A Phase 1/1b/2 Study of Cabozantinib in Combination With Selumetinib for Plexiform Neurofibroma in Adults and Adolescents With Neurofibromatosis Type 1

Based on the clinical activity of both selumetinib and cabozantinib as monotherapies in clinical trials, the demonstrated activity of these agents in reduced doses in preclinical studies, and the non-overlapping toxicity profiles, the study will assess the tolerability and efficacy of selumetinib and cabozantinib in combination in participants with NF1 ≥16 years old with progressive and/or symptomatic PN in a phase 1/1b/2 clinical trial.
Trial Design Phase 1 This will be an open label, dose escalation phase. Dose level escalation will be determined by a rolling six design. In this design, up to 6 participants can be enrolled at a given dose level and then evaluated for dose limiting toxicity (DLT) within the DLT window. The DLT window is defined as 16 weeks in this study based on the long half-life of cabozantinib and the desire to have maximum confidence about long-term tolerability of the combination prior to proceeding to the next dose level.
Phase 1b Once the recommended phase 2 dose has been determined in phase 1, an expanded cohort of 12 participants will be enrolled in phase 1b portion of the study.
Phase 2 This will be an open label, single-arm phase using the recommended phase 2 dose.

开始日期2026-08-01

申办/合作机构

The University of Alabama at Birmingham

[+2]

CTIS2026-525267-40-00

/ Recruiting临床4期IIT

Intensified Monitoring of PhArmacology of Cabozantinib as a tool for Toxicity management in patients with renal cell carcinoma

开始日期2026-07-30

申办/合作机构-

CTIS2023-505575-69-01

/ Not yet recruiting临床3期IIT

Fight Osteosarcoma Through European Research evolving study platform from diagnosis to relapse (FOSTER evolving study platform)

开始日期2026-07-06

申办/合作机构

Institut Gustave Roussy EURL

100 项与苹果酸卡博替尼相关的临床结果

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100 项与苹果酸卡博替尼相关的转化医学

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100 项与苹果酸卡博替尼相关的专利（医药）

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2,484

项与苹果酸卡博替尼相关的文献（医药）

2026-12-31·OncoImmunology

Efficacy and safety of cabozantinib plus nivolumab in advanced non-clear cell renal cell carcinoma: a nationwide multicenter study

Article

作者: Shin, Sang Joon ; Park, Ji Hyun ; Kim, Eo Jin ; Kang, Byung Woog ; Im, Hyeon-Su ; Kim, Chang Gon ; Park, Inkeun ; Jung, Eun Hee ; Jo, Jungmin ; Kim, Junkyu ; Park, Se Hoon ; Kim, In-Ho ; Kim, Se Hyun ; Lee, Jae-Lyun ; Rha, Sun Young ; Beom, Seung Hoon ; Park, Joo-Hwan

Non-clear cell renal cell carcinoma (nccRCC) represents a biologically heterogeneous group of tumors for which optimal systemic treatment strategies remain poorly defined despite recent therapeutic advances. To address this gap, we evaluated the clinical activity and safety of cabozantinib plus nivolumab in patients with advanced nccRCC. In this nationwide, multicenter retrospective cohort study conducted in the Republic of Korea, 62 patients received the combination across multiple lines of therapy, with most treated in the first-line setting. Papillary RCC was the most common histologic subtype (50.0%), followed by FH-deficient (22.6%), TFE3-rearranged (9.7%), chromophobe (6.5%), collecting duct (6.5%), and unclassified tumors (4.8%). With a median follow-up of 22.2 months (95% confidence interval [CI], 15.4-29.1), the objective response rate (ORR) was 45.2% (95% CI, 32.4-57.9) and the disease control rate (DCR) was 93.6% (95% CI, 87.3-99.8). Responses were seen across histologic subtypes (ORR = 48.4% in papillary, 50.0% in FH-deficient, 50.0% in TFE3-rearranged, 25.0% in chromophobe, 25.0% in collecting duct, and 33.3% in unclassified tumors; P = 0.876). Median progression-free and overall survival were 9.7 months (95% CI, 7.7-11.6) and 22.0 months (95% CI, 15.2-28.7), respectively. Grade 3-4 treatment-emergent adverse events occurred in 46.8% of patients, and treatment discontinuation due to toxicity was reported in 6.5%. These findings demonstrate that cabozantinib plus nivolumab provides clinically meaningful and durable antitumor activity with manageable toxicity across diverse histologic subtypes in advanced nccRCC, supporting further prospective evaluation of cabozantinib plus nivolumab in advanced nccRCC.

