A Phase 1 Study of Combination Tovorafenib (DAY101) and Rituximab Treatment in Relapsed or Refractory Classical Hairy Cell Leukemia and Phase 2 Randomized Study Comparing Tovorafenib (DAY101) and Rituximab With Cladribine and Rituximab for Front-Line Treatment of Classical Hairy Cell Leukemia

This phase I/II trial tests the safety, side effects, and effectiveness of tovorafenib in combination with rituximab in patients with classical hairy cell leukemia (cHCL) that has come back after a period of improvement (recurrent) or that has not responded to previous treatment (refractory) and compares the effect of tovorafenib and rituximab to current standard treatment of cladribine and rituximab in cHCL patients that have not yet received treatment. Tovorafenib blocks certain proteins made by the mutated BRAF gene, which may help keep cancer cells from growing. It is a type of kinase inhibitor. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Cladribine damages the cell's deoxyribonucleic acid and may kill cancer cells. It is a type of antimetabolite. Giving tovorafenib in combination with rituximab may be safe and tolerable and more effective than cladribine with rituximab in treating patients with untreated, recurrent or refractory cHCL.

开始日期2026-06-27

申办/合作机构

National Cancer Institute

NCT07206849

/ Not yet recruiting临床2期IIT

A Phase 2 Study of Tovorafenib in Pediatric and Young Adult Patients Newly Diagnosed With High-Grade Glioma (HGG), Including Diffuse Intrinsic Pontine Glioma (DIPG), Which Harbor Alterations in the Mitogen-Activated Protein Kinase (MAPK) Pathway

The goal of this study is to determine the efficacy of the study drugs tovorafenib to treat pediatric and young adult patients newly diagnosed with a high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (MAPK) that this drug targets.
The main question the study aims to answer is whether tovorafenib can prolong the life of patients diagnosed with HGG, including DIPG.

开始日期2026-05-01

申办/合作机构

Nationwide Children's Hospital

[+1]

CTIS2024-516896-34-00

/ Not yet recruiting临床1/2期IIT

Phase I/II combination umbrella trial in progressive/relapsed/refractory pediatric low-grade glioma (pLGG) (EPILOGUE)

开始日期2026-02-28

申办/合作机构

Universitätsklinikum Heidelberg

100 项与 Tovorafenib 相关的临床结果

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100 项与 Tovorafenib 相关的转化医学

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100 项与 Tovorafenib 相关的专利（医药）

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项与 Tovorafenib 相关的文献（医药）

2026-06-01·CURRENT THERAPEUTIC RESEARCH-CLINICAL AND EXPERIMENTAL

Understanding Pharmacokinetic-Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2024 to Better Manage the Risk of Drug Interactions With Concomitant Medications: A Review of Clinical Data From New Drug Applications

Review

作者: Owens, Katie ; Argon, Sophie ; Yu, Jingjing ; Ragueneau-Majlessi, Isabelle ; Wang, Yan

Objective:

This analysis aimed to provide a mechanistic understanding and an evaluation of the clinical relevance of pharmacokinetic drug-drug interactions (DDIs) associated with drugs approved by the Food and Drug Administration in 2024.

Methods:

Drug metabolism, transport, and absorption-based DDI data available in New Drug Applications (NDAs) of small molecular drugs approved (n = 34) was analyzed. The mechanism and clinical outcome of these interactions were characterized based on in vitro, in silico, and clinical data.

Results:

As objects, 11 drugs were identified as clinical substrates. Of these, 7 drugs were substrates of CYP3A, 3 of CYP2C9, one of CYP1A2, and one of CYP2C8, including the sensitive substrates vanzacaftor (CYP3A) and vorasidenib (CYP1A2). As precipitants, 6 drugs (acoramidis, cefepime/enmetazobactam, givinostat, lazertinib, mavorixafor, and resmetirom) were clinical inhibitors of CYP enzymes (2C8, 2C9, 2D6, 2E1, and 3A), with mavorixafor being a CYP2D6 strong inhibitor. Two drugs (elafibranor and tovorafenib) showed weak induction of CYP3A. Regarding transporter data, 3 drugs were substrates of transporters, including seladelpar (BCRP and OAT3), sulopenem (OAT3), and vadadustat (OAT1/3), and 8 drugs (arimoclomol, danicopan, givinostat, lazertinib, mavorixafor, resmetirom, vadadustat, and vazacaftor/tezacaftor/deutivacaftor) were inhibitors of transporters. All clinical DDIs with AUC changes ≥ 2-fold triggered labeling recommendations. Several DDIs with an AUC change <2 also had labeling recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index.

Conclusions:

Mechanistic DDI insights from newly approved therapies can be extrapolated to inform the management of commonly co-administered drugs, supporting a safer and more effective use of new drug products in the context of polypharmacy.

2025-12-26·Neuro-Oncology Practice

Clinical experience with tovorafenib in adults with treatment-refractory high- and low-grade gliomas

Article

作者: Devkota, Anirudra ; Welch, Mary R ; Schreck, Karisa C ; Bagley, Stephen J ; Ioannou, Maria ; Holdhoff, Matthias ; Justin, Jordan T ; Ozer, Byram H ; Mehta, Setu ; Romo, Carlos G

Abstract:

Background:

BRAF alterations are common in pediatric low-grade gliomas (LGG) and a subset of high-grade gliomas (HGG) in adults and children. BRAF-targeted therapy can be effective at preventing tumor growth, though resistance commonly emerges in HGG. Recently, tovorafenib was FDA approved for recurrent or refractory LGG with BRAFV600 alterations or BRAF rearrangements. While the trial showed it is effective for children with LGG previously treated with BRAF or MEK inhibitors, the safety in adults and efficacy in HGG is unknown.

Methods:

A cohort of appropriate patients was identified through routine clinical care. This research was conducted in accordance with IRB regulations with a waiver of written consent.

Results:

Seven adults (5 HGG, 2 LGG) who received tovorafenib were identified. All patients had received prior BRAF-targeted therapy, and all patients with HGG had received prior radiation and temozolomide as well. Three individuals (2 HGG, 1 LGG) experienced stable disease or better for 4 or more months. Median duration of treatment was 8 weeks (range 3 weeks to 10 months). Two individuals experienced CTCAE grade 4 intratumoral hemorrhage (1 HGG, 1 LGG). Two patients remain on therapy at 4 and 10 months of treatment (1 HGG, 1 LGG).

Conclusion:

Our experience with tovorafenib indicates some limited efficacy in HGG in combination with other standard treatments. These observations demonstrate the need for further clinical trials in patients with HGG to understand potential clinical utility, either earlier in the disease course or in combination with other therapies.

2025-12-01·COMPUTATIONAL BIOLOGY AND CHEMISTRY

Identification of different lung adenocarcinoma subtypes in combination with antidiuretic hormone-related genes and creation of an associated index to predict prognosis and guide immunotherapy

Article

作者: Dai, Hong ; Lv, Yuankai ; Zheng, Hao ; Cai, Xiaoping

BACKGROUND:

Lung adenocarcinoma (LUAD) is one of the most aggressive and rapidly lethal tumor types. Previous studies have demonstrated the involvement of antidiuretic hormone (ADH)-related genes in cancer. However, the role of ADH-related genes in LUAD remains unclear. Therefore, investigating the characteristics of these genes in LUAD is essential.

METHODS:

Differentially expressed genes (DEGs) associated with ADH in LUAD were identified using the STRING database. Consensus clustering was performed, and a protein-protein interaction network was constructed for the DEGs between subtypes. Genes extracted from the PPI network underwent univariate, LASSO, and multivariate Cox regression analyses to develop a predictive model for LUAD. A nomogram integrating clinical data and risk scores was created, and its prognostic power for overall survival (OS) in LUAD patients was evaluated. Additionally, LUAD patients were analyzed for targeted therapies, immune landscape, functional enrichment, and mutation profiles. Finally, qRT-PCR was used to examine the expression of signature genes in LUAD cells.

