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更新于：2026-07-15
Lirafugratinib
利拉富格拉替尼
更新于：2026-07-15
概要
基本信息
药物类型 小分子化药 |
别名 Lirafugratinib Hydrochloride、RLY 4008、RLY-4008 + [1] |
靶点 |
作用方式 拮抗剂 |
作用机制 FGFR2拮抗剂(成纤维细胞生长因子受体-2拮抗剂) |
在研适应症 |
非在研适应症- |
非在研机构- |
最高研发阶段申请上市 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评突破性疗法 (美国)、孤儿药 (美国)、孤儿药 (欧盟)、优先审评 (美国) |
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结构/序列
分子式C28H24FN7O2 |
InChIKeyXOQVZSSDIQQUGO-UHFFFAOYSA-N |
CAS号2549174-42-5 |
关联
3
项与 利拉富格拉替尼 相关的临床试验NCT07359820
A Phase 2, Open-Label, Single-Arm Study of Lirafugratinib in Patients With Previously Treated, Unresectable, Locally Advanced or Metastatic Solid Tumors (Excluding Cholangiocarcinoma) With FGFR2 Fusion or Rearrangement
ISRCTN27020581
A Phase I, open-label, single-dose study designed to assess the absorption, distribution, metabolism and excretion of [14C]-RLY-4008 in healthy male participants
NCT04526106
A First-in-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients With Intrahepatic Cholangiocarcinoma (ICC) and Other Advanced Solid Tumors
100 项与 利拉富格拉替尼 相关的临床结果
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100 项与 利拉富格拉替尼 相关的转化医学
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100 项与 利拉富格拉替尼 相关的专利（医药）
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14
项与 利拉富格拉替尼 相关的文献（医药）2026-06-01ANNALS OF ONCOLOGY
Mechanisms of clinical resistance to selective FGFR2 inhibition by lirafugratinib
Article
作者: Nugent, F W ; Hajian, B ; Wan, J ; Silveira, V S ; Chevalier, N ; Corcoran, R B ; Ellis, H ; Kehlmann, A ; Lau, K ; Sellers, W R ; Balasooriya, E R ; Vijay, V ; Juric, D ; Varkaris, A ; Bardeesy, N ; Gritti, I ; Shekhar, M ; Zhen, Y ; Albertelli, L ; Piot, S
BACKGROUND:
Pan-fibroblast growth factor receptor (FGFR) inhibitors, targeting FGFR1-3 or FGFR1-4, are Food and Drug Administration-approved for FGFR2-driven cholangiocarcinoma. However, acquired resistance and dose-limiting toxicities from systemic FGFR inhibition constrain efficacy. Lirafugratinib (RLY-4008), a first-in-class FGFR2-selective inhibitor with activity against resistance-associated FGFR2 kinase domain mutations, shows promise in patients with FGFR2-altered solid tumors (ReFocus trial, NCT04526106). Defining acquired resistance mechanisms to selective FGFR2 targeting is essential for therapeutic development.
PATIENTS AND METHODS:
Circulating tumor DNA (ctDNA) samples from 28 patients treated with lirafugratinib (16 FGFR inhibitor-naive, 12 FGFR inhibitor-refractory) were analyzed using targeted next-generation sequencing. Genomic alterations observed were compared with those reported in prior studies of pan-FGFR inhibitor resistance and validated in preclinical models.
RESULTS:
Polyclonal FGFR2 kinase domain mutations and receptor tyrosine kinase-mitogen activated protein kinase (RTK-MAPK) bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naive context (8/16 and 9/16 patients, respectively). Resistance profiles differed markedly from pan-FGFR inhibitors, with decreased FGFR2 V565F/L and N550H/K mutations, increased M538I and L618F mutations, and more frequent RTK-MAPK bypass alterations. The variant allele fraction was typically higher for FGFR2 kinase domain mutations, consistent with these alterations serving as primary resistance drivers. Preclinical studies confirmed differential sensitivity of these FGFR2 mutations to lirafugratinib. Importantly, lirafugratinib demonstrated clinical efficacy in the FGFR inhibitor-refractory setting, with ctDNA dynamics showing resolution of multiple FGFR2 mutations and persistence or emergence of others.