2026-08-01·JOURNAL OF NEUROIMMUNOLOGY

Re-challenge of immune checkpoint inhibitor after ICI-encephalitis: A case report

Article

作者: Shah, Suma ; Baker, Virginia

Immune-checkpoint inhibitor (ICI) related encephalitis (ICI-IE) is a severe adverse event, associated with high morbidity and mortality and requiring prompt ICI discontinuation. The safety of rechallenge with ICI after initial adverse event is largely unknown and must be considered only after cautiously weighing risks and benefits of resuming treatment. A 66-year-old otherwise healthy female was diagnosed with localized renal cell carcinoma, which was treated with immunotherapy, ipilimumab/ nivolumab. After the second cycle of treatment, she developed subacute progressive personality changes, memory loss and encephalopathy, and was diagnosed with CTCAE grade III immune-related limbic encephalitis. Her chemotherapy regimen with ipilimumab and nivolumab were promptly discontinued and she was treated with seven days of intravenous solumedrol with prolonged oral steroid taper. Four years later, she had recurrent metastatic disease, prompting the decision to pursue palliative immunotherapy with cabozantinib and immune checkpoint rechallenge with Nivolumab. Given her history of ICI-IE, neuroimmunology was consulted to discuss risks of rechallenge with ICI. Over 9 months after initiation of therapy, she remained without recurrence of immune-related adverse events (irAE) related to treatment. We present one of the first reports of successful rechallenge of immune checkpoint inhibition after ICI-IE in the setting of recurrent metastatic renal cell carcinoma. This treatment success may bolster the management options for refractory oncologic disease. Given potential risks associated with ICI rechallenge, it is imperative to employ a multidisciplinary approach with consideration of potential risks and benefits of treatment.

2026-08-01·THYROID

Targeted Therapy-Induced Erythrocytosis in Thyroid Cancers: An Underrecognized Safety Signal from a Retrospective Study

Article

作者: Spagnoletti, Andrea ; Romanò, Rebecca ; Locati, Laura Deborah ; Meschia, Lorenzo ; Colombo, Elena ; Demurtas, Sara ; Marchesi, Silvia ; Alfieri, Salvatore ; Cavalieri, Stefano ; Licitra, Lisa ; Guidetti, Anna ; Miceli, Rosalba ; De Monte, Matteo ; Sciortino, Carolina ; Salvetti, Monica ; Ottini, Arianna ; Bergamini, Cristiana ; Paolini, Biagio ; Buriolla, Silvia ; Carpenedo, Monica ; Nuzzolese, Imperia ; Barretta, Francesco

Background::

Antiangiogenic and targeted therapies represent the most effective systemic options for advanced thyroid cancers. In this setting, toxicity management is essential to ensure treatment adherence. Among hematological toxicities, erythrocytosis has been rarely investigated, and its clinical pattern and management remain unclear.

Materials and Methods::

We conducted a retrospective cohort study including patients with any advanced thyroid cancer histology treated with antiangiogenic or targeted therapies between 2012 and 2023 at two Italian referral centers. Therapies included RET inhibitors ( RET i: selpercatinib, pralsetinib), cabozantinib, the BRAF / MEK inhibitor combination dabrafenib + trametinib, lenvatinib, sorafenib, and vandetanib. Erythrocytosis, defined according to 2022 World Health Organization criteria, was assessed through serial hemoglobin and hematocrit measurements up to 36 months from treatment start. Associations with clinical variables, event-free survival (EFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and acute vascular events were assessed using Fisher’s exact and regression models, as appropriate.

