A Phase 2, Multicenter, Open Label, Two Parts Clinical Study to Evaluate the Efficacy and Safety of Safusidenib Erbumine in Patients with Isocitrate Dehydrogenase 1 (IDH1) Mutant Glioma

This is a Phase 2, multicenter, open label, two parts, clinical study to evaluate the efficacy, safety, and PK of safusidenib. Patients with recurrent or progressive histologically confirmed IDH1 mutant WHO Grade 2/3 glioma10 outside Japan, will be enrolled in this study. It was divided into 2 parts.
Part 1: Up to 25 patients will be randomized 1:1:1:1:1 (5 patients per group) to receive one of the daily oral doses of safusidenib at 125 mg twice a day (BID), 250 mg BID, 500 mg once daily (QD), 375 mg BID, or 500 mg BID. The PK characteristics and safety and initial efficacy data will be assessed in Part 1.
Part 2: It is planned to open 2 glioma subtype cohorts: Grade 2 and Grade 3 glioma cohorts with 30 eligible patients enrolled in each cohort. Total 60 patients will be enrolled.
Part 2 is to evaluate the efficacy of safusidenib in the treatment of recurrent/progressive WHO CNS Grade 2 and grade 3 IDH1 mutant glioma.
Exploratory Surgery Cohort: This cohort will be conducted in parallel with Part 2, for explorative purpose once RP2D is decided. 5 patients with primarily enhancing lesions and other 5 with primarily non-enhancing lesions will be enrolled. Participants will receive oral safusidenib treatment continuously, with 28 days as a cycle, until disease progression, unacceptable toxicity, consent withdrawal, start of new anti-cancer therapy, investigator decision or death, upon whichever earlier.
Besides baseline, the anti-tumor response will be evaluated every 8 weeks following RANO or RANO-LGG criteria as applicable, until disease progression, consent withdrawal or death, upon whichever earlier.

开始日期2023-06-05

申办/合作机构

Nuvation Bio, Inc.

[+1]

NCT05814536

/ Terminated临床1期

A Phase I, Multi-center, Open-label, Single-arm Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of AB-218 for Treating Adult Patients With Advanced IDH1 Mutant Cholangiocarcinoma and Other Solid Tumors

This is an open label, single-arm Phase I study to evaluate the safety, tolerability, PK and preliminary efficacy of AB-218, an oral IDH1 inhibitor, for the treatment of adult patients with advanced IDH1 mutant cholangiocarcinoma and other solid tumors who have failed at least one prior therapy in the advanced stage.
The study contains a dose escalation part and a dose expansion part. In the dose escalation part, participants are enrolled sequentially into one of 3 dose levels of AB-218 (125 mg BID, 250 mg BID and 500 mg BID) following a 3+3 rule. Intensive PK sampling will be performed during the dose escalation part. Participants will be followed up for DLTs from the date of first study dose to 28 days afterwards. When all participants in the dose escalation part have completed the 28-day DLT observation period, SMC will review the available data including but not limited to safety, tolerability and PK, and then recommend the dose for the study dose expansion part.
In the dose expansion part, there are 2 disease cohorts planned: cholangiocarcinoma (CCA) and other IDH1 mutant solid tumors. It is planned to enrol 30 participants in the CCA cohort and another 15 participants in other IDH1 mutant solid tumors, to assess the safety and preliminary efficacy of AB-218. Sparse PK samples will be collected to further evaluate the PK profile in the different target populations.
Each participant will undergo screening up to 28 days prior to the start of the treatment period. The treatment period consists of a visit on Day 1 of every 28-day cycle and continues until any of disease progression, unacceptable toxicity, withdrawal of consent or death. An end of treatment (or early discontinuation) visit occurs 30 days (± 7 days) after the last dose of study medication, and a survival follow call every 12 weeks until death, withdrawal of informed consent, loss to follow-up (LTFU) or termination of the study by the sponsor, whichever occurs first.

开始日期2023-05-06

申办/合作机构

葆元生物医药科技（杭州）有限公司初创企业

CTR20230597

/ Terminated临床1期

一项评价 AB-218 治疗晚期 IDH1 突变型胆管癌和其他实体瘤成人患者的安全性、药代动力学和初步疗效的 I 期、多中心、开放、单臂研究

1、评价 AB-218 治疗具有 IDH1 突变的晚期胆管癌和其他实体瘤（不包括脑胶质瘤）患者的安全性和耐受性 2、在晚期 IDH1 突变实体瘤（不包括脑胶质瘤）患者中确定 AB-218 的RP2D

开始日期2023-04-19

申办/合作机构

葆元生物医药科技（杭州）有限公司初创企业

[+1]

100 项与 Safusidenib 相关的临床结果

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100 项与 Safusidenib 相关的转化医学

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100 项与 Safusidenib 相关的专利（医药）

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项与 Safusidenib 相关的文献（医药）

2024-10-20·Future Oncology

A perioperative study of Safusidenib in patients with IDH1 -mutated glioma

Article

作者: Cain, Sarah A ; Tobler, Robert ; Rosenthal, Mark ; Topp, Monique ; Best, Sarah A ; Whittle, James R ; Freytag, Saskia ; Drummond, Katharine J

This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with IDH1 mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28 days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention.Clinical Trial Registration: NCT05577416 (ClinicalTrials.gov).