CONCLUSIONS:
Lirafugratinib retains activity against multiple mutations that confer clinical resistance to pan-FGFR inhibitors. However, diverse resistance mechanisms, including various kinase domain mutations and RTK-MAPK bypass alterations, remain challenges in the treatment of FGFR2-altered tumors, even with selective FGFR2 kinase inhibition.
2026-04-15CLINICAL CANCER RESEARCH
Recurrent Resistance Mutations to Lirafugratinib Inform Treatment Sequencing in
FGFR2
-Driven Tumors
Article
作者: Badoual, Cécile ; Nikolaev, Sergey ; Samaniego, Juliette ; Bourien, Héloise ; Barbé, Rémy ; Nicotra, Claudio ; Alonso-Garcia, Inmaculada ; Boilève, Alice ; Nakazawa, Seshiru ; Jang, Dong Man ; Rodriguez, Julieta ; Cotteret, Sophie ; Bernard, Elsa ; Soares, Miguel ; Italiano, Antoine ; André, Fabrice ; Loriot, Yohann ; Friboulet, Luc ; Ducreux, Michel ; Mosele, Fernanda ; Nobre, Catline ; Beshiri, Kristi ; Da Silva, Alice ; Olaussen, Ken A. ; Facchinetti, Francesco ; Alonso-De-Castro, Beatriz ; Eck, Michael J. ; Brayé, Floriane ; Bigot, Ludovic ; Smolenschi, Cristina ; Delavigne, Mathis ; Tselikas, Lambros ; Ngo-Camus, Maud ; Hollebecque, Antoine ; Méteau, Mélissandre ; Vasseur, Damien
Abstract:
Purpose::
The use of reversible fibroblast growth factor receptor 2 (FGFR) inhibitors leads to the emergence of “undruggable” FGFR2 kinase domain mutations, hampering sequential treatment strategies. Lirafugratinib and futibatinib are irreversible FGFR inhibitors with the most promising clinical activity against FGFR2-driven tumors.
Experimental Design::
We characterized resistance to lirafugratinib with circulating tumor DNA, tissue whole-exome sequencing, and bulk RNA sequencing in 30 patients with FGFR2-driven cancers, treated in the phase I/II ReFocus trial (NCT04526106) and enrolled in the UNLOCK program at Gustave Roussy.
Results::
Among the 30 patients included, 18 (60%) had intrahepatic cholangiocarcinoma and 12 (40%) had other tumor types. Twenty-two patients (73%) were FGFR inhibitor–naïve. Among those experiencing primary resistance to lirafugratinib, we identified potential resistance mechanisms in five of six pretreatment samples. Patients with acquired lirafugratinib resistance manifested an unprecedented emergence of FGFR2 mutations in the M538 and/or L618 residues of the kinase domain, documented in 11 of 16 cases (69%). Compared with futibatinib resistance, FGFR2 molecular brake (N550) and gatekeeper (V565) mutations were rare. Leveraging the spectrum of FGFR2 kinase domain mutations at resistance to lirafugratinib and futibatinib, respectively, we identified the complementarity of the two irreversible inhibitors. On the basis of viability assays in FGFR2::BICC1–dependent Ba/F3 models and in vivo studies on patient-derived xenografts, we propose treatment sequences with the two agents. After lirafugratinib progression, three patients received futibatinib and experienced prolonged disease response.
Conclusions::
The complementary activity of lirafugratinib and futibatinib against FGFR2 kinase domain mutations supports their sequential use when precise resistance mutations are detected in patients.