Results::

Among 173 screened patients, 135 were included in the final analysis (median follow-up 68.5 months). Erythrocytosis occurred in 24 patients (17.8%), with 16/24 (66.6%) experiencing recurrent events (total: 50). Median time to onset was 1.28 months (Q1–Q3: 0.76–5.14). RET i showed the highest incidence (46.7%), followed by vandetanib (20.7%). Among 14/24 tested patients, no JAK2 V617F or exon 12 alterations were detected. Management involved temporary treatment interruption in 60.0% (30/50) of events, with 53.3% (16/30) resuming at a reduced dose; in selected cases (4/9, 44.4%), hematology-guided phlebotomy was performed without drug discontinuation. Erythrocytosis was not associated with EFS, OS, or ORR, but was associated with higher DCR ( p = 0.031). Incidence of acute vascular events was comparable among patients with (8.3%) and without (14.4%) erythrocytosis.

Conclusions::

Erythrocytosis represents an underrecognized, early, recurrent, and indolent adverse event of antiangiogenic and targeted therapies, particularly RET i, in advanced thyroid cancer. Its biological mechanisms and optimal management strategies warrant further investigation.

1,548

项与苹果酸卡博替尼相关的新闻（医药）

2026-07-31

·BioSpace

Handa Oncology Receives FDA Tentative Approval for OMCAZIO (cabozantinib) Capsules