RESULTS:

Based on ADH-related DEGs, LUAD patients were stratified into two clusters (Cluster 1 and Cluster 2) with distinct survival outcomes. A predictive model incorporating nine feature genes was subsequently constructed using DEGs from these two subtypes. The receiver operating characteristic curve demonstrated the model's prognostic accuracy in predicting OS in LUAD patients. Compared to the high-risk group, patients in the low-risk group exhibited higher immune infiltration levels and immunophenoscore, along with lower tumor immune dysfunction and exclusion scores. Enrichment analysis revealed that immune response pathways and ligand-receptor interactions were the primary functional categories distinguishing the high- and low-risk groups. The low-risk group showed a significantly lower gene mutation burden. Drug sensitivity analysis identified several potential targeted therapies, including Dabrafenib, ARQ-680, Vemurafenib, BGB-283, MLN-2480, and GDC-0994, which might act on hub genes. qRT-PCR validation confirmed that DNAH12 was significantly downregulated in tumor tissues, while DKK1, DLX2, IGFBP1, NTSR1, RPE65, and VGF were markedly upregulated.

CONCLUSION:

This study provided potential prognostic biomarkers for LUAD and might facilitate the development of effective immunotherapy strategies for LUAD patients.

248

项与 Tovorafenib 相关的新闻（医药）

2026-04-02

·allsci.com

Fore Bio’s plixorafenib receives FDA Breakthrough Therapy status for BRAF-mutated glioma

Fore Biotherapeutics, a registration-stage oncology company headquartered in Philadelphia, Pennsylvania, announced that the FDA has granted Breakthrough Therapy Designation (BTD) to plixorafenib (FORE8394), a BRAF-targeted small-molecule kinase inhibitor functioning as both a dimer and paradox breaker, for the treatment of adult patients with BRAF V600E-mutated high-grade glioma (HGG). The company describes this as the first BTD awarded to a targeted therapy for HGG. The designation adds to previously received Fast Track Designation for BRAF Class 1 and Class 2 alterations and Orphan Drug Designation (ODD) for primary brain and central nervous system (CNS) malignancies, and confers more frequent FDA engagement, senior reviewer involvement, and eligibility for rolling and priority review of a future marketing application. The FDA based its decision on data from approximately 25 patients enrolled across the completed Phase I/IIa clinical trial and the ongoing Phase II FORTE basket study, which evaluates plixorafenib monotherapy across recurrent or progressive BRAF V600 primary CNS tumors — including HGG, low-grade gliomas (LGG), and other primary brain and spinal cord tumors in adults and children. Phase I/IIa results, presented at ASCO 2023 and SNO 2023, showed a 67% overall response rate (ORR) in a pre-specified subgroup of MAPK inhibitor-naive patients with BRAF V600-mutated primary CNS tumors, with a clinical benefit rate (CBR) exceeding 75%. In a broader V600-altered, MAPK inhibitor-naive population, plixorafenib achieved a 42% response rate, a median duration of response (mDOR) of 17.8 months, and a CBR above 70%. The drug-related adverse event discontinuation rate across tumor types was below 2%. Within FORTE, the BRAF V600E CNS basket met its pre-specified interim efficacy analysis in Q3 2025, with the Independent Data Monitoring Committee (IDMC) supporting continuation based on responses assessed by blinded independent central review (BICR). Topline data from the CNS basket are expected by the end of 2026, and Fore has stated that a positive primary analysis would support a New Drug Application (NDA) submission under the Accelerated Approval pathway. The FORTE Master Protocol is a global Phase II registration-intended trial operating under a Bayesian adaptive design, with four sub-protocol baskets covering recurrent or progressive BRAF V600 primary CNS tumors, solid tumors with BRAF fusions, and rare BRAF V600-mutated solid tumors. Approved BRAF inhibitors — including vemurafenib, dabrafenib, and encorafenib — were developed primarily for melanoma and carry a class liability: paradoxical MAPK pathway activation in cells with wild-type BRAF or RAS mutations, which can drive tumor growth and necessitates co-administration of a MEK inhibitor to suppress this effect. That combination requirement introduces additional toxicity and, in CNS tumors, may be complicated by differential blood-brain barrier penetration between agents. Plixorafenib is engineered to address both limitations. Its dimer-breaking mechanism disrupts the BRAF dimerization that underlies paradoxical activation, and its paradox-breaker profile allows monotherapy use without the MEK inhibitor dependency that characterizes earlier-generation BRAF inhibitors. Whether this translates to more durable responses in HGG — where rapid resistance emergence has limited prior BRAF-targeted approaches — remains to be established from the full FORTE dataset. The competitive landscape in BRAF-mutated CNS tumors is evolving. Dabrafenib plus trametinib received FDA approval in 2022 for BRAF V600E-mutated low-grade glioma in pediatric patients aged 1 year and older, but HGG in adults lacks an approved targeted option in the BRAF-altered setting. Tovorafenib (DAY101), a RAF inhibitor developed by Day One Biopharmaceuticals, received FDA approval in 2024 for pediatric low-grade glioma with BRAF alterations, further establishing BRAF as a validated target in CNS oncology — though again in a distinct population and histologic grade from plixorafenib’s current BTD indication. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website