2026-04-01DRUG METABOLISM AND DISPOSITION
Lirafugratinib attenuates ABCG2-dependent drug efflux and restores chemosensitivity in multidrug-resistant nonsmall cell lung cancer cells
Article
作者: Lin, Bing-Huan ; Wu, Chung-Pu ; Li, Yen-Ching ; Wu, Yu-Shan ; Hung, Tai-Ho ; Ambudkar, Suresh V ; Chang, Yu-Tzu ; Murakami, Megumi
The therapeutic efficacy of many anticancer drugs is frequently compromised by multidrug resistance, a process often driven by elevated activity of ATP-binding cassette (ABC) efflux pumps in tumor cells. These membrane transporters actively expel chemotherapeutic agents in an ATP-dependent fashion, thereby lowering intracellular drug exposure and diminishing treatment responses. The shortage of clinically approved agents capable of overcoming ABC transporter-mediated resistance highlights the urgency of identifying alternative approaches, including the repurposing of small-molecule targeted therapies to inhibit drug efflux. Here, we examine lirafugratinib, an orally available and highly selective fibroblast growth factor receptor 2 inhibitor currently undergoing clinical evaluation for intrahepatic cholangiocarcinoma and other solid tumors, as a potential modulator of ABCG2-mediated drug resistance. Our findings reveal that lirafugratinib, at concentrations that do not impair cell viability, restores sensitivity to ABCG2-substrate chemotherapeutic drugs and enhances apoptosis in ABCG2-overexpressing nonsmall cell lung cancer cells. Mechanistically, lirafugratinib impedes the efflux capability of ABCG2 without altering its protein expression. ATPase experiments and molecular docking analysis further indicate that lirafugratinib engages the drug-binding region of ABCG2 and modulates its ATP hydrolysis cycle. Collectively, these results suggest that lirafugratinib may be utilized as a chemosensitizing agent to counteract multidrug resistance in nonsmall cell lung cancer with high ABCG2 expression, supporting its evaluation in combination therapies. Further in vivo studies and clinical trials are required to substantiate its clinical applicability. SIGNIFICANCE STATEMENT: This work identifies lirafugratinib, a highly selective fibroblast growth factor receptor 2 inhibitor, as a previously unrecognized suppressor of ABCG2-dependent MDR. By limiting efflux-mediated depletion of anticancer drugs while maintaining its own activity, lirafugratinib resensitizes resistant nonsmall cell lung cancer cells to cytotoxic agents, supporting its potential utility in combination regimens for tumors with elevated ABCG2 expression.
182
项与 利拉富格拉替尼 相关的新闻（医药）2026-07-14
