于WHO2级、KPS≥60的患者 ►少突胶质细胞瘤（2A类），首选 ►IDH突变星形细胞瘤（2A类），首选 04 作为复发或进展性疾病的治疗方案，用于KPS ≥60的患者 ►少突胶质细胞瘤，WHO3级（2B类），首选 ►IDH突变型星形细胞瘤，WHO3级或4级（2B类），首选 ▼IDH突变、1p19q共缺失的少突胶质细胞瘤：系统治疗方案选择 ▼IDH突变的星形细胞瘤：系统治疗方案选择二、胶质瘤分子标志物相关的靶免药物汇总 2.1 获批或指南推荐检测的分子标志物及其药物 1 靶向药物分子标志物：IDH1/2 异柠檬酸脱氢酶（IDH）是三羧酸循环中的一种关键性限速酶，包括IDH1、IDH2和IDH3这3种异构酶，其功能是催化异柠檬酸生成α-酮戊二酸（α-KG）。IDH的特定突变会导致α-KG的代谢异常，D-2-羟戊二酸（D-2-HG）高浓度积累，引起基因的表观修饰异常和氧化还原失衡。超过90%的IDH基因突变为IDH1 R132 突变（常见R132H突变），其余为IDH2 R172突变。 ▼胶质瘤中IDH突变频率、突变类型及其占比 Vorasidenib Vorasidenib（AG-881）是首个获批应用于胶质瘤中的IDH抑制剂。其获批基于INDIGO临床试验（NCT04164901），该试验是一项3期、多中心、随机、双盲、安慰剂对照研究，比较了Vorasidenib与安慰剂在仅接受过手术治疗的IDH1或IDH2突变的2级胶质瘤（少突胶质瘤、星形细胞瘤）残余或复发性患者中的疗效。试验数据显示，Vorasidenib的客观缓解率（ORR）为18%，包括1例部分缓解（PR）和3例轻微缓解（MR）。使用该药物观察到的无强化低级别胶质瘤患者的中位无瘤生存期为36.8个月（95%CI：11.2-40.8个月），强化胶质瘤患者的中位无瘤生存期为3.6个月（95%CI：1.8-6.5个月）。此外，在多名患者中观察到持续的肿瘤缩小。研究结论指出：在2级IDH突变胶质瘤患者中，Vorasidenib显著提高了无进展生存期，并延迟了下一次干预的时间。艾伏尼布艾伏尼布是首个获指南推荐应用于胶质瘤的IDH1抑制剂。该推荐基于以下研究结果：在66例晚期胶质瘤患者中，艾伏尼布耐受性良好，无剂量限制性毒性报道。未达到最大耐受剂量；扩大队列选择500毫克，每天一次。≥ 3 级不良事件发生率为19.7%；3% （n= 2）被认为与治疗有关。非增强型胶质瘤患者（n = 35），客观缓解率为2.9%，部分缓解1例。35例非增强型胶质瘤患者中有30例（85.7%）病情稳定，而31例增强型胶质瘤患者中有14例（45.2%）病情稳定。非增强型和增强型胶质瘤组的中位无进展生存期分别为13.6个月（95% Cl：9.2-33.2个月）和1.4个月（95% Cl：1.0-1.9个月）。在探索性分析中，艾伏尼布降低了非增强性肿瘤的体积和生长速度。结论：在mIDH1晚期胶质瘤患者中，艾伏尼布 500 mg /天1次具有良好的安全性、延长疾病控制时间和减少非增强性肿瘤的生长。目前，还有多款在研的IDH抑制剂，如Olutasidenib、DS-1001（AB-218）的初步研究已表明其在胶质瘤中具有较好的临床应用前景。 2 靶向药物分子标志物：BRAF突变/融合、NF1突变 BRAF基因变异会导致下游MEK/ERK信号通路持续激活，促进肿瘤的生长增殖和侵袭转移。在不同的脑胶质瘤中，BRAF变异的形式不同，主要包括BRAF融合和BRAF V600E。在毛细胞星形细胞瘤（PA，WHO 1级）中高发KIAA1549-BRAF融合（约60%-70%），被认为是PA的诊断标志物。在各个级别的胶质瘤中均检测到BRAF V600E突变，在多形性黄色星形细胞瘤（PXA，WHO 2/3级）中约为70%，在上皮样胶质母细胞瘤中约为50%，在胚胎发育不良性神经上皮瘤（DNET）中约为30%，在节细胞胶质瘤（WHO 1级）中约50%，在PA中约为10%。BRAF基因变异是儿童低级别胶质瘤（LGG）中最常见的致癌驱动因素。神经纤维瘤病1型（NF1）是最常见的常染色体显性肿瘤易感性综合征，由NF1基因胚系突变导致。高达30%的NF1患者会在20岁前患脑肿瘤，其中大部分是低级别胶质瘤，最常见于视觉通路，最常见的病理学亚型是PA。 ▼各类型胶质瘤中 BRAF基因变异频率 ▼常见BRAF融合的断点频率针对BRAF基因变异，NCCN指南推荐用于胶质瘤的靶向药物有：达拉非尼+曲美替尼、维莫非尼±考比替尼、司美替尼，已获药监局批准的药物有Tovorafenib、达拉非尼+曲美替尼。针对NF1基因突变，NCCN指南推荐药物有司美替尼。 