临床结果孤儿药上市批准快速通道临床2期

2026-03-22

·头颈健康之声

2025-2026肿瘤进展年度盘点——儿童肿瘤

点击蓝字关注我们 2025-2026 肿瘤进展年度盘点儿童肿瘤摘要 2025年至2026年初是儿童肿瘤学历史上具有里程碑意义的时期。这一阶段的特点是从传统的细胞毒性化疗向分子靶向治疗和免疫治疗的决定性转变，标志着精准医学从理论探索走向了大规模临床应用的标准护理（Standard of Care, SOC）。本综述基于发表于《新英格兰医学杂志》（NEJM）、《柳叶刀》（The Lancet）及其子刊、《临床肿瘤学杂志》（JCO）、《美国医学会杂志》（JAMA）以及《肿瘤学年鉴》（Annals of Oncology）等高影响力SCI期刊的文献，并结合2025年美国临床肿瘤学会（ASCO）、美国血液学会（ASH）和国际儿科肿瘤学会（SIOP）年会的会议报道，全面总结了这一时期的重大研究进展。特别值得关注的是，美国食品药品监督管理局（FDA）在此期间批准了多种针对特定分子改变的“首创”（First-in-class）药物，打破了多个儿科难治性肿瘤数十年无新药可用的僵局。针对H3 K27M突变型弥漫性中线胶质瘤（DMG）的dordaviprone（Modeyso）、针对BRAF改变型低级别胶质瘤的tovorafenib（Ojemda），以及针对KMT2A重排和NPM1突变型急性白血病的revumenib（Revuforj）的获批，不仅改变了临床实践指南，更深刻重塑了我们对肿瘤生物学的理解 1。与此同时，大型合作组试验如COG AALL1731确立了免疫治疗在急性淋巴细胞白血病一线治疗中的地位，而ARST1431在横纹肌肉瘤中的阴性结果则为靶向信号通路的复杂性提供了重要警示 4。本报告将深入剖析这些进展背后的科学机制、临床数据及其对全球儿科肿瘤治疗格局的深远影响。第一章血液系统恶性肿瘤：免疫与靶向治疗的双重革命 2025年的儿科血液肿瘤研究呈现出前所未有的活力。随着双特异性T细胞接合器（BiTEs）、抗体偶联药物（ADCs）和表观遗传修饰剂的成熟，传统的“高强度化疗”范式正在被“高精准度、低长期毒性”的新策略所挑战。 1.1 急性淋巴细胞白血病（ALL）：免疫治疗前移至一线 B细胞急性淋巴细胞白血病（B-ALL）是儿童最常见的恶性肿瘤。尽管总体生存率较高，但复发仍是导致儿童癌症死亡的主要原因之一。2025年的核心议题是如何通过早期干预清除微小残留病（MRD），从而预防复发。 1.1.1 Blinatumomab在一线标准风险B-ALL中的确证性研究（COG AALL1731） 2025年ASH年会及同期《NEJM》发表的COG AALL1731 III期临床试验结果，被誉为近十年来儿科ALL治疗最重要的进展之一。该研究旨在评估将CD19/CD3双特异性T细胞接合器blinatumomab纳入标准化疗骨架，对新诊断的标准风险（SR）B-ALL患儿预后的影响 4。研究背景与机制： Blinatumomab通过双臂结构同时结合白血病细胞表面的CD19抗原和细胞毒性T细胞表面的CD3抗原，在不依赖主要组织相容性复合体（MHC）的情况下激活T细胞，介导穿孔素依赖性的肿瘤细胞裂解。此前，该药物主要用于复发/难治性（R/R）病例或MRD阳性患者。AALL1731试图回答：在预后相对良好的标准风险患者中，早期引入免疫治疗能否进一步降低复发率并减少化疗毒性？关键数据分析： ● 无病生存期（DFS）的显著获益：研究结果显示，在化疗基础上加用blinatumomab显著改善了DFS。在3年随访节点，blinatumomab组的DFS高达96.0%，而仅接受化疗的对照组为87.9% 7。 ● 风险比（Hazard Ratio）：疾病进展或死亡的风险比（HR）为0.39（95% CI），意味着免疫治疗组的风险降低了61%。这一效应值在儿科肿瘤的大型III期试验中极为罕见且具有高度临床意义 8。 ● 复发率的大幅下降：免疫治疗组的复发率被压低至3.3%，显著低于对照组的11.8% 7。 ● 亚组分析：获益在不同亚组中具有一致性，包括不同年龄、基线白细胞计数以及特定的遗传学亚型。特别是在MRD阴性但具有复发风险特征的“标准风险-平均（SR-Average）”和“标准风险-高（SR-High）”亚组中，blinatumomab均显示出优越性 7。临床意义与实践改变： AALL1731的数据支持将blinatumomab作为新诊断B-ALL的标准治疗组成部分，而不仅仅是挽救性治疗。这种“免疫巩固”策略可能通过清除常规化疗无法触及的静止期克隆（Quiescent Clones）来发挥作用。此外，与传统的高强度化疗模块相比，blinatumomab的毒性谱主要集中在细胞因子释放综合征（CRS）和神经毒性，且多为可控，减少了严重感染和长期的器官毒性风险。2025年初对COG成员机构的调查显示，这一方案已在美国迅速普及，成为事实上的新标准 9。 1.1.2 Inotuzumab Ozogamicin在复发/难治性疾病中的应用除了CD19靶点，靶向CD22的抗体偶联药物Inotuzumab Ozogamicin (InO) 在2025年也取得了重要进展。InO通过CD22内吞作用将刺孢霉素（calicheamicin）送入细胞内，导致DNA双链断裂。试验结果综述： ● 在多项II期临床试验中，InO在复发/难治性儿科B-ALL患者中展现了极高的缓解率。汇总数据显示，完全缓解（CR/CRi）率达到约80%，且在应答者中，**66.7%**达到了MRD阴性状态 10。 ● 安全性考量：肝静脉闭塞病（VOD/SOS）仍是InO的主要剂量限制性毒性，特别是在后续进行造血干细胞移植（HSCT）的患者中。2025年的研究数据建议采用分次给药方案（Fractionated Schedule）并限制累积剂量，以在保持疗效的同时降低VOD风险 10。 ● 桥接移植的角色： InO的高MRD阴性率使其成为理想的移植前桥接药物，显著提高了后续移植的成功率和无事件生存期（EFS） 13。 1.2 急性髓系白血病（AML）：Menin抑制剂开启靶向新纪元长期以来，儿科AML的治疗一直依赖于高强度化疗（如阿糖胞苷和蒽环类药物），生存率的提升进入瓶颈期。2025年，随着Menin抑制剂的获批和应用，AML治疗迎来了精准医学的曙光。 1.2.1 Revumenib (Revuforj) 的获批与机制解析 2024年底至2025年，FDA先后批准了首个口服Menin抑制剂revumenib，用于治疗携带**KMT2A重排（KMT2Ar）或NPM1突变（NPM1m）**的复发/难治性急性白血病成人及1岁以上儿童患者 3。分子机制： KMT2A（曾用名MLL）基因重排在婴儿白血病和治疗相关性AML中尤为常见，预后极差。KMT2A融合蛋白需与Menin蛋白结合才能招募染色质修饰复合物，从而上调HOXA9和MEIS1等致白血病基因的表达，维持细胞的未分化状态。Revumenib通过阻断Menin与KMT2A融合蛋白的相互作用，切断了这一致癌转录程序的“电源”，迫使白血病细胞分化为正常的成熟细胞 15。关键临床试验（AUGMENT-101）：该批准基于AUGMENT-101（NCT04065399）这一关键II期临床试验的数据： ● KMT2A重排队列：总缓解率（ORR）达到64%，完全缓解/部分血液学恢复的完全缓解（CR/CRh）率为23-24% 17。 ● NPM1突变队列：在这一亚组中，CR+CRh率为23.1%-26%，中位缓解持续时间为4.7个月 19。 ● 儿科特异性数据：研究证实了revumenib在儿科患者（包括婴儿）中的药代动力学特征与成人相似，且疗效一致，这对于无论是作为移植桥接还是姑息治疗都具有重要意义 16。耐药性与未来方向：尽管疗效显著，但单药治疗的耐药性问题已在临床中浮现，主要机制包括MEN1基因的继发突变。因此，2025年的研究重点已迅速转向联合治疗。 ● 联合策略：在ASH 2025上展示的SAVE试验结果表明，revumenib联合维奈克拉（Venetoclax）和地西他滨/西达本胺（decitabine/cedazuridine）在复发/难治性AML中实现了高达**88%**的ORR 17。 ● 新靶点协同： Cancer Discovery发表的一项研究揭示，对于预后极差的NUP98重排儿科AML，联合抑制Menin和KAT6A/7组蛋白乙酰转移酶复合物可产生协同致死效应，即使在对Menin抑制剂耐药的细胞中也有效。这为下一代联合方案提供了强有力的临床前证据 21。 1.3 慢性髓系白血病（CML）：Asciminib的儿科应用尽管CML在儿童中罕见，但通过ASC4KIDS研究，Asciminib在2025年确立了其在儿科CML中的地位。这是一种变构BCR-ABL1抑制剂，特异性结合激酶的肉豆蔻酰口袋（STAMP机制），而非传统的ATP结合位点。 ● 优势：该机制避免了传统TKI（如伊马替尼、达沙替尼）常见的脱靶毒性，对于处于生长发育期的儿童尤为重要。数据显示其安全性良好，且能有效克服部分ATP位点突变导致的耐药 22。第二章中枢神经系统（CNS）肿瘤：攻克不可治愈之症儿科神经肿瘤学在2025-2026年取得了突破性进展，尤其是针对弥漫性中线胶质瘤（DMG）和低级别胶质瘤（LGG），多种能够穿透血脑屏障（BBB）的靶向药物获得了监管部门的批准。 2.1 弥漫性中线胶质瘤（DMG）：从绝望到希望 DMG（包括DIPG）长期以来被视为儿科肿瘤中的“绝症”，中位生存期不足一年，且缺乏有效的系统性治疗。H3 K27M突变是其核心驱动因素，导致全基因组H3K27三甲基化（H3K27me3）缺失和表观遗传失调。 2.1.1 Dordaviprone (Modeyso) 的历史性获批 2025年8月6日，FDA加速批准dordaviprone（前称ONC201）用于治疗携带H3 K27M突变的复发性DMG成人及儿童患者 1。这是人类历史上首个获批用于该致死性疾病的系统性疗法。作用机制深度解析： Dordaviprone的作用机制独特且复杂。作为DRD2（多巴胺受体D2）拮抗剂和ClpP（线粒体酪蛋白水解酶P）激动剂，它通过诱导线粒体应激反应（Integrated Stress Response, ISR），能够部分逆转H3 K27M突变导致的表观遗传沉默，恢复H3K27me3水平，并抑制肿瘤代谢 24。临床数据支撑： ● 生存获益：基于多项临床试验和扩展使用项目（Expanded Access Programs）的综合分析，dordaviprone治疗组的中位总生存期（OS）延长至约22个月，显著优于历史对照的约12个月 24。 ● 缓解率：综合客观缓解率（ORR）约为22%。虽然这一数字看似不高，但在一种自然病程为快速进展死亡的疾病中，能够实现病灶缩小和长期疾病稳定（Stable Disease）已是巨大的突破 25。 ● 指南更新：该药迅速被纳入NCCN指南，作为H3 K27M突变型DMG的2A类推荐治疗 26。目前，确认性III期临床试验ACTION正在进行中，以进一步验证其长期生存获益。 2.1.2 GD2靶向CAR-T细胞治疗除了小分子药物，细胞治疗在CNS肿瘤中也取得了惊人进展。