2023-02-14·Neuro-oncology

The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas

Article

作者: Natsume, Atsushi ; Yamasaki, Fumiyuki ; Ito, Kazumi ; Hata, Nobuhiro ; Kumabe, Toshihiro ; Tsubouchi, Hiroshi ; Tachibana, Masaya ; Narita, Yoshitaka ; Yamaguchi, Tomoyuki ; Mineharu, Yohei ; Ichimura, Koichi ; Nishikawa, Ryo ; Muragaki, Yoshihiro ; Arakawa, Yoshiki ; Shinojima, Naoki ; Miyakita, Yasuji ; Nakamura, Hideo ; Asahi, Takashi ; Nishijima, Soichiro ; Motomura, Kazuya ; Kakurai, Yasuyuki ; Sugiyama, Kazuhiko ; Saito, Ryuta ; Matsushita, Yuko ; Okamoto, Naoko

Abstract:

Background:

Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001.

Methods:

This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method.

Results:

The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples.

Conclusions:

DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

2020-02-01·Molecular cancer therapeutics2区 · 医学

A Potent Blood–Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model

2区 · 医学

Article

作者: Katsumoto, Takuo ; Shima, Yutaka ; Suzuki, Kanae ; Saya, Hideyuki ; Nishiya, Yumi ; Matsunaga, Hironori ; Nakagawa, Makoto ; Baba, Daichi ; Suzuki, Makoto ; Ichimura, Koichi ; Ogawara, Yoko ; Imaoka, Tomoki ; Machida, Yukino ; Yamagata, Kazutsune ; Itoh, Masato ; Seki, Takahiko ; Yamaguchi, Masayuki ; Kitabayashi, Issay ; Sampetrean, Oltea ; Hattori, Ayuna ; Nakamura, Koichi

Abstract:

Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood–brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