Tovorafenib 2024年4月23日，FDA加速批准Tovorafenib（RAF抑制剂）用于BRAF基因融合/重排或BRAF V600突变的6个月及以上复发或难治性儿童低级别胶质瘤患者。这是首个获批用于BRAF融合/重排脑胶质瘤适应症的RAF抑制剂，其获批是基于一项多中心、开放标签、单臂临床试验FIREFLY-1（NCT04775485，II期）的研究结果。FIREFLY-1旨在评估Tovorafenib作为每周一次的单药疗法治疗6个月至25岁患有复发或进展性pLGG患者的疗效与安全性，研究共纳入137名患者（第1组：77名患者携带已知的BRAF激活突变，第2组：60名患者携带已知的RAF变异）。研究结果显示，在第1组RAPNO-LGG标准可评估的76例患者中，最佳ORR为51%，其中包括28例PR（37%）和11例MR（14%），中位持续响应时间（DoR）为13.8个月（95%CI：11.3-NE[不可估计]）。目前正在开展全球III期试验LOGGIC/FIREFLY-2（NCT05566795），旨在评估新诊断的LGG患者每周一次的Tovorafenib单药疗法，入组患者均具有已知的激活RAF改变。司美替尼 NCCN指南推荐用于BRAF变异包括BRAF V600E突变或BRAF融合和NF1突变的复发或进展性局限性胶质瘤成人患者。该推荐基于一项多中心 II 期试验（NCT01089101）的第1组和第3组研究结果：司美替尼对复发性、难治性或进展性伴有常见BRAF变异的PA和NF1相关pLGG具有活性。第1组包括患有WHO 1级毛细胞星形细胞瘤（PA）的儿童，25例符合条件且可评估的肿瘤中有18例（72%）具有 KIAA1549-BRAF融合，有7例（28%）具有BRAF V600E 突变。9例（36%）患者达到PR，9例（36%）疾病稳定（SD）和7例（28%）疾病进展（PD）。2年PFS为70%（95%CI：47%−85%）。在具有 KIAA1549-BRAF 融合的肿瘤中7例（38.9%）PR，而在BRAF V600E肿瘤中2例（28.6%）PR 。第3组包括25例患有任何NF1相关pLGG（WHO 1级和2级）的儿童接受治疗。10例（40%）患者达到 PR，15例（60%） SD和1例（4%）PD。2年PFS为96%（95% CI：74%-99.4%）。 3 靶向分子标志物：MET融合脑胶质瘤中MET异常形式主要有MET融合、MET ex14跳突、MET扩增及MET蛋白过表达；约12%脑胶质瘤被发现存在MET融合，其中PTPRZ1-MET（简称ZM）融合通常与MET ex14跳突同时出现在既往有低级别病史的胶质母细胞瘤中，发生率约为14%，并与更差的预后相关。 ▼MET融合断点（A）及其在5个癌种中的情况（B）和伴侣基因染色体分布（C）注：BC：脑癌，LC：肺癌，IC：小肠癌，GC：胃癌，BDC：胆管癌伯瑞替尼伯瑞替尼（Vebreltinib，PLB-1001）是一种高选择性MET抑制剂，于2024年4月23日获得NMPA批准用于既往治疗失败的具有PTPRZ1-MET融合基因的IDH突变型星形细胞瘤（WHO 4级）或有低级别病史的胶质母细胞瘤成人患者。这使其成为我国首个获批治疗脑胶质瘤MET异常患者的靶向药。获批主要是基于一项随机、对照、开放、多中心的II/III期临床研究（FUGEN，NCT06105619），该研究旨在对比伯瑞替尼与TMZ剂量密度方案或依托泊苷+顺铂方案的安全性和有效性。截至2023年12月，该研究共纳入了84例患者。结果显示，相较于TMZ剂量密度方案或顺铂联合依托泊苷方案，伯瑞替尼单药方案mOS为6.31个月，对照组为3.38个月，降低48%的死亡风险，可显著改善ZM融合脑胶质瘤患者生存。整体安全耐受，常见不良反应多为1-2级，可通过临床管理恢复。 4 靶向药物分子标志物：NTRK融合编码TRK融合蛋白（TRKA、TRKB、TRKC）的基因包括NTRK1、NTRK2或NTRK3的基因，这些基因融合蛋白增加了激酶功能，并与许多实体瘤发生有关。大约0.55-2%的胶质瘤/神经上皮肿瘤含有NTRK融合，但在儿童高级别胶质瘤（HGG）中NTRK融合发生率可能高达5.3%，弥漫性内生性脑桥胶质瘤（DIPG）达4%，3岁以下非脑干HGG达40%。 ▼中枢神经系统肿瘤中NTRK融合的发生率及高频的融合基因类型小分子TRK抑制剂拉罗替尼（Larorectinib，FDA/NMPA）、恩曲替尼（Entrectinib，FDA/NMPA）、瑞普替尼（Repotrectinib，FDA）已在成人和儿童各种癌症的多项试验中显示出抗肿瘤活性，并已获得国内外药监局批准用于NTRK融合的实体瘤患者。