斯坦福大学团队在《Nature》上发表的数据显示，GD2靶向CAR-T细胞在H3K27M突变型DMG中展现了强大的抗肿瘤活性 27。 ● 给药途径创新：试验采用静脉输注（IV）联合脑室内注射（ICV）的策略，以克服血脑屏障并增强局部免疫效应。 ● 疗效：在11名可评估患者中，9名观察到了影像学缓解，部分患者肿瘤体积缩小超过50%甚至接近消失 27。 ● 转化研究见解：通过对脑脊液的单细胞RNA测序分析，研究人员发现CAR-T细胞的输注诱导了广泛的免疫微环境重塑。治疗失败主要归因于CAR-T细胞的耗竭以及抑制性髓系细胞的代偿性扩增，这为下一代抗耗竭CAR-T的设计指明了方向 29。 2.2 儿童低级别胶质瘤（pLGG）：MAPK通路的全面封锁 pLGG是儿童最常见的脑肿瘤，其发生发展高度依赖于MAPK/ERK信号通路的异常激活，最常见的分子改变是BRAF融合（如KIAA1549-BRAF）和BRAF V600E突变。 2.2.1 Tovorafenib (Ojemda) 的标准确立继2024年4月获得加速批准后，2025年公布的FIREFLY-1试验更新数据进一步巩固了tovorafenib作为复发/难治性BRAF改变型pLGG标准治疗的地位 2。药物特性与数据： ● 广谱抑制： Tovorafenib是一种II型RAF抑制剂，其独特之处在于能同时抑制单体和二聚体BRAF。这一点至关重要，因为第一代抑制剂（如威罗菲尼）无法有效抑制BRAF融合蛋白形成的二聚体，甚至可能因反常激活（Paradoxical Activation）导致肿瘤生长。 ● 疗效数据：更新数据显示，独立审查委员会评估的ORR达到51%-53%（基于RANO或RAPNO标准）。更为关键的是，中位缓解持续时间（DOR）为13.8个月，中位至下一次治疗时间（TTNT）长达42.6个月 30。 ● 安全性：主要不良反应为皮肤毒性（皮疹）和头发颜色改变，相比于卡铂/长春新碱等化疗方案，其对骨髓和神经系统的毒性极低，极大地改善了患儿的生活质量。 2.2.2 Vorasidenib在IDH突变型胶质瘤中的应用对于年龄较大的青少年患者，IDH1/2突变型胶质瘤是重要的亚型。INDIGO III期试验表明，脑渗透性IDH抑制剂vorasidenib能显著延长无进展生存期（PFS），从安慰剂组的11.1个月提升至27.7个月 33。这使得“观察等待”（Watch-and-wait）策略被主动干预所取代，有望推迟放化疗的使用，保护青少年的神经认知功能。 2.3 髓母细胞瘤与高级别胶质瘤 ● 髓母细胞瘤风险分层： SIOP 2025发布的大型回顾性研究指出，即便在非转移性髓母细胞瘤中，TP53突变和MYCN扩增也是独立的复发预测因子。这一发现挑战了现有的风险分层系统，提示对于这部分“标危”患者，可能需要更激进的治疗或新型靶向药物 35。 ● PDGFRA靶向：达纳-法伯癌症研究所（Dana-Farber）领导的团队发现，约15%的儿童高级别胶质瘤存在PDGFRA改变。应用PDGFRA抑制剂avapritinib在部分复发患者中观察到了显著的影像学和临床缓解，为这一高致死性肿瘤提供了新的靶点 36。第三章实体肿瘤（非CNS）：挑战与机遇并存与白血病和脑肿瘤的快速进展相比，2025年儿童实体肿瘤（特别是肉瘤）的研究呈现出一种复杂的局面：一方面是神经母细胞瘤中靶向治疗的深化，另一方面是横纹肌肉瘤中关键靶向试验的折戟。 3.1 神经母细胞瘤（Neuroblastoma）：ALK抑制剂的前线突围神经母细胞瘤是婴儿最常见的颅外实体瘤。高危组患者的治疗一直是难点。 3.1.1 Lorlatinib重塑ALK驱动型疾病治疗约15%的高危神经母细胞瘤患者携带ALK突变或扩增，这通常预示着对传统治疗耐药。第三代ALK抑制剂lorlatinib因其卓越的血脑屏障穿透力和对耐药突变的覆盖能力，成为研究焦点。 ● 临床突破：基于I期试验中高达**63%**的联合治疗缓解率（lorlatinib + 化疗），2025年COG和SIOPEN均启动了III期临床试验，正式将lorlatinib纳入新诊断ALK异常高危神经母细胞瘤的一线诱导治疗方案 37。这标志着神经母细胞瘤进入了基因型驱动的精准诱导治疗时代。 3.1.2 Naxitamab免疫治疗针对GD2抗原的人源化单抗Naxitamab联合GM-CSF的方案，在2025年被证实对化疗耐药的骨/骨髓复发患者有效。研究显示其能有效清除化疗无法触及的微小残留病灶，为复发患者提供了新的挽救手段 39。 3.2 横纹肌肉瘤（Rhabdomyosarcoma）：ARST1431的教训与FaR-RMS的进展 3.2.1 ARST1431试验：Temsirolimus的失败 2025年《柳叶刀·肿瘤学》发表了COG ARST1431 III期试验结果。该研究旨在评估在中危横纹肌肉瘤的标准VAC/VI化疗骨架中加入mTOR抑制剂temsirolimus的疗效。 ● 结果分析：令人失望的是，试验未能显示出EFS的统计学显著改善 5。 ● 科学启示：这一失败深刻揭示了实体瘤信号通路的冗余性。单纯抑制下游的mTOR可能不足以阻断由PAX3-FOXO1等强力融合蛋白驱动的致癌信号。未来的研究必须转向直接靶向融合蛋白本身或其关键的转录辅因子。 3.2.2 维持治疗的确立与FaR-RMS试验尽管靶向治疗受挫，EpSSG RMS2005试验的长期随访数据（发表于JCO）为化疗优化提供了确凿证据。 ● 维持治疗：数据显示，高危患者在标准治疗后接受6个月的低剂量长春瑞滨（vinorelbine）联合环磷酰胺（cyclophosphamide）维持治疗，其10年总生存率（OS）从70.8%显著提升至82.9% 40。这确立了维持治疗作为全球高危横纹肌肉瘤的标准护理。 ● FaR-RMS进展：正在进行的全球性多臂多阶段试验FaR-RMS公布了中期数据，确定了**伊立替康（irinotecan）**联合长春新碱和放线菌素D（IRIVA方案）的推荐II期剂量（50 mg/m²），为后续的高危组随机对照奠定了基础 41。 3.3 尤文肉瘤（Ewing Sarcoma）：生物标志物与血管靶向 ● STAG2预后价值： COG的一项大型分子流行病学研究（发表于JCO）发现，STAG2突变（发生率约7.6%）是局限期尤文肉瘤复发的独立强预后因子（HR显著升高）42。这一发现对于未来的临床试验分层至关重要，提示STAG2突变患者可能需要更强的治疗强度。 ● Pazopanib的潜力：一项回顾性研究显示，多靶点抗血管生成药物pazopanib在多发转移性尤文肉瘤儿童中取得了令人惊讶的疗效，2年生存率达到85% 44。尽管尚需前瞻性验证，但这为这一极高危人群提供了一种口服、低毒的维持治疗选项。第四章精准医学技术与全球健康视野 4.1 基因组测序与液体活检随着Pediatric MATCH（NCI-COG）和INFORM（欧洲）等大型精准医学项目的推进，全基因组/全外显子组测序已成为复发难治性儿科肿瘤的标准诊断流程。2025年的数据显示，约40%-50%的难治性病例可检出潜在可靶向的变异，但获得药物的可及性仍是瓶颈 46。此外，液体活检（ctDNA）在实体瘤疗效监测中的价值日益凸显，ctDNA的早期清除与优异的EFS高度相关 48。 4.2 影像学风险与AI应用《NEJM》发表的一项涉及370万儿童的大规模研究（Smith-Bindman等）量化了儿科医学影像（CT等）辐射暴露与血液系统恶性肿瘤风险的关联，强调了在诊断过程中平衡风险与收益的重要性，并推动了低剂量成像技术和AI辅助诊断的应用 49。 4.3 全球健康差距 AACR 2025年报告指出，尽管美国儿科癌症的5年生存率已达87%，但在低收入和中等收入国家（LMIC），这一数字往往低于30% 50。SIOP 2025年会和POEM协作组致力于推广适应资源匮乏环境的诊疗指南，通过建立区域性转诊网络和加强基本药物供应来缩小这一鸿沟 52。结语：迈向治愈的新征程 2025-2026年，儿科肿瘤学在机制驱动的药物研发上取得了历史性胜利。Modeyso、Revuforj、Ojemda等药物的获批，不仅挽救了生命，更验证了“即使是最难治的儿科肿瘤，只要找到关键驱动因子，也是可治愈的”这一信念。然而，挑战依然严峻。实体瘤中靶向融合蛋白的困难、免疫治疗在冷肿瘤中的乏力、以及昂贵的新疗法在全球范围内的可及性问题，都是未来十年必须攻克的堡垒。临床医生应积极拥抱基因组学检测，及时转诊适合的患者参与临床试验，并严格执行维持治疗标准，以期让每一个患儿都能从科技进步中获益。 (注：本报告所引用的数据和结论均基于截至2026年初的公开文献和会议资料，具体临床决策请遵循最新的专业指南。) 引用的著作 1. FDA grants accelerated approval to dordaviprone for diffuse midline glioma, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dordaviprone-diffuse-midline-glioma 2. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patients-relapsed-or-refractory-braf-altered-pediatric 3. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation 4. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children, https://pubmed.ncbi.nlm.nih.gov/39651791/ 5. Previously Untreated Intermediate-Risk Rhabdomyosarcoma Addition of Temsirolimus to Chemotherapy in Young Patients - The ASCO Post, ， https://ascopost.com/news/july-2024/previously-untreated-intermediate-risk-rhabdomyosarcoma-addition-of-temsirolimus-to-chemotherapy-in-young-patients/ 6. AALL1731 Trial Adding Blinatumomab to Standard Chemotherapy Improves Outcomes in Pediatric B-Cell ALL - The ASCO Post, https://ascopost.com/issues/january-25-2025/aall1731-trial-adding-blinatumomab-to-standard-chemotherapy-improves-outcomes-in-pediatric-b-cell-all/ 7. BLINCYTO® (blinatumomab) Clinical Data | Pediatric & AYA COG AALL1731 Study, https://www.blincytohcp.com/clinical-data/pediatric-aya/cog-aall-1731-study 8. BLINCYTO® (BLINATUMOMAB) ADDED TO CHEMOTHERAPY SIGNIFICANTLY IMPROVES SURVIVAL IN NEWLY DIAGNOSED PEDIATRIC PATIENTS WITH B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) - Amgen, https://www.amgen.com/newsroom/press-releases/2024/12/blincyto-blinatumomab-added-to-chemotherapy-significantly-improves-survival-in-newly-diagnosed-pediatric-patients-with-bcell-precursor-acute-lymphoblastic-leukemia-ball 9. National landscape of real-world pediatric blinatumomab care delivery in the United States: A report from the Children's Oncology Group - ASH Publications, https://ashpublications.org/blood/article/146/Supplement%201/1077/555355/National-landscape-of-real-world-pediatric 10. Inotuzumab ozogamicin combined with chemotherapy in pediatric B-cell precursor CD22 + acute lymphoblastic leukemia: results of the phase IB ITCC-059 trial - Haematologica, https://haematologica.org/article/view/haematol.2023.284409 11. Inotuzumab ozogamacin in refractory or 1st or greater relapse of pediatric B-ALL as bridge to cure: A single center experience | Blood - ASH Publications, https://ashpublications.org/blood/article/146/Supplement%201/3351/548648/Inotuzumab-ozogamacin-in-refractory-or-1st-or 12. Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621 - ASCO Publications, https://ascopubs.org/doi/abs/10.1200/JCO.21.01693 13. Highlights from ASH 2025 - Update in ALL - ALAN - Acute Leukemia Advocates Network, https://acuteleuk.org/highlights-from-ash-2025-update-in-all/ 14. FDA approves revumenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-npm1-mutation 15. Roswell Park Leukemia Expert Led ASH 2025 Studies Assessing 2 New Treatment Strategies for Advanced AML, https://www.roswellpark.org/newsroom/202512-roswell-park-leukemia-expert-led-ash-2025-studies-assessing-2-new-treatment 16. Winship helps win FDA approval for first aggressive leukemia therapy, https://winshipcancer.emory.edu/newsroom/articles/2025/winship-helps-win-fda-approval-for-first-aggressive-leukemia-therapy.php 17. ASH Studies Bolster Support for Menin Inhibitor in Acute Leukemia - The ASCO Post, https://ascopost.com/issues/may-10-2025/ash-studies-bolster-support-for-menin-inhibitor-in-acute-leukemia/ 18. Syndax Announces Revumenib Abstracts to Be Presented at the 66th ASH Annual Meeting, https://ir.syndax.com/news-releases/news-release-details/syndax-announces-revumenib-abstracts-be-presented-66th-ash 19. Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study | Blood | American Society of Hematology - ASH Publications, https://ashpublications.org/blood/article/146/9/1065/537139/Menin-inhibition-with-revumenib-for-NPM1-mutated 20. FDA Approves Revumenib for Acute Myeloid Leukemia with Susceptible NPM1 Mutation, https://www.oncologynewscentral.com/drugs/info/fda-approves-revumenib-for-acute-myeloid-leukemia-with-susceptible-npm1-mutation 21. Dual Menin and KAT6A-7 Inhibition Improves Outcomes in NUP98-Rearranged Pediatric AML Models - The ASCO Post, https://ascopost.com/news/june-2025/dual-menin-and-kat6a-7-inhibition-improves-outcomes-in-nup98-rearranged-pediatric-aml-models/ 22. Asciminib pediatric formulation shows a tolerable safety profile in pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP): Second interim analysis from the ASC4KIDS study | Blood - ASH Publications, https://ashpublications.org/blood/article/146/Supplement%201/7312/550745/Asciminib-pediatric-formulation-shows-a-tolerable 23. A new chapter in CML treatment: the promise of asciminib - PMC - NIH, https://pmc.ncbi.nlm.nih.gov/articles/PMC11981358/ 24. ONC201 FDA Approval | ChadTough Defeat DIPG Foundation, https://chadtough.org/research/onc201/ 25. NCCN Adds Dordaviprone to Clinical Practice Guidelines in H3K27M-Mutant Diffuse High-Grade Glioma | OncLive, https://www.onclive.com/view/nccn-adds-dordaviprone-to-clinical-practice-guidelines-in-h3k27m-mutant-diffuse-high-grade-glioma 26. Modeyso™ (dordaviprone) Included in National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology for H3 K27M-mutant Diffuse Glioma - PR Newswire, https://www.prnewswire.com/news-releases/modeyso-dordaviprone-included-in-national-comprehensive-cancer-network-nccn-clinical-practice-guidelines-in-oncology-for-h3-k27m-mutant-diffuse-glioma-302549794.html 27. Experimental CAR T-Cell Therapy Shrinks Tumors in Children with Deadly Brain Cancer, https://www.cancer.gov/news-events/cancer-currents-blog/2025/car-t-cell-therapy-gd2-diffuse-midline-gliomas 28. Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas - PubMed, https://pubmed.ncbi.nlm.nih.gov/39537919/ 29. 