项与 Safusidenib 相关的新闻（医药）

2025-01-07

·抗体圈

大佬买下中国Biotech，赢麻了

2024年，选择拥抱美国纳斯达克成为了不少国内Biotech资本路径选择，也被市场投资人认为是“上岸”的另一种方式。严格意义上来说，选择美股意味着Biotech要面临更专业、更残酷的资本环境，如果自身核心产品处于临床早期，必须拿出过硬的数据才能继续享受美股对待生科行业“友好”的投融资环境，要说是“上岸”显然是太早的。而有那么一家Biotech，即将收获一款商业化产品，他就是早前与Nuvation Bio合并的葆元医药。早前，信达生物宣布新一代ROS1酪氨酸激酶抑制剂他雷替尼（Taletrectinib）获得NMPA批准上市，用于经ROS1-TKI治疗后进展的ROS1阳性局部晚期或转移性非小细胞肺癌（NSCLC）成人患者的治疗，成为公司第13款商业化产品，而他雷替尼的原研方正是葆元医药。 2024年12月底，Nuvation Bio宣布他雷替尼NDA已获FDA受理并予以优先审评，用于治疗ROS1阳性晚期NSCLC患者，该NDA的处方药使用者费用法案（PDUFA）日期为2025年6月23日。如果明年6月顺利获批，Nuvation Bio将成为在美国有商业化产品的Biotech，当前公司大约有5.5亿美元现金及短期投资，最新市值为9.73亿美元。值得一提的，Nuvation Bio的实控人David Hung也是一个传奇人物，其曾经创立的Medivation在2016年被辉瑞以近140亿美元成功收购。 01 BIC的ROS1抑制剂商业化前景可观他雷替尼是新一代的ROS1小分子抑制剂，其主要特点在于该药可穿过血脑屏障（对脑部病灶有治疗效果）、针对ROS1-TKI（克唑替尼）耐药后患者仍然有效，同时安全性和耐受性良好（相比其他ROS1药物使用过程中因不良反应中止治疗或者减少剂量的比例较低）。 ROS1和ALK一样都属于胰岛素样受体酪氨酸激酶超家族成员，其参与人体多个通路的调控，进而影响细胞的存活和增殖。ROS1基因在非小细胞肺癌（NSCLC）被发现最早可追溯到2007年，在非小细胞肺癌中突变率并不高（全球阳性率为1%-3%）；ROS1重排在中国作为致癌驱动基因改变，大约占晚期非小细胞肺癌患者的2％至3％，NTRK大约占其它晚期实体瘤患者的0.5%。不过，ROS1融合被视为NSCLC中的一个经典的“钻石突变”，一方面其被发现以来相关靶向药不断面市，另一方面ROS1重排肺癌患者预后较好，总生存期较长。克唑替尼作为第一代ALK抑制剂，长期霸占ROS1阳性晚期NSCLC一线治疗推荐，疗效已经充分验证；2020年的一项大型多中心回顾性研究显示克唑替尼一线治疗ROS1重排晚期NSCLC患者的疗效(一线占比100%) ：中位PFS达23个月，中位OS达60个月。克唑替尼效果很好，但未满足临床需求仍然存在，急需新一代ROS1抑制剂补位。目前针对ROS1阳性非小细胞癌患者，特别是其中超过三分之一的患者发生脑转移，以及超过一半以上的患者进展至耐药突变，目前这部分患者治疗选择有限。 BMS/再鼎医药的瑞普替尼是其中一个选择，其二期研究显示其治疗初治患者mPFS达35.7个月，优于NCCN指南中两个一线推荐方案恩曲替尼和克唑替尼。 Nuvation Bio（葆元医药）的他雷替尼是新一代ROS1抑制剂中的潜在Best in class。他雷替尼在国内的获批、FDA优先审评及NDA受理是基于两项II期研究（TRUST-I和TRUST-II）的汇总分析结果，TRUST-I是一项中国二期单臂注册临床，主要评估塔雷替尼在未接受过TKI治疗或先前接受过克唑替尼治疗的晚期ROS1阳性NSCLC患者中的疗效；TRUST-II则是一项全球性的扩展试验，扩大人种范围探索他雷替尼的疗效和安全性，而该项试验更探索了他雷替尼在脑转移晚期ROS1阳性NSCLC患者的疗效。 Nuvation Bio的两项关键研究TRUST-I和TRUST-II在ESMO上展示的汇总结果显示，中位PFS达46个月，中位DOR达44个月，接近4年，非头对头数据对比下优于瑞普替尼的34个月DOR和36个月PFS，堪称同类最佳。安全性层面，他雷替尼延续了在2023 ESMO大会上公布的结果，三级以上的不良事件包括：观察到一些AST和ALT升高（肝功能指标，8-10%），胃肠道相关事件（1-2%）。29%的患者因治疗相关不良事件需要减少剂量，6.5%的患者因TEAE停药。对比瑞普替尼29%三级不良事件的发生率，他雷替尼安全性潜力更大。基于他雷替尼在ROS1阳性NSCLC初治患者中长达近4年的PFS及良好的耐受性，Jefferies测算他雷替尼销售峰值可能超过10亿美元。