目前，针对NTRK融合的成人复发或进展性胶质母细胞瘤以及儿童HGG患者，NCCN指南推荐首选拉罗替尼和恩曲替尼；针对成人患者，2024.V2版NCCN指南新增推荐了瑞普替尼。瑞普替尼瑞普替尼获批基于多中心、单臂、开放标签的I/II期临床试验TRIDENT-1（NCT03093116），该研究纳入了3例TKI经治的胶质母细胞瘤患者，ORR为33.3%，DoR为23.5个月。文献研究报道一名2岁的女性婴儿半球型脑胶质瘤，伴有ZBTB43-NTRK2融合和CDKN2A/2B半合子缺失，在左额颞肿瘤首次手术切除后，接受了诱导化疗，自体外周血干细胞移植（aPBSCT）联合卡铂和塞替派，以及质子治疗（55.8 Gy）。第二次手术切除残留肿瘤后，参加了口服瑞普替尼的临床试验，在3年随访期间未发生疾病复发。 ▼瑞普替尼在TKI经治的NTRK融合胶质母细胞瘤患者中的疗效 ▼NTRK融合的婴儿半球型脑胶质瘤的治疗过程 5 免疫药物分子标志物：超突变遗传性癌症易感性综合征CMMRD（结构性错配修复缺陷综合征，由MMR基因[MLH1、PMS2、MSH2、MSH6]的双等位基因突变导致）经常导致儿童弥漫性高级别胶质瘤的发展，其特点是比偶发脑肿瘤或其他实体肿瘤具有更高的突变负荷。由此产生的超突变肿瘤可能对免疫检查点抑制敏感。针对超突变的复发或进展性的儿童中枢神经系统肿瘤患者，NCCN指南推荐首选纳武利尤单抗、帕博利珠单抗。然而，其有效性的证据目前仅限于病例报告和单一机构的经验。 ▼CMMRD和林奇综合征的遗传模式图（林奇综合征为MMR基因杂合突变，CMMD为MMR基因双等位基因突变）一项研究报告了两个患有复发性多灶性GBM的bMMRD（biallelic MMR deficiency syndrome，同CMMRD）的姐弟，存在POLE突变和高肿瘤突变负荷（预测具有较高的新生抗原），接受了抗程序性死亡-1（PD-1）抑制剂纳武利尤单抗的治疗，在几个月的治疗后，这两个孩子的临床和放射学反应都很明显。另一项案例研究报道，一例5岁女孩存在纯合MSH6 c.1883G>A 突变而患有GBM和CMMRD，接受免疫检查点抑制剂（ICI）纳武利尤单抗治疗，肿瘤缩小了60%，临床症状得到改善，响应持续10个月。研究表明，将CMMRD的基因组和/或分子检测纳入常规儿科肿瘤学临床护理可以确定可能从ICI中受益的患者亚群。一项在丹娜-法伯/波士顿儿童医院对11例复发性或难治性中枢神经系统肿瘤儿童患者进行的回顾性研究显示，免疫检查点抑制剂在儿童患者中具有相当好的耐受性，值得进一步的临床试验研究。 2.2 临床试验/案例报道的其他分子标志物及药物 1 靶向药物分子标志物：ALK融合婴儿半球胶质瘤携带 ALK、ROS1、NTRK1/2/3 或MET受体酪氨酸激酶重排，与其他儿科高级别胶质瘤相比，更适合治疗，生存结果更好。一名3岁的婴儿半球胶质瘤患者肿瘤细胞显示ALK 具有弥漫性免疫反应，RNA 测序显示SPECC1L-ALK融合，于是采用ALK抑制剂洛拉替尼治疗，至8个月，仅残余较小的肿瘤，实行探查性手术后未发现肿瘤，停止治疗6 个月后疾病进展，恢复洛拉替尼治疗，治疗一个月实现几乎完全缓解。另一项案例研究报道，一名3岁婴儿型半球胶质瘤，DNA测序检出QKI-ALK融合，经常规放化疗治疗进展后，采用阿来替尼治疗2个月左右，治疗期间发生肺部转移，更换为洛拉替尼治疗，实现脑部和肺部病灶的完全缓解。 2 靶向药物分子标志物：FGFR变异约有8%的胶质瘤患者会发生FGFR基因组改变，尤其是FGFR1和FGFR3，并且在约3%-5%的GBM患者中存在FGFR3-TACC3（F3T3）融合突变。研究表明F3T3融合是染色体4p16上70kb区域串联复制的结果，通常伴有低水平的局灶扩增，存在该基因融合的肿瘤细胞大量表达嵌合蛋白。FGFR1-TACC1（F1T1）融合在特定的低级别胶质瘤(如室外神经细胞瘤)中可达60%。文献报道1例胶质母细胞瘤患者，携带FGFR3扩增和FGFR3-TACC3融合，经安罗替尼和替莫唑胺治疗2个月后实现部分缓解。原发性脊髓胶质母细胞瘤（PSC GBM）检出FGFR3 p.S249C，接受10个周期的安罗替尼联合伊立替康化疗，随访约10个月期间，患者症状明显减轻，疗效得以维持。有文章报道，两例携带有FGFR3-TACC3融合突变的GBM患者，在接受安罗替尼治疗后疾病得到持续缓解。一项在复发性胶质瘤患者（携带FGFR改变）中进行的多中心II期临床研究（NCT01975701）数据显示，26名接受FGFR抑制剂Infigratinib治疗的患者的6个月PFS率为16.0%，中位PFS为1.7个月，客观缓解率为3.8%。