A novel 505(b)(2) alternate-salt formulation of cabozantinib designed to improve absorption, with no clinically significant food effect TAIPEI, TW / ACCESS Newswire / July 31, 2026 / Handa Pharmaceuticals, Inc. ("Handa") (TSE:6620) announced that the U.S. Food and Drug Administration ("FDA") has granted tentative approval to OMCAZIO TM (cabozantinib) capsules, a novel alternate-salt formulation of cabozantinib developed by Handa's U.S. subsidiary, Handa Oncology, LLC (the "Company"). OMCAZIO (cabozantinib) capsules are indicated for the treatment of: adult patients with advanced renal cell carcinoma (RCC); adult patients with advanced RCC, in combination with nivolumab, as a first-line treatment; adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNET). OMCAZIO was developed under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act. In bioavailability/bioequivalence studies, OMCAZIO was shown to be bioequivalent to CABOMETYX ®1 at a lower dose, and demonstrated no clinically significant food effect, and improved absorption of cabozantinib. ezstandalone.cmd.push(function () { ezstandalone.showAds(131); }); Because OMCAZIO is bioequivalent to CABOMETYX at a lower dose, the OMCAZIO label includes the following recommendations for converting patients between the two products: CABOMETYX tablets dosage OMCAZIO capsules dosage 60 mg once daily 34.5 mg once daily 40 mg once daily 23 mg once daily 20 mg once daily 11.5 mg once daily "Tentative approval marks an important regulatory milestone for Handa. We developed OMCAZIO with the goal of providing an alternative oral cabozantinib formulation that may offer greater flexibility for patients and healthcare providers." said Bill Liu, Chairman and CEO of Handa. "We are continuing our commercial readiness activities and look forward to making OMCAZIO available to patients following FDA final approval." A tentative approval indicates that FDA has determined that an application meets the agency's standards for safety, effectiveness and manufacturing quality. Cabozantinib is one of the commonly used oral targeted therapies in oncology. According to Exelixis, Inc., U.S. net product revenues for CABOMETYX were approximately $2.11 billion in 2025. 2 Important Safety Information Boxed Warning: WARNING: RISK OF SERIOUS ADVERSE REACTIONS OR REDUCED EFFECTIVENESS DUE TO MEDICATION ERRORS OMCAZIO is not substitutable on a mg-to-mg basis with other cabozantinib products. Inappropriate substitution or incorrect conversion of OMCAZIO capsules for another cabozantinib product can increase the risk of serious adverse reactions. Confirm that the intended cabozantinib product at the intended dosage and strength is being prescribed and dispensed. WARNINGS AND PRECAUTIONS Risk of Serious Adverse Reactions or Reduced Effectiveness Due to Medication Errors: Cabozantinib is available in multiple dosage forms and strengths. OMCAZIO is not substitutable on a mg-to-mg basis with other cabozantinib products. Confirm that the intended cabozantinib product is being prescribed and dispensed. Hemorrhage: Do not administer OMCAZIO if recent history of hemorrhage. Perforations and Fistulas: Monitor for symptoms. Discontinue OMCAZIO for Grade 4 events. Thromboembolic Events: Discontinue OMCAZIO for myocardial infarction or serious venous or arterial thromboembolic events. Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt OMCAZIO for hypertension not adequately controlled with anti-hypertensive therapy. Discontinue OMCAZIO for hypertensive crisis or severe hypertension that cannot be controlled. Cardiac Failure: Monitor for signs and symptoms of cardiac failure throughout treatment. Diarrhea: May be severe. Interrupt OMCAZIO until diarrhea resolves or improve to ≤Grade 1, then resume at reduced dose. Recommend standard antidiarrheal treatments. Palmar-Plantar Erythrodysesthesia (PPE): Interrupt OMCAZIO treatment until PPE resolves or improves to Grade 1. Hepatotoxicity: When used with nivolumab, higher frequencies of Grade 3 and 4 ALT and AST elevation may occur than with OMCAZIO alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider withholding OMCAZIO and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life- threatening hepatotoxicity. Adrenal Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OMCAZIO and/or nivolumab depending on severity. Proteinuria: Monitor urine protein. Interrupt OMCAZIO until proteinuria resolves to ≤Grade 1, resume OMCAZIO at a reduced dose. Discontinue for nephrotic syndrome. Osteonecrosis of the jaw (ONJ): Withhold OMCAZIO for at least 3 weeks prior to invasive dental procedures and for development of ONJ. Impaired Wound Healing: Withhold OMCAZIO for at least 3 weeks before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of OMCAZIO after resolution of wound healing complications has not been established. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue OMCAZIO. Thyroid Dysfunction: Monitor thyroid function before and during treatment with OMCAZIO. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Adverse Reactions The most common adverse reactions (≥20%) include: OMCAZIO as a single agent - diarrhea, fatigue, palmar‑plantar erythrodysesthesia (PPE), decreased appetite, hypertension, nausea, vomiting, decreased weight, and constipation. OMCAZIO in combination with nivolumab - diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. Drug Interactions Strong CYP3A inhibitors: Reduce the OMCAZIO dosage if coadministration cannot be avoided. Strong or moderate CYP3A inducers: Increase the OMCAZIO dosage if coadministration cannot be avoided. Contraindication: None. Use in Specific Populations Lactation: Advise not to breastfeed. Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing OMCAZIO if abnormalities occur. About OMCAZIO OMCAZIO is a novel alternate-salt capsule formulation of cabozantinib, a tyrosine kinase inhibitor. The formulation is engineered to improve absorption and can be administered with or without food. OMCAZIO has received tentative approval from the FDA and is not yet available for commercial distribution in the United States. About Handa Pharmaceuticals, Inc. Handa is a specialty pharmaceutical company that focuses on developing high-quality medications that address significant unmet medical needs in oncology and neurology. Handa's leadership has a proven track record of building effective teams, high quality product portfolios and successful pharmaceutical businesses. For more information, please visit Forward-Looking Statements This document and the related information released concurrently contain forward-looking statements. Except for statements of historical fact, all statements regarding the future business operations, possible events, and outlook of Handa - including, but not limited to, forecasts, targets, estimates, and operational plans - are forward-looking statements. These statements are subject to various factors and uncertainties that could cause actual results