而这样的销售预测，不仅源于ROS1阳性NSCLC患者在他雷替尼治疗下的长生存期，并且基于第一代ROS1药物过去在该领域大约5亿美元的年销售额、BMS/再鼎医药的瑞普替尼6-8亿美元销售峰值预测（初治患者36个月PFS）。 02 IDH1的新故事 ROS1之后，Nuvation Bio下一个催化也源自于合并的葆元医药，其mIDH1抑制剂正在进行一项针对2级和3级IDH1突变神经胶质瘤患者的全球临床二期。 IDH1是参与三羧酸循环的重要酶，IDH1基因突变会导致细胞内促癌的代谢产物a-羟戊二酸的增加，已有大量研究证实其突变与多种肿瘤的发生、发展、转移和预后有密切关系。证据显示，目前IDH1突变率高且全球主要开发的肿瘤适应症分别为胶质瘤、IDH突变的急性髓系白血病（AML）和IDH1突变的分化软骨肉瘤。对于Nuvation Bio来说，IDH1抑制剂的故事可能会比ROS1更性感。据Jefferies数据显示，带IDH1突变的胶质瘤在美国有1.3~1.8万名患者，而ROS1阳性的晚期NSCLC患者仅有2~4千名患者。目前全球已获批的IDH1靶向药物有三款，艾伏尼布、Olutasidenib均获批用于治疗IDH1突变AML患者，而施雅维的IDH1/2抑制剂Vorasidenib是FDA批准的首个且唯一一款用于治疗IDH突变2级胶质瘤的靶向药物，于2024年8获批。 Vorasidenib在针对治疗带IDH1/2突变二级胶质瘤患者的INDIGO三期研究数据显示，Vorasidenib组和安慰剂组的中位PFS分别为27.7个月、11.1个月，展现出了较为显著的疗效。安全层面，Vorasidenib组和安慰剂组≥3级不良反应的发生率分别为22.8%和13.5%，其中Vorasidenib组患者肝损伤指标升高、腹泻等患者比例显著高于安慰剂组；Vorasidenib组治疗和安慰剂组停止、剂量减少和剂量中断的不良事件发生率分别为6.3% vs 1.2%、10.8% vs 3.1%和29.9% vs 22.7%。 Nuvation Bio的mIDH1抑制剂Safusidenib，有望向Vorasidenib发起冲击。Safusidenib一项针对胶质瘤患者的一期临床数据显示（入组患者范围在2~4级胶质瘤），在12例非强化胶质瘤患者和35例强化胶质瘤患者中，非强化和强化患者的客观缓解率（ORR）分别为33%和17%。尽管Safusidenib的早期数据ORR对比Vorasidenib同期临床有所逊色，但Safusidenib如果能在2级脑胶质瘤后更晚期患者做出优异疗效，在进军Vorasidenib的领地也是一个不错的策略。 03 一款好药物，会获得市场正向回馈在海外市场，我们可以看到不少随着自身核心产品商业化逐渐放量，市值节节攀升的Biotech公司，其背后均有与国内公司合作的影子。比如在眼科领域， Tarsus Pharmaceuticals治疗蠕形螨性睑缘炎的XDEMVY滴眼液在2023年7月获得FDA批准， 2024年前三个季度的销售额分别为2470万美元、4080万美元、4500万美元，不断超出市场预期，公司股价年内涨幅远超1倍。该药的大中华区权益在2024年3月，被远大医药花费1500万美元引进。在呼吸疾病领域，维罗纳制药的慢性肺阻塞吸入式新药Ensifentrine在2024年6月底获得FDA的批准，这是近十几年来首个COPD新药。该药在2024Q3正式商业化，首个季度销售560万美元（超出市场200万美元预期），另外在近期外资机构的市场调研中发现该药物在Q4的使用量攀升（预计2024Q4销售可能达到1700万美元），并且有望在2025年进一步加速，这为该药冲击10-15亿美元销售峰值提供了强劲的支持。维罗纳制药的股价在2024年6月以来上涨了2.7倍，另外2021年6月，优锐医药以2500美元首付和自身母公司1500万美元的股权引入了Ensifentrine大中华区权益。上述两个案例在海外并不罕见，比较经典的例子还有华东医药合作伙伴Arcutis Biotherapeutics、Kiniksa Pharmaceuticals，分别凭借着特应性皮炎&银屑病创新制剂、复发性心包炎新药商业化放量带动了自身市值的持续上涨。未来或许更加值得期待的是像康方生物和Summit这样的合作案例，海外Biotech凭借国产分子的临床进展和商业化推动其市场价值不断兑现，那么Nuvation Bio会是全新的例子吗？结语：或许投资者应该深刻意识到，尽然国内支付端体系不够完善无法完全支持国产创新药兑现其蕴含的所有价值，但从近年来日益井喷的出海事件能够看出，国产创新药正在支棱起来，未来通过出海仍有大量的机会，无论是中国资本市场，还是海外。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