但是4名携带FGFR1（K656E，n = 2) 或FGFR3（ K650E; n = 1）点突变或FGFR3-TACC3融合突变的肿瘤患者疾病控制持续时间超过1年。另外一项临床研究（NCT04083976）报道了FGFR抑制剂厄达替尼在具有FGFR改变的14种实体瘤体治疗中的有效性，其中30名高级别胶质瘤患者的ORR为20%。一项佩米替尼的II期临床研究纳入9例为F3T3融合的胶质瘤（共纳入13例FGFR变异），1例完全缓解，1例部分缓解，2例疾病稳定。目前一项旨在评估佩米替尼在先前治疗过的胶质母细胞瘤或其他原发性中枢神经系统肿瘤患者（携带FGFR1-3改变，包括融合/重排，激活突变或框内缺失）中的疗效和安全性的研究（NCT05267106，II期）正在进行招募中。一项关于Zoligratinib（Debio-1347）的单中心研究纳入5例FGFR变异的儿童胶质瘤患者，1例F3T3融合，1例F1T1融合，在融合的患者中1例PR，1例SD。参考资料【1】 Shen D , Zhang J , Yuan K ,et al.Landscape of IDH1/2 mutations in Chinese patients with solid tumors: A pan-cancer analysis[J].Molecular Genetics & Genomic Medicine, 2021.DOI:10.1002/mgg3.1697. 【2】Watts JM, Baer MR, Yang J, et al. 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Ann Clin Transl Neurol. 2023;10(5):836-841. doi:10.1002/acn3.51766 【35】Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. 2022;23(1):53-64. doi:10.1016/S1470-2045(21)00578-7 【36】Mellinghoff IK, Ellingson BM, Touat M, et al. Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma. J Clin Oncol. 2020;38(29):3398-3406. doi:10.1200/JCO.19.03327 【37】Ivosidenib off-label use for IDH mutant gliomas: The MD Anderson Cancer Center real life experience.Meeting Abstract | 2023 ASCO Annual Meeting I.DOI: 10.1200/JCO.2023.41.16_suppl.e14022 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) e14022-e14022. 【38】Miller JJ, Gonzalez Castro LN, McBrayer S, et al. Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions. Neuro Oncol. 2023;25(1):4-25. doi:10.1093/neuonc/noac207 【39】https://fore.bio/fore-biotherapeutics-to-present-promising-new-data-from-phase-1-2a-trial-evaluating-plixorafenib-fore8394-in-patients-with-braf-altered-advanced-solid-and-central-nervous-system-tumors-at-asco-2023/ 【40】https://fore.bio/fore-biotherapeutics-announces-oral-presentation-at-sno-2023-reporting-updated-phase-1-2a-results-for-plixorafenib-in-braf-v600-advanced-solid-tumors-including-novel-data-for-patients-with-braf-v600/ 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床3期临床结果临床2期免疫疗法