·AI药闻
临床3期孤儿药临床2期突破性疗法
2026-07-12
抗体药物偶联物临床3期临床结果申请上市临床申请
2026-07-08
·澄颐堂
100 项与 利拉富格拉替尼 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| FGFR2融合或重排的胆管癌 | 申请上市 | 美国 | 2026-01-30 | |
| 晚期恶性实体瘤 | 临床2期 | 美国 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 澳大利亚 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 法国 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 德国 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 中国香港 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 意大利 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 荷兰 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 新加坡 | 2020-09-02 | |
| 晚期恶性实体瘤 | 临床2期 | 韩国 | 2020-09-02 |
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临床结果
临床结果
适应症
分期
评价
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临床1期 | FGFR2突变实体瘤 FGFR2 alteration | 28 | (FGFR inhibitor-naive) | 鏇夢餘廠襯鹽繭獵鏇製(窪憲憲觸壓鹹鑰鏇醖構) = 膚餘製製廠積醖憲簾蓋 窪遞鏇觸願繭觸齋獵夢 (糧遞齋積餘網蓋淵憲獵 ) 更多 | 积极 | 2026-06-01 | |
临床2期 | FGFR2融合或重排的胆管癌 FGFR2 fusion or rearrangement | 20 | 衊繭醖築鹹獵顧製獵夢(憲鹹鑰襯積鬱範鏇鏇鹽) = 蓋憲繭夢衊淵積衊願廠 膚醖鹽鑰廠簾廠廠觸築 (衊繭糧艱獵顧顧鏇遞鑰 ) | 积极 | 2026-05-29 | ||
临床1/2期 | FGFR2融合或重排的胆管癌 FGFR Rearrangement | FGFR2 Fusion | 116 | 積衊艱窪鬱窪願壓鏇鑰(遞餘範網餘願鹽繭襯鑰) = 窪艱製選獵鹽鏇齋觸淵 夢壓窪觸鹽夢構網壓衊 (壓簾簾廠廠衊鹹製糧範, 37.1 ~ 56.1) 更多 | 积极 | 2026-01-08 | ||
临床1/2期 | 实体瘤 FGFR2 fusions | FGFR2 amplifications | FGFR2 mutations | 84 | (patients with FGFR2 fusions) | 網繭膚淵艱獵積觸艱艱(廠糧夢顧積獵簾鹽簾餘) = 醖鹽窪願網鹽齋鬱膚鑰 壓鏇築膚簾鏇獵壓壓衊 (鏇廠鹽憲遞憲壓衊構遞 ) | 积极 | 2023-10-12 | |
(patients with breast cancer across all FGFR2 alterations, 10 of whom had HR+/HER2- breast cancer) | 網繭膚淵艱獵積觸艱艱(廠糧夢顧積獵簾鹽簾餘) = 夢範襯憲鏇衊鏇壓築鏇 壓鏇築膚簾鏇獵壓壓衊 (鏇廠鹽憲遞憲壓衊構遞 ) | ||||||
临床1/2期 | 75 | (FGFRi-naïve CCA f/r) | 壓製鹹範獵餘遞鬱鹽鏇(鹽壓窪製壓蓋襯遞襯憲) = 70 mg QD 願鬱製鑰遞齋鬱簾構廠 (醖遞獵鹹膚鑰鹹繭憲襯 ) 更多 | 积极 | 2023-05-26 | ||
(Prior-FGFRi CCA f/r) | |||||||
临床1/2期 | - | - | 願鑰齋壓艱蓋鹹鏇廠齋(簾獵觸範夢餘鑰鹹網衊) = 網淵鑰醖鏇齋願觸廠遞 鹽蓋襯獵簾壓壓醖膚鏇 (構遞網網衊窪壓醖遞衊 ) | - | 2023-04-04 | ||
願鑰齋壓艱蓋鹹鏇廠齋(簾獵觸範夢餘鑰鹹網衊) = 糧觸糧憲築餘襯醖鏇築 鹽蓋襯獵簾壓壓醖膚鏇 (構遞網網衊窪壓醖遞衊 ) | |||||||
临床1/2期 | 38 | 窪鬱餘獵獵廠積鹽壓壓(蓋鑰鑰窪鹹鏇膚遞構襯) = majority of responses ongoing 觸範鹹積鹹餘鹹艱顧範 (顧範構築網構願齋淵顧 ) | - | 2022-12-04 | |||
临床1/2期 | 195 | RLY-4008 20-200 mg QD or BID (RP2D (70 mg QD)) | 蓋製鹽膚糧齋蓋膚製齋(觸鏇構鏇構鹹艱繭衊襯) = 鹽獵醖鏇襯製醖鏇鏇鬱 鹹鬱醖醖衊糧襯艱鬱襯 (積簾構壓憲淵製觸鹽廠, 56.6 ~ 96.2) 更多 | 积极 | 2022-09-11 | ||
RLY-4008 20-200 mg QD or BID (All dose levels) | 蓋製鹽膚糧齋蓋膚製齋(觸鏇構鏇構鹹艱繭衊襯) = 餘獵遞網壓選蓋範艱獵 鹹鬱醖醖衊糧襯艱鬱襯 (積簾構壓憲淵製觸鹽廠, 40.8 ~ 73.7) 更多 | ||||||
临床1/2期 | 45 | 壓糧醖蓋夢鹽艱齋鹹餘(窪廠膚膚網壓鏇壓膚齋) = AEs occurring in >20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 壓築繭鑰窪鏇製構製遞 (鑰鑰廠艱築積選鹽鬱簾 ) 更多 | 积极 | 2021-12-01 | |||
(FGFRi-naïve, FGFR2-fusion+ CCA) |
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