269 Humanized anti-CAR antibodies affect durable response to GD2-CAR T-cells in diffuse midline glioma | Journal for ImmunoTherapy of Cancer, https://jitc.bmj.com/content/13/Suppl_2/A299 30. Day One's OJEMDA™ (tovorafenib) Receives US FDA Accelerated Approval for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma (pLGG), the Most Common Form of Childhood Brain Tumor, https://ir.dayonebio.com/news-releases/news-release-details/day-ones-ojemdatm-tovorafenib-receives-us-fda-accelerated 31. Updated FIREFLY-1 Data Further Support Tovorafenib as a SOC in R/R Pediatric Low-Grade Glioma | OncLive, https://www.onclive.com/view/updated-firefly-1-data-further-support-tovorafenib-as-a-soc-in-r-r-pediatric-low-grade-glioma 32. Day One Announces Three Year Follow-Up Data From OJEMDA™ (tovorafenib) Phase 2 FIREFLY-1 Trial at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting - Investor Relations, https://ir.dayonebio.com/news-releases/news-release-details/day-one-announces-three-year-follow-data-ojemdatm-tovorafenib/ 33. First Targeted Therapy for Glioma Headed for FDA Approval - American Brain Tumor Association, https://www.abta.org/mindmatters/mm-first-targeted-therapy-for-glioma-vorasidenib/ 34. Hope for Brain Tumors: New Drug With Miami Roots Emerges - InventUM, https://news.med.miami.edu/hope-for-brain-tumors-with-new-drug-therapy/ 35. Molecular subtypes, prognostic factors, and treatment optimization in pediatric medulloblastoma: a real-world study from China - Frontiers, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1597123/full 36. Potential targeted therapy for pediatric brain cancer identified by Dana-Farber/Boston Children's team, https://www.dana-farber.org/newsroom/news-releases/2025/potential-targeted-therapy-for-pediatric-brain-cancer-identified-by-dana-farberboston-childrens-team 37. A new era for treating high-risk neuroblastoma – research advances to look out for in 2024, https://www.icr.ac.uk/research-and-discoveries/cancer-blogs/detail/science-talk/a-new-era-for-treating-high-risk-neuroblastoma-research-advances-to-look-out-for-in-2024 38. Researchers Show Lorlatinib is Safe, Effective for Patients with High-Risk Neuroblastoma, https://www.chop.edu/news/researchers-show-lorlatinib-safe-effective-patients-high-risk-neuroblastoma 39. Y-mAbs Announces Publication of Phase 2 Interim Results in Nature Communications, https://ir.ymabs.com/news-releases/news-release-details/y-mabs-announces-publication-phase-2-interim-results-nature 40. High-Risk Rhabdomyosarcoma: Long-Term Outcomes With Maintenance Chemotherapy, https://ascopost.com/news/march-2025/high-risk-rhabdomyosarcoma-long-term-outcomes-with-maintenance-chemotherapy/ 41. A phase Ib study within the EpSSG Frontline and Relapsed Rhabdomyosarcoma study (FaR-RMS). - ASCO, https://www.asco.org/abstracts-presentations/246132 42. Molecular Characterization Informs Prognosis in Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group - ASCO Publications, https://ascopubs.org/doi/10.1200/JCO-25-00157 43. Molecular characterization informs prognosis in patients with localized Ewing sarcoma: A report from the Children's Oncology Group | medRxiv, https://www.medrxiv.org/content/10.1101/2025.01.20.25320840v1.full-text 44. Pazopanib in patients with primary multi-metastatic bone Ewing sarcoma - Frontiers, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1653015/pdf 45. Drug which stops tumors' blood supply could help kids with bone cancer live longer, https://www.frontiersin.org/news/2025/10/23/drug-stops-tumors-blood-supply-help-kids-bone-cancer-frontiers-oncology 46. The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development - MDPI, 2026， https://www.mdpi.com/2072-6694/13/17/4324 47. Precision Medicine for Childhood Cancer: Current Limitations and Future Perspectives, https://ascopubs.org/doi/10.1200/PO.23.00117 48. MSK Research Highlights, September 4, 2025 | Memorial Sloan Kettering Cancer Center, https://www.mskcc.org/news/msk-research-highlights-september-4-2025 49. Amol Akhade: NEJM Study Links Pediatric Imaging to Hematologic Cancer Risk - Oncodaily, https://oncodaily.com/science/pediatric-imaging-372697 50. AACR Pediatric Cancer Progress Report 2025 - The ASCO Post, https://ascopost.com/news/december-2025/aacr-pediatric-cancer-progress-report-2025/ 51. Understanding the Global Burden of Pediatric Cancers, https://cancerprogressreport.aacr.org/pediatric/pcpr25-contents/pcpr25-understanding-the-global-landscape-of-pediatric-cancers/ Highlights From the 2025 Pediatric Oncology East and Mediterranean Biennial Conference - ASCO Publications, https://ascopubs.org/doi/10.1200/GO-25-00585 扫码关注“头颈健康之声” 内容丨李祥攀编辑丨陈蓉审核丨李祥攀/陈平/许秋妮了解更多肿瘤科普知识,请关注武汉大学人民医院头颈肿瘤科微信公众号 “头颈健康之声” 地址：武汉市洪山区白沙四路与光霞路交叉路口武汉大学人民医院洪山院区5号楼4楼健康热线：027-88041911转82550、82551