2024-10-25

·Endpoints

Tyra's stock dips as it gives first look in challenge to J&J’s bladder cancer drug Balversa

Tyra Biosciences unveiled early trial results on its FGFR3-specific inhibitor in advanced bladder cancer patients on Friday, the public company’s first presentation of human data since its inception in 2018. The biotech’s data were highly anticipated: Its shares $TYRA were up over 100% ahead of the readout, but they fell 18% Friday morning on the update. While the company tested a range of doses in the Phase 1 portion of its SURF301 study in metastatic urothelial carcinoma, its efficacy results focused on the patients who received at least 90 mg, where it believes the drug achieved “adequate target coverage.” Five of the 10 patients who received a 90 mg daily dose of TYRA-300 achieved a partial response, as did one patient who received a 120 mg dose. According to Tyra, three of those six responses are still ongoing. The company said 41 patients with FGFR3+ cancer have enrolled as of Aug. 15, including those who were previously treated with Johnson & Johnson’s Balversa. Tyra’s ultimate goal is to develop a safer treatment than Balversa, which in 2019 became the first FGFR-targeted drug to receive FDA accelerated approval for bladder cancer and earlier this year was granted full approval in advanced FGFR3+ urothelial carcinoma. In its confirmatory trial, Balversa resulted in a response rate of 35% in FGFR3+ advanced bladder cancers. TYRA-300, which goes only after FGFR3 while sparing other isoforms (FGFR1/2/4), aims to evade or lessen certain side effects including eye problems, mouth sores and inflammation, and increased phosphate levels. As we started to see a profile and hear from investigators that this was a really well-tolerated drug, we got really excited that the sparing of FGFR1 and 2 thesis could play out,” CEO Todd Harris said of the safety data in an interview with Endpoints News . The biotech said in a release that SURF301 patients experienced “infrequent FGFR2- and FGFR1-associated toxicities.” TD Cowen analyst Tyler Van Buren wrote in a note Friday that “TYRA-300 boasts a superior tolerability profile compared to pan-FGFR inhibitors,” like Balversa. In 15 patients at the 90 mg dose, the most common adverse events were liver enzyme increases and dry mouth, which 6 trial participants experienced. One grade 3 case of elevated liver enzyme levels resulted in treatment discontinuation and one grade 3 case of diarrhea was reported as a dose-limiting toxicity at 90 mg. “These data give us confidence to advance TYRA-300 through Part B in SURF301 and explore larger opportunities with Phase 2 studies in metastatic urothelial cancer, non-muscle invasive bladder cancer and achondroplasia,” said Tyra CEO Todd Harris in a statement. Harris told Endpoints News that for both non-muscle invasive bladder cancer and achondroplasia, a form of dwarfism, Tyra expects to test lower doses of TYRA-300 than the 90 mg it highlighted in urothelial carcinoma.