优先审批并购上市批准申请上市临床结果

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. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial [published correction appears in Lancet Haematol. 2023 Jan;10(1):e9]. Lancet Haematol. 2023;10(1):e46-e58. doi:10.1016/S2352-3026(22)00292-7 【3】Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023;389(7):589-601. doi:10.1056/NEJMoa2304194 【4】Kilburn LB, Khuong-Quang DA, Hansford JR, et al. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med. Published online November 17, 2023. doi:10.1038/s41591-023-02668-y 【5】Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20):5562-5571. doi:10.1158/1078-0432.CCR-12-1773 【6】Natsume A, Arakawa Y, Narita Y, et al. The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas. Neuro Oncol. 2023;25(2):326-336. doi:10.1093/neuonc/noac155 【7】Mellinghoff IK, Lu M, Wen PY, et al. Vorasidenib and Ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial [published correction appears in Nat Med. 2023 Jul 3;:]. Nat Med. 2023;29(3):615-622. doi:10.1038/s41591-022-02141-2 【8】Di Stefano AL, Fucci A, Frattini V, et al. Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma. Clin Cancer Res. 2015;21(14):3307-3317. doi:10.1158/1078-0432.CCR-14-2199 【9】Wang Y, Liang D, Chen J, et al. Targeted Therapy with Anlotinib for a Patient with an Oncogenic FGFR3-TACC3 Fusion and Recurrent Glioblastoma. Oncologist. 2021;26(3):173-177. doi:10.1002/onco.13530 【10】Liu R, Wei W, Hou H, Cong P, Zhou Y, Yu X. Case Report: Targeted Therapy with Anlotinib for a Rare Case of Spinal Cord Glioblastoma with FGFR3 Mutation. Onco Targets Ther. 2022;15:771-776. Published 2022 Jul 11. doi:10.2147/OTT.S362185. 【11】Picca A, Sansone G, Santonocito OS, Mazzanti CM, Sanson M, Di Stefano AL. Diffuse Gliomas with FGFR3-TACC3 Fusions: Oncogenic Mechanisms, Hallmarks, and Therapeutic Perspectives. Cancers (Basel). 2023;15(23):5555. Published 2023 Nov 23. doi:10.3390/cancers15235555 【12】Lassman AB, Sepúlveda-Sánchez JM, Cloughesy TF, et al. Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study. Clin Cancer Res. 2022;28(11):2270-2277. doi:10.1158/1078-0432.CCR-21-2664 【13】Pant S, Schuler M, Iyer G, et al. Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study. Lancet Oncol. 2023;24(8):925-935. doi:10.1016/S1470-2045(23)00275-9 【14】Spanggaard, I.; Matrana, M.; Rocha-Lima, C.; Mahipal, A.; Vieito, M.; Hervieu, A.; Ahn, M.-J.; Goyal, L.; Ahnert, J.R.; Veronese, L.;et al. Pemigatinib For Previously Treated Central Nervous System Tumors With Activating FGFR Mutations or Translocations: Results From FIGHT-207 (S17.004). Neurology 2023, 100, 4218. 【15】Farouk Sait S, Gilheeney SW, Bale TA, et al. Debio1347, an Oral FGFR Inhibitor: Results From a Single-Center Study in Pediatric Patients With Recurrent or Refractory FGFR-Altered Gliomas. JCO Precis Oncol. 2021;5:PO.20.00444. Published 2021 May 20. doi:10.1200/PO.20.00444 【16】Lasorella A, Sanson M, Iavarone A. FGFR-TACC gene fusions in human glioma. Neuro Oncol. 2017;19(4):475-483. doi:10.1093/neuonc/now240 【17】McDonald MF, Athukuri P, Anand A, et al. Varied histomorphology and clinical outcomes of FGFR3-TACC3 fusion gliomas. Neurosurg Focus. 2022;53(6):E16. doi:10.3171/2022.9.FOCUS22420 【18】Zhang K N , Zhao Z , Chen J ,et al.MET fusions and splicing variants convergently define a subgroup of glioma sensitive to MET inhibitors[J].Holistic Integrative Oncology, 2022, 1.DOI:10.1007/s44178-022-00014-9. 【19】Desai AV, Robinson GW, Gauvain K, et al. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. 2022;24(10):1776-1789. doi:10.1093/neuonc/noac087 【20】Bouffet E, Larouche V, Campbell BB, et al. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol. 2016;34(19):2206-2211. doi:10.1200/JCO.2016.66.6552 【21】AlHarbi M, Ali Mobark N, AlMubarak L, et al. Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency. Oncologist. 2018;23(12):1401-1406. doi:10.1634/theoncologist.2018-0163 【22】Cacciotti C, Choi J, Alexandrescu S, et al. Immune checkpoint inhibition for pediatric patients with recurrent/refractory CNS tumors: a single institution experience. J Neurooncol. 2020;149(1):113-122. doi:10.1007/s11060-020-03578-6 【23】Schreck KC, Langat P, Bhave VM, et al. Integrated molecular and clinical analysis of BRAF-mutant glioma in adults. NPJ Precis Oncol. 2023;7(1):23. Published 2023 Feb 28. doi:10.1038/s41698-023-00359-y 【24】Torre M, Vasudevaraja V, Serrano J, et al. Molecular and clinicopathologic features of gliomas harboring NTRK fusions. Acta Neuropathol Commun. 2020;8(1):107. Published 2020 Jul 14. doi:10.1186/s40478-020-00980-z 【25】Gambella A, Senetta R, Collemi G, et al. NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target. Int J Mol Sci. 2020;21(3):753. Published 2020 Jan 23. doi:10.3390/ijms21030753 【26】Westphalen CB, Krebs MG, Le Tourneau C, et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population [published correction appears in NPJ Precis Oncol. 2021 Sep 17;5(1):86]. NPJ Precis Oncol. 2021;5(1):69. Published 2021 Jul 20. doi:10.1038/s41698-021-00206-y 【27】Fangusaro J, Onar-Thomas A, Young Poussaint T, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20(7):1011-1022. doi:10.1016/S1470-2045(19)30277-3 【28】Brown NF, Carter T, Kitchen N, Mulholland P. Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol. 2017;6(4):291-296. doi:10.2217/cns-2017-0006 【29】Marks AM, Bindra RS, DiLuna ML, et al. Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib. Pediatr Blood Cancer. 2018;65(5):e26969. doi:10.1002/pbc.26969 【30】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 【31】Hou Z, Wu H, Luo N, et al. Almonertinib Combined with Anlotinib and Temozolomide in a Patient with Recurrent Glioblastoma with EGFR L858R Mutation. Oncologist. 2023;28(5):449-452. doi:10.1093/oncolo/oyac280 【32】Neyns B, Sadones J, Joosens E, et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol. 2009;20(9):1596-1603. doi:10.1093/annonc/mdp032 【33】Bagchi A, Orr BA, Campagne O, et al. Lorlatinib in a Child with ALK-Fusion-Positive High-Grade Glioma. N Engl J Med. 2021;385(8):761-763. doi:10.1056/NEJMc2101264 【34】Lai M, Li S, Li H, et al. Lorlatinib for ALK-fused, infant-type hemispheric glioma with lung metastasis: a case report. 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