2026-03-19

·TiPLab

Day One 的 RAF 靶向小分子和 ADC 产品组合

2026 年 3 月 6 日，施维雅（Servier）宣布将以25 亿美元收购 Day One。此次收购将增强施维雅在罕见肿瘤领域的产品组合特别是在儿童低级别胶质瘤领域占据领先地位，并拓展其肿瘤产品线，涵盖从早期到 III 期临床试验的各个阶段。 Day One 的 RAF 靶向小分子和 ADC 产品组合 by TiPLab 木桃 Day One Biopharmaceuticals致力于以同等力度推进儿童和成人新型靶向疗法的临床开发。以往，大多数制药公司将癌症新疗法的发现和开发重点集中在成人肿瘤类型上。 Day One的产品管线中包括1个RAF小分子靶向药 + 2个ADC（靶向PTK7 与 B7-H4）的组合，且两个ADC是通过收购或许可而来。首个商业化产品 tovorafenib：于 2019 年从 Millennium/Takeda获得。Tovorafenib是一种口服、可穿透血脑屏障、高选择性的 II 型 RAF激酶（由RAS激活，属于MAPK信号通路）抑制剂，能够同时抑制单体和二聚体 RAF 激酶（包括：突变型 BRAF V600E、野生型 BRAF 和野生型 CRAF 激酶），可用于治疗多种 RAS 或 RAF 突变的实体瘤。 Tovorafenib 目前已在美国上市用于治疗儿童低级别胶质瘤（pLGG），并继续推进确证性临床试验和前线适应症的临床试验。可能与施维雅的 Voranigo（2024 年获批用于治疗 12 岁及以上携带 IDH1 或 IDH2 突变的星形细胞瘤或少突胶质细胞瘤患者）形成协同作用。 2024年，FDA通过加速审批途径批准OJEMDA™（tovorafenib）用于治疗年龄在 6 个月及以上、患有复发性或难治性儿童低级别胶质瘤（pLGG）且携带 BRAF 融合/重排或 BRAF V600 突变的患者。OJEMDA 是目前唯一一种每周一次给药的 pLGG 全身治疗药物，可空腹或随餐服用，剂型包括片剂和口服混悬液。儿童低级别胶质瘤是儿童中最常见的脑肿瘤。目前尚无公认的标准治疗方案。已获批准的 BRAF 抑制剂，例如 vemurafenib （Genentech）和 encorafenib（辉瑞），属于 I 型 RAF 抑制剂，仅抑制 RAF 单体，限用于 BRAF V600 突变的肿瘤。 Emi-Le（XMT-1660，emiltatug ledadotin）：2026 年 1 月通过收购 Mersana 获得。Emi-Le是一种靶向 B7-H4 的 ADC（DAR 6），有效载荷为auristatin抗微管蛋白，采用 Mersana 开发的专有linker-payload技术。B7-H4 在腺样囊性癌（ACC）以及其他成人和儿童癌症中高表达。目前，Emi-Le 正在一项针对多种成人肿瘤类型（包括乳腺癌、卵巢癌、子宫内膜癌和腺样囊性癌）的 I 期剂量递增和补充研究中进行评估。在 I 期临床试验的初步临床数据中，Emi-Le 总体耐受性良好，并在多种肿瘤类型中观察到了确切的客观缓解。 DAY301：2024年从麦科思生物（MabCare）许可获得。DAY301一种靶向 PTK7 （蛋白酪氨酸激酶 7）的 ADC，由一种人源化抗 PTK7 IgG1 mAb与拓扑异构酶 I 抑制剂exatecan mesylate通过高度稳定且具有亲水修饰（聚肌氨酸pSAR）的缬氨酸-丙氨酸（VA）可裂解连接子偶联而成（DAR 8），旨在用于治疗晚期实体瘤患者，目前正处于临床I期。 PTK7 在多种成人和儿童癌症的细胞表面均有持续高表达，包括铂耐药性卵巢癌、三阴性乳腺癌、非小细胞肺癌、神经母细胞瘤和骨肉瘤。已有临床前数据表明DAY301 可能具有较宽的治疗窗口。 Tovorafenib 相关专利家族： PCT/US2008/068762（核心化合物）：中美欧均有多个授权专利。其中，US8293752B2保护通式结构，预计于2031-08-04到期，并且 PTE 仍在申请中。 PCT/US2015/022792（制剂）：中美欧均有多个授权专利。其中，US10426782B2将于2035-06-23到期。其他专利家族：包括2个药物制剂专利族，预计将于2040年和2043年到期；1个合成方法专利家族，预计将于 2038 年到期；多个医药用途专利家族涉及tovorafenib联合MEK抑制剂治疗癌症或tovorafenib治疗 pLGG，预计将于 2040 年之后到期。除了专利保护，tovorafenib在美国的NCE市场独占期和儿科用药独占期分别在2029年和2031年到期。 DAY301 相关专利家族： 1个活性成分家族（PCT/CN2024/084819）预计到期 2044年到期，3 个ADC linker家族预计2042年到期。 Emi-Le 相关专利家族： ADC结构：1个专利族（PCT/US2012/041931）涵盖 Emi-Le 的有效载荷及其合成方法，包括10个授权US专利，预计专利期限至 2032 年。2个专利族涵盖 Emi-Le、中间体及其合成方法（PCT/US2022/011119），预计专利期限至 2041 ~2042 年。医药用途：3个家族分别涉及使用 Emi-Le 治疗腺样囊性癌、三阴性乳腺癌或联用治疗癌症的方法，预计将于 2043 年至2046年到期。1个专利族针对 Emi-Le 的治疗方案，预计将于 2046 年到期。 * 以上文字仅为促进讨论与交流，不构成法律意见或咨询建议。 © 作为一家专业服务公司，TiPLab坚持原创的系统的研究，注重系统性知识积累与专业影响力。欢迎读者个人分享转发，各专业平台媒体如需转载请联系TiPLab获得授权。 TiPLab提供基于研究的核心知识产权服务 FTO：技术商业化实施的侵权风险防范 TiPLab通过对细分技术领域内核心技术和重要专利的长期研究，结合自身在数据检索和分析方面的专长，致力于帮助客户深入了解、积极应对潜在的专利侵权风险。 Due Diligence：商业活动中的知识产权尽职调查在企业许可交易、融资、并购、上市等过程中，TiPLab帮助企业和投资方了解目标技术/产品的专利保护强度及产品商业化过程中潜在的专利侵权风险，从而为商业谈判和决策提供支持依据。 Patenting：全球范围内高价值专利资产的创设 TiPLab熟知全球主要国家和地区的法律实践和细分领域内的前沿技术进展情况，通过前瞻性的专利布局策略，帮助客户通过创设有价值的专利资产而获取、保持和巩固独特的竞争优势。

100 项与 Tovorafenib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15266

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
BRAF 融合或重排阳性的低级别胶质瘤	美国	Day One Biopharmaceuticals, Inc.	2024-04-23
BRAF V600 突变的低级别胶质瘤	美国	Day One Biopharmaceuticals, Inc.	2024-04-23
低级神经胶质瘤	美国	Day One Biopharmaceuticals, Inc.	2024-04-23