临床结果加速审批上市批准

2024-10-25

·BioSpace

Tyra Looks to Challenge J&J’s Balversa With Early Data for FGFR3 Blocker in Urothelial Carcinoma

iStock, wildpixel Bank of America analysts said prior to Thursday’s readout that Tyra Biosciences’ TYRA-300 could rival Johnson & Johnson’s kinase inhibitor Balversa, which has suffered from safety concerns and poor tolerability. Tyra Biosciences on Thursday unveiled early proof-of-concept data for its investigational and potential first-in-class FGFR3 inhibitor TYRA-300, touting “encouraging” anti-tumor action in heavily pretreated patients with metastatic urothelial carcinoma. The findings come from the Phase I/II SURF301 trial, which is designed to conduct an initial assessment of the anti-cancer efficacy of TYRA-300 and determine its recommended Phase II dose. Interim results showed that all FGFR3-positive patients who received at least 90 mg of TYRA-300 experienced anti-tumor activity. According to Tyra, 50% of patients on 90-mg TYRA-300 once-daily reached partial response, as did the sole patient treated with a once-daily 120-mg dose. Disease control rate, defined as partial response with stable disease, was documented in 100% of patients who were given at least a 90-mg dose of TYRA-300 once-a-day. In terms of safety, SURF301 found TYRA-300 to be well-tolerated overall and resulted in “infrequent” adverse events associated with FGFR2 and FGFR1. In all TYRA-300-treated patients, there were four treatment-related serious adverse events, one dose-limiting toxicity and one study dropout due to a side effect associated with the study drug. There were no adverse events of grade 4 severity or higher. Tyra CEO Todd Harris in a statement said that these interim data “are in line with our expectations” and “provide clinical support” for TYRA-300 to address the “difficult problem” of creating an effective FGFR3 blocker that matches the efficacy, but bests the safety, of pan-FGFR inhibitors. “These data give us confidence to advance TYRA-300 through Part B in SURF301,” Harris said. Tyra will also “explore larger opportunities with Phase II studies in metastatic urothelial cancer, non-muscle invasive bladder cancer and achondroplasia.” Tyra presented these at an oral late-breaking session at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, held this week in Barcelona, Spain. Designed to be taken orally, TYRA-300 is a next-generation investigational precision therapy that selectively targets FGFR3. This mechanism of action allows TYRA-300 to sidestep current limitations of the FGFR inhibitor drug class, namely growing treatment-emergent resistance mutations and off-target side effects, according to the biotech’s website . With Thursday’s readout, Tyra begins its long trek to challenge J&J in the FGFR3 arena. The pharma owns Balversa, which like TYRA-300, is an orally available kinase inhibitor that the FDA granted accelerated approval for locally advanced or metastatic urothelial carcinoma in 2019. In January 2024, the regulator upgraded Balversa to full approval , allowing its use in patients with susceptible genetic alterations to the FGFR3 gene. However, unlike TYRA-300, Balversa‘s mechanism of action also involves targeting FGFR1, FGFR2 and FGFR4, which has resulted in substantial off-target effects. Jefferies analysts in a Friday note to investors said TYRA-300’s preliminary proof-of-concept data “exceeded” their expectations on both the safety and efficacy fronts, with safety looking “much cleaner” compared to J&J’s Balversa “with the caveat that the safety is grouped together across 10-120mg doses.” Last week, ahead of Tyra’s SURF301 readout, Bank of America analysts flagged these safety concerns for Balversa, saying that its “poor tolerability has made it largely a non-starter,” according to Seeking Alpha . Tyra, the analysts contend, could take advantage of this market gap and make safety its key differentiating factor versus other FGFR inhibitors for urothelial carcinoma.