2024-05-14

·BioSpace

Nuvation Bio Reports First Quarter 2024 Financial Results and Provides Business Update

Acquisition of AnHeart Therapeutics transformed Nuvation Bio into a late-stage, global oncology company with potential to become a commercial organization by the end of 2025 Updated data from the pivotal Phase 2 TRUST-I clinical study of taletrectinib, a ROS1 inhibitor, to be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting First patient treated in a Phase 1/2 study of NUV-1511, the company’s first drug-drug conjugate (DDC) to enter the clinic, for the treatment of various advanced solid tumors Strong balance sheet with cash, cash equivalents, and marketable securities of $597.0 million as of March 31, 2024 NEW YORK--(BUSINESS WIRE)-- Nuvation Bio Inc. (NYSE: NUVB), a late-stage, global biopharmaceutical company tackling some of the greatest unmet needs in oncology by developing differentiated and novel therapeutic candidates, today reported financial results for the first quarter ended March 31, 2024, and provided a business update. “The first quarter of 2024 included multiple significant events for Nuvation Bio. We announced and subsequently completed the acquisition of AnHeart Therapeutics, which transformed Nuvation Bio into a late-stage, global company developing multiple clinical programs for some of the most difficult-to-treat cancers. We also treated the first patient in a Phase 1/2 study of NUV-1511, our first DDC to enter the clinic,” said David Hung, M.D., Founder, President, and Chief Executive Officer of Nuvation Bio. “With our robust cash balance and the recent appointment of Colleen Sjogren as our Chief Commercial Officer, along with some new key hires and the integration of new colleagues from AnHeart, we are thoughtfully scaling our organization to execute on our goal of potentially becoming a commercial organization by the end of 2025, while continuing to advance multiple internal programs in various stages of preclinical and clinical development.” Recent Pipeline Updates: Taletrectinib, ROS1 inhibitor: Advanced ROS1-positive non-small cell lung cancer (NSCLC) Taletrectinib is being evaluated for the treatment of patients with advanced ROS1-positive NSCLC in two Phase 2 single-arm pivotal studies: TRUST-I in China, and TRUST-II, a global study. Updated data from the Phase 2 TRUST-I clinical study (NCT04395677) evaluating taletrectinib in patients in China with advanced ROS1-positive NSCLC will be reported in an oral presentation (abstract #8520) at the 2024 ASCO Annual Meeting on Saturday, June 1, 2024, at 4:30-6:30 p.m. CT/5:30-7:30 p.m. ET. Safusidenib, mIDH1 inhibitor: Grades 2 and 3 IDH1-mutant glioma Safusidenib is being evaluated in a global Phase 2 study for the treatment of patients with grades 2 and 3 IDH1-mutant glioma. NUV-868, BD2-selective BET inhibitor: Advanced solid tumors NUV-868 is being evaluated in a Phase 1b dose escalation study in combination with olaparib for the treatment of patients with ovarian cancer, pancreatic cancer, metastatic castration-resistant prostate cancer (mCRPC), triple negative breast cancer, and other solid tumors, and in combination with enzalutamide for the treatment of patients with mCRPC. NUV-1511, DDC: Advanced solid tumors NUV-1511, the Company’s first clinical-stage DDC, is being evaluated in a Phase 1/2 study for the treatment of patients with advanced solid tumors who previously received and progressed on or after treatment with Enhertu® and/or Trodelvy® per approved U.S. Food and Drug Administration (FDA) labeling, human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, mCRPC, advanced pancreatic cancer, and platinum-resistant ovarian cancer (PROC). Corporate Updates: Announced entry into a definitive agreement to acquire AnHeart Therapeutics in March 2024 and completed the acquisition in April 2024. Appointed Colleen Sjogren as Chief Commercial Officer. Ms. Sjogren will lead Nuvation Bio’s commercial strategy and operations, including marketing, sales, and market access. First Quarter 2024 Financial Results As of March 31, 2024, Nuvation Bio had cash, cash equivalents and marketable securities of $597.0 million. For the three months ended March 31, 2024, research and development expenses were $12.8 million, compared to $18.8 million for the three months ended March 31, 2023. The decrease was primarily due to a $6.7 million decrease in third-party research services and drug manufacturing costs as a result of completing the Phase 1 monotherapy study of NUV-868, offset by a $0.7 million increase in personnel-related costs driven by stock-based compensation and other benefits. For the three months ended March 31, 2024, general and administrative expenses were $7.3 million, compared to $7.7 million for the three months ended March 31, 2023. The decrease was due to a $0.5 million decrease in professional fees, $0.4 million decrease in insurance, and a $0.2 million decrease in personnel-related costs, offset by a $0.4 million increase in legal fees, a $0.2 million increase in occupancy expense, and a $0.1 million increase in miscellaneous expense. For the three months ended March 31, 2024, Nuvation Bio reported a net loss of $14.8 million, or $(0.07) per share. This compares to a net loss of $21.7 million, or $(0.10) per share, for the comparable period in 2023. About Nuvation Bio Nuvation Bio is a late-stage, global biopharmaceutical company tackling some of the greatest unmet needs in oncology by developing differentiated and novel therapeutic candidates. Nuvation Bio’s portfolio of development candidates includes taletrectinib (ROS1), safusidenib (mIDH1), NUV-868 (BET), and NUV-1511 (DDC). Nuvation Bio was founded in 2018 by biopharma industry veteran David Hung, M.D., who previously founded Medivation, Inc., which brought to patients one of the world’s leading prostate cancer medicines. Nuvation Bio has offices in New York, San Francisco, and Shanghai. For more information, please visit and . Forward Looking Statements Certain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” “should,” “would,” “plan,” “predict,” “potential,” “seem,” “seek,” “future,” “outlook” and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, the expected timing of becoming a commercial organization, the potential therapeutic benefit of Nuvation Bio’s product candidates, the potential of the DDC platform, the advancement of our preclinical and clinical programs, and the strength of Nuvation Bio’s balance sheet. These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of the management team of Nuvation Bio and are not predictions of actual performance. These forward-looking statements are subject to a number of risks and uncertainties that may cause actual results to differ from those anticipated by the forward-looking statements, including but not limited to the challenges associated with conducting drug discovery and initiating or conducting clinical studies due to, among other things, difficulties or delays in the regulatory process, enrolling subjects or manufacturing or acquiring necessary products; the emergence or worsening of adverse events or other undesirable side effects; risks associated with preliminary and interim data, which may not be representative of more mature data; and competitive developments. Risks and uncertainties facing Nuvation Bio are described more fully in its Form 10-Q filed with the SEC on May 14, 2024 under the heading “Risk Factors,” and other documents that Nuvation Bio has filed or will the SEC. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date of this press release. Nuvation Bio disclaims any obligation or undertaking to update, supplement or revise any forward-looking statements contained in this press release. NUVATION BIO INC. and Subsidiaries Condensed Balance Sheets Unaudited (In thousands, except share and per share data) March 31, December 31, 2024 2023 Assets Current assets: Cash and cash equivalents $ 34,510 $ 42,649 Prepaid expenses and other current assets 6,796 1,519 Marketable securities 562,466 568,564 Interest receivable on marketable securities 4,283 3,702 Total current assets 608,055 616,434 Property and equipment, net 686 717 Lease security deposit 141 141 Operating lease right-of-use assets 3,168 3,605 Other non-current assets 1,075 587 Total assets $ 613,125 $ 621,484 Liabilities and stockholders' equity Current liabilities: Accounts payable $ 2,436 $ 2,209 Current operating lease liabilities 2,023 1,972 Accrued expenses 11,303 9,793 Total current liabilities 15,762 13,974 Warrant liability 1,812 353 Non-current operating lease liabilities 1,509 2,035 Total liabilities 19,083 16,362 Stockholders' equity Class A and Class B common stock and additional paid in capital, $0.0001 par value per share; 1,060,000,000 (Class A 1,000,000,000, Class B 60,000,000) shares authorized as of March 31, 2024 and December 31, 2023, 219,083,219 (Class A 218,083,219, Class B 1,000,000) and 219,046,219 (Class A 218,046,219, Class B 1,000,000) shares issued and outstanding as of March 31, 2023 and December 31, 2022, respectively 952,807 947,745 Accumulated deficit (357,596 ) (342,804 ) Accumulated other comprehensive (loss) income (1,169 ) 181 Total stockholders' equity 594,042 605,122 Total liabilities and stockholders' equity $ 613,125 $ 621,484 NUVATION BIO INC. and Subsidiaries Condensed Statements of Operations and Comprehensive Loss (In thousands, except per share data) For The Three Months Ended March 31, 2024 2023 Operating expenses: Research and development $ 12,842 $ 18,787 General and administrative 7,357 7,734 Total operating expenses 20,199 26,521 Loss from operations (20,199 ) (26,521 ) Other income (expense): Interest income 7,130 4,979 Investment advisory fees (265 ) (230 ) Change in fair value of warrant liability (1,459 ) 142 Net gain (loss) on marketable securities 1 (96 ) Total other income (expense), net 5,407 4,795 Loss before income taxes (14,792 ) (21,726 ) Provision for income taxes — — Net loss $ (14,792 ) $ (21,726 ) Net loss per share attributable to common stockholders, basic and diluted $ (0.07 ) $ (0.10 ) Weighted average common shares outstanding, basic and diluted 219,048 218,741 Comprehensive loss: Net loss $ (14,792 ) $ (21,726 ) Other comprehensive loss, net of taxes: Change in unrealized (loss) gain on available-for-sale securities, net (1,350 ) 2,588 Comprehensive loss $ (16,142 ) $ (19,138 )