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
肿瘤	申请上市	加拿大	Ipsen Biopharmaceuticals, Inc.	2025-10-01
毛细胞白血病	临床2期	美国	National Cancer Institute	2026-06-27
BRAF V600E 突变阳性低级别胶质瘤	临床2期	-	Day One Biopharmaceuticals, Inc.	2026-05-01
脑转移瘤	临床2期	-	Day One Biopharmaceuticals, Inc.	2026-05-01
弥漫内生性脑桥神经胶质瘤	临床2期	-	Day One Biopharmaceuticals, Inc.	2026-05-01
高级别胶质瘤	临床2期	-	Day One Biopharmaceuticals, Inc.	2026-05-01
WHO III 级混合胶质瘤	临床2期	-	Day One Biopharmaceuticals, Inc.	2026-05-01
难治性朗格汉斯细胞组织细胞增生症	临床2期	美国	National Cancer Institute	2024-03-28
难治性朗格汉斯细胞组织细胞增生症	临床2期	澳大利亚	National Cancer Institute	2024-03-28
难治性朗格汉斯细胞组织细胞增生症	临床2期	加拿大	National Cancer Institute	2024-03-28

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临床结果

适应症

分期

评价

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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


NCT04775485 (FIREFLY-1, Company_Website) 人工标引	临床2期	BRAF V600 突变的低级别胶质瘤 BRAF Fusion \| BRAF Rearrangement	137	Tovorafenib (efficacy analyses)	糧鹽鏇鏇淵廠壓構構壓(鑰簾襯艱襯鹹鑰壓艱糧) = 夢鬱選憲顧積獵夢繭繭憲鹽製簾糧鹽築襯鹹積 (壓築壓獵獵願選窪廠範 ) 更多	积极	2026-02-27
NCT04775485 (FIREFLY-1, Company_Website) 人工标引	临床2期	BRAF V600 突变的低级别胶质瘤 BRAF Fusion \| BRAF Rearrangement	137	Tovorafenib (safety data)	-	积极	2026-02-27
NCT04775485 (FIREFLY-1, GlobeNewswire) 人工标引	临床2期	BRAF V600 突变的低级别胶质瘤 \| BRAF 融合或重排阳性的低级别胶质瘤 BRAF Mutation \| BRAF Fusion	137	OJEMDA (tovorafenib)	製選膚餘鹽網糧鏇繭淵(壓繭鑰顧膚廠製願糧築) = 鬱餘鬱鹹廠憲膚餘衊蓋淵構製積憲繭簾觸鏇願 (夢醖簾範餘築醖繭膚夢 ) 更多	积极	2025-11-24
NCT04775485 (FIREFLY-1, GlobeNewswire) 人工标引	临床2期		137	OJEMDA (tovorafenib) (Exploratory analyses：entered a treatment-free observation period)	蓋鏇網構構壓壓製憲願(衊選選鹽膚製醖艱觸膚) = 鏇壓鬱衊鹹醖餘範艱夢鏇夢製鬱窪積選鏇構鹹 (繭艱鹽醖構築蓋獵鑰鹹 ) 更多	积极	2025-11-24
NCT04985604 (CTgov)	临床2期	复发性实体肿瘤 \| BRAF融合胶质瘤 \| 膀胱尿路上皮癌 ... 更多	23	Tovorafenib (Melanoma Cohort)	範餘鑰構艱壓憲壓蓋鹽 = 製鬱衊積觸艱衊積遞鬱襯繭選壓繭艱顧淵選鬱 (築積顧製鹽築醖簾範餘, 衊簾糧憲壓積築獵醖蓋 ~ 鬱顧遞廠窪顧製範築鏇) 更多	-	2025-10-02
NCT04985604 (CTgov)	临床2期	复发性实体肿瘤 \| BRAF融合胶质瘤 \| 膀胱尿路上皮癌 ... 更多	23	Tovorafenib (Tissue Agnostic Cohort)	範餘鑰構艱壓憲壓蓋鹽 = 願積壓蓋膚蓋壓鏇鑰簾襯繭選壓繭艱顧淵選鬱 (築積顧製鹽築醖簾範餘, 網餘廠選繭網鹹範選齋 ~ 壓簾願艱繭糧餘餘簾築) 更多	-	2025-10-02
NCT04775485 (FIREFLY-1, ASCO2025)	临床2期	BRAF V600 突变的低级别胶质瘤 BRAF-altered	137	Tovorafenib	醖衊蓋構構醖鑰憲願鏇(壓築鬱夢壓鹹製鏇網製) = 壓鹽鏇鬱顧遞齋窪衊顧製憲衊餘壓膚簾鏇顧遞 (選衊齋蓋觸夢淵簾顧衊 ) 更多	-	2025-05-30
NCT03429803 \| NCT04775485 \| NCT05760586 (ASCO2025)	临床1/2期	局部晚期恶性实体瘤 \| 晚期恶性实体瘤 \| BRAF V600 突变的低级别胶质瘤 ... BRAF 更多	167	Tovorafenib	衊築顧鬱糧觸夢鏇鑰積(積衊遞壓窪獵築積齋選) = 餘衊選構觸構窪選鹹襯膚衊選廠積鹽構選網鹹 (顧蓋膚觸範醖築繭獵艱, 0.4 ~ 2.2)	-	2025-05-30
NCT04985604 (ESMO2024)	临床2期	实体瘤 \| 复发性黑色素瘤	-	Tovorafenib 600 mg	遞窪築衊鹹醖襯襯簾廠(襯醖窪願壓淵觸鏇鑰膚) = 39% 餘壓鑰糧壓衊齋鹹醖獵 (網願鬱鑰鹽構餘艱顧餘 ) 更多	-	2024-09-14
NCT03429803 (ASCO2024) 人工标引	临床1期	低级神经胶质瘤 MAPK pathway activated	35	Tovorafenib 530 mg/m2	鹹壓壓製鹽觸築淵廠選(夢醖淵選範壓蓋壓遞構) = 齋衊糧艱夢鹽衊襯獵廠積窪遞壓壓鏇觸築艱獵 (製築簾顧淵鬱醖觸糧顧 ) 更多	积极	2024-05-24
NCT04775485 (FIREFLY-1, FDA_CDER) 人工标引	临床2期	BRAF V600 突变的低级别胶质瘤 \| BRAF 融合或重排阳性的低级别胶质瘤 BRAF Rearrangement \| BRAF V600E	137	OJEMDA	鬱膚顧築廠鏇顧蓋鏇觸(顧餘糧築憲壓壓壓選膚) = 窪憲網壓選壓鹽製鹽網憲積築選繭膚襯衊鑰鏇 (糧醖願憲糧遞膚廠獵齋, 40 ~ 63) 更多	积极	2024-04-23
NCT04775485 (FIREFLY-1, SNO2023)	临床2期	低级神经胶质瘤 BRAF	136	Tovorafenib 420 mg/m2	淵觸觸艱窪壓鑰醖蓋觸(鹹膚選淵醖製遞繭齋鑰) = 蓋構繭網獵鹽廠鑰醖鏇餘獵廠鹽積遞衊鹽醖鬱 (衊製範蓋壓鏇窪醖網願 )	积极	2023-11-10
NCT04775485 (FIREFLY-1, SNO2023)	临床2期	低级神经胶质瘤 BRAF	136	MAPK inhibitor therapy	淵觸觸艱窪壓鑰醖蓋觸(鹹膚選淵醖製遞繭齋鑰) = 夢齋夢鑰廠簾製積網顧餘獵廠鹽積遞衊鹽醖鬱 (衊製範蓋壓鏇窪醖網願 )	积极	2023-11-10
NCT04775485 (FIREFLY-1, SNO2023)	临床2期	视神经胶质瘤 BRAF V600E mutation	77	Tovorafenib 420 mg/m2 weekly	壓憲網衊鹽鏇夢顧窪構(簾蓋艱艱衊憲範襯憲淵) = 夢壓觸淵積築願網遞襯遞鹹範衊鏇膚獵積選壓 (築憲觸膚觸觸艱積鬱構 ) 更多	积极	2023-11-10