临床结果临床2期上市批准AACR会议

100 项与厄达替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10927	厄达替尼	L01XE	DB12147

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
转移性尿路上皮癌	欧盟	Janssen-Cilag International NV	2024-08-22
转移性尿路上皮癌	冰岛	Janssen-Cilag International NV	2024-08-22
转移性尿路上皮癌	列支敦士登	Janssen-Cilag International NV	2024-08-22
转移性尿路上皮癌	挪威	Janssen-Cilag International NV	2024-08-22
不可切除的尿路上皮癌	欧盟	Janssen-Cilag International NV	2024-08-22
不可切除的尿路上皮癌	冰岛	Janssen-Cilag International NV	2024-08-22
不可切除的尿路上皮癌	列支敦士登	Janssen-Cilag International NV	2024-08-22
不可切除的尿路上皮癌	挪威	Janssen-Cilag International NV	2024-08-22
FGFR2阳性尿路上皮癌	韩国	Janssen Korea Ltd.	2022-11-24
FGFR3阳性尿路上皮癌	韩国	Janssen Korea Ltd.	2022-11-24
膀胱癌	加拿大	Janssen Biotech, Inc.	2019-12-09
尿路上皮癌	加拿大	Janssen, Inc.	2019-10-25
FGFR阳性尿路上皮癌	美国	Janssen Biotech, Inc.	2019-04-12

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
晚期尿路上皮癌	申请上市	中国	Janssen Biotech, Inc.	2023-12-15
晚期尿路上皮癌	申请上市	中国	Janssen-Cilag SpA	2023-12-15
晚期尿路上皮癌	申请上市	中国	Shanghai Johnson & Johnson Pharmaceutical Ltd.	2023-12-15
非肌层浸润性膀胱肿瘤	临床3期	美国	Janssen Research & Development LLC	2024-04-18
非肌层浸润性膀胱肿瘤	临床3期	中国	Janssen Research & Development LLC	2024-04-18
非肌层浸润性膀胱肿瘤	临床3期	日本	Janssen Research & Development LLC	2024-04-18
非肌层浸润性膀胱肿瘤	临床3期	阿根廷	Janssen Research & Development LLC	2024-04-18
非肌层浸润性膀胱肿瘤	临床3期	奥地利	Janssen Research & Development LLC	2024-04-18
非肌层浸润性膀胱肿瘤	临床3期	比利时	Janssen Research & Development LLC	2024-04-18
非肌层浸润性膀胱肿瘤	临床3期	巴西	Janssen Research & Development LLC	2024-04-18

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临床结果

适应症

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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