临床1期临床2期财报并购ASCO会议

100 项与 Safusidenib 相关的药物交易

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研发状态

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
IDH1突变胶质瘤	临床2期	美国	Nuvation Bio, Inc.	2023-06-05
WHO II级胶质瘤	临床2期	日本	Daiichi Sankyo Co., Ltd.	2020-07-08
IDH1突变的胆管癌	临床1期	中国	葆元生物医药科技（杭州）有限公司初创企业	2023-04-19
IDH1突变的胆管癌	临床1期	中国	上海合全医药有限公司	2023-04-19
IDH1阳性实体瘤	临床1期	中国	上海合全医药有限公司	2023-04-19
IDH1阳性实体瘤	临床1期	中国	葆元生物医药科技（杭州）有限公司初创企业	2023-04-19
胆管癌	临床1期	-	葆元生物医药科技（杭州）有限公司初创企业	2022-03-21

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临床结果

适应症

分期

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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


CTNI-15 (SNO2024)	N/A	IDH1突变胶质瘤 2-HG	10	Safusidenib 250 mg BID	範艱築齋範積衊顧繭鏇(膚鏇齋夢選願膚鑰簾衊) = 築廠艱繭繭繭襯蓋積淵範顧艱簾願蓋積齋範構 (夢窪醖選構獵築選淵艱 ) 更多	积极	2024-11-11
NCT05577416 (Part A, ESMO2024)	早期临床1期	IDH1突变胶质瘤 2-HG	10	Safusidenib	選衊遞淵獵觸憲選壓糧(廠鏇顧壓網願範壓範觸) = 淵憲簾鏇壓獵鑰襯壓構構選顧鹽齋構廠鏇醖鹹 (齋糧顧憲鏇繭衊壓醖夢 )	积极	2024-09-13
NCT03030066 (Pubmed) 人工标引	临床1期	胶质瘤 IDH1 Mutation	47	DS-1001 (enhancing tumors)	鬱鹽醖蓋顧糧鏇夢鏇積(積範夢繭夢膚鏇獵獵獵) = not reached 艱範鏇獵衊鏇選觸蓋鏇 (製齋夢壓選醖願鬱願築 )	积极	2022-06-20
NCT03030066 (Pubmed) 人工标引	临床1期	胶质瘤 IDH1 Mutation	47	DS-1001 (non-enhancing tumors)		积极	2022-06-20
NCT03030066 (ESMO2019)	临床1期	胶质瘤	47	DS-1001b	積醖衊醖積簾衊築鹽廠(餘鏇構衊鹹製築膚觸築) = 網夢膚餘積糧鏇願遞範鑰夢網範繭餘範願膚廠 (製鑰蓋鑰簾獵築鑰壓鹽 )	-	2019-09-28