NCT03210714 (APEC1621B, CTgov)	临床2期	难治性软组织肉瘤 \| 难治性中枢神经系统淋巴瘤 \| 复发性髓母细胞瘤 ... 更多	20	Computed Tomography+Erdafitinib	餘壓積遞壓獵襯憲壓衊(鹽壓廠衊糧壓糧鏇製簾) = 糧簾鹽鬱夢鏇範鬱蓋糧衊製鏇獵繭衊壓餘鑰糧 (鹽餘蓋鏇鑰觸襯顧糧繭, 憲遞築餘醖鏇憲夢襯獵 ~ 網鬱夢醖繭鏇積廠淵顧) 更多	-	2024-09-19
ESMO2024	N/A	FGFR阳性胆管癌	-	TAR-210	膚淵網醖齋遞築壓製繭(簾觸膚廠願淵積糧蓋築) = 顧鬱築窪窪鬱襯夢憲艱窪觸鏇糧製餘糧襯壓製 (廠鹹糧範顧願夢構鹹襯 ) 更多	-	2024-09-15
NCT02699606 (Pubmed \| BMC Cancer) 人工标引	临床2期	晚期恶性实体瘤 FGFR genomic aberrations	35	Erdafitinib (cholangiocarcinoma)	憲觸齋顧遞夢壓繭糧網(夢膚繭顧膚窪觸顧窪憲) = 積蓋窪壓衊願艱構範鹽襯窪鹹製選製襯衊獵鹽 (鹹觸顧願窪餘憲製餘範, 20.7 ~ 63.6) 更多	积极	2024-08-13
NCT02699606 (Pubmed \| BMC Cancer) 人工标引	临床2期	晚期恶性实体瘤 FGFR genomic aberrations	35	Erdafitinib (RET/FGFR-altered NSCLC)	憲觸齋顧遞夢壓繭糧網(夢膚繭顧膚窪觸顧窪憲) = 鏇範範選繭憲艱艱選淵襯窪鹹製選製襯衊獵鹽 (鹹觸顧願窪餘憲製餘範 ) 更多	积极	2024-08-13
NCT04083976 (RAGNAR, ASCO2024) 人工标引	临床2期	乳腺癌 FGFR Mutation (Activating)	16	Erdafitinib	齋憲憲糧獵積糧夢鬱積(窪選遞簾積膚鹹壓廠蓋) = 糧顧膚鹹鏇齋夢網糧鹽簾願鏇簾蓋艱淵鏇衊遞 (製選製餘窪壓獵糧願糧, 11 ~ 59) 更多	积极	2024-05-24
NCT04083976 (RAGNAR, ASCO2024) 人工标引	临床2期	非小细胞肺癌 CDKN2A \| FGFR mutations \| FGFR fusions ... 更多	23	Erdafitinib	(願築夢鹽製鏇網鹽糧蓋) = 蓋構夢製觸齋繭積鏇獵餘鹹網製願鏇獵築餘衊 (夢築獵鏇製獵窪範願鑰, 10 ~ 48) 更多	积极	2024-05-24
NCT04083976 (RAGNAR, ASCO2024) 人工标引	临床2期	晚期恶性实体瘤 FGFR1 \| FGFR2 \| FGFR3 ... 更多	53	Erdafitinib	餘鏇淵醖製壓膚製壓積(壓遞夢鑰壓選製壓餘鹽) = 糧積獵遞觸淵衊窪鬱夢鑰窪夢壓鏇願廠範鹹衊 (築鏇簾艱壓艱鹽選範鑰 ) 更多	不佳	2024-05-24
NCT02699606 \| NCT04083976 (RAGNAR and LUC2001, ASCO2024)	临床2期	食管癌 \| 晚期恶性实体瘤 \| 晚期非小细胞肺癌 ... 更多	78	Erdafitinib 8 mg daily	製蓋鬱獵夢鏇夢鏇顧壓(鑰壓顧餘獵蓋鬱簾餘願) = 68% 構窪壓鬱遞窪艱廠積餘 (夢憲鏇遞製積糧鬱顧積 ) 更多	积极	2024-05-24
NCT03390504 (THOR study (Cohort 2), ASCO2024)	临床3期	尿路上皮癌 FGFR3 alterations (FGFRalt)	-	Erdafitinib	鹽鬱鑰簾鹹醖廠鹽醖醖(範積顧鹹獵鏇顧衊淵糧) = 鏇艱範範齋鬱膚選網顧夢鏇願鬱糧鹹齋鬱鏇選 (觸網窪選築遞獵襯鹽製 ) 更多	积极	2024-05-24
NCT03390504 (THOR study (Cohort 2), ASCO2024)	临床3期	尿路上皮癌 FGFR3 alterations (FGFRalt)	-	Pembrolizumab	鹽鬱鑰簾鹹醖廠鹽醖醖(範積顧鹹獵鏇顧衊淵糧) = 顧淵顧膚簾獵範鑰積糧夢鏇願鬱糧鹹齋鬱鏇選 (觸網窪選築遞獵襯鹽製 ) 更多	积极	2024-05-24
UNITE study (ASCO2024)	N/A	转移性尿路上皮癌 FGFR2/3-altered \| MTAP loss	633	Erdafitinib	顧齋顧鹽繭範齋壓壓鏇(範襯餘製繭襯範衊鑰餘) = 廠蓋襯願艱糧繭壓範膚廠膚築鏇簾鏇蓋積獵簾 (願蓋遞窪夢鬱蓋簾願鑰 ) 更多	积极	2024-05-24
TAR-210 (AUA2024)	临床1期	FGFR阳性非肌层浸润性膀胱肿瘤 select FGFR alterations	-	ERDAFITINIB	齋廠夢選齋鹹鬱築鏇憲(壓艱夢夢淵積構廠網簾) = Most common treatment-related adverse events were grade 1/2 lower urinary tract events 鏇鑰積遞齋夢窪選壓選 (積積鑰淵範構餘製簾構 )	积极	2024-05-01
TAR-210 (AUA2024)	临床1期	FGFR阳性非肌层浸润性膀胱肿瘤 select FGFR alterations	-	ERDAFITINIB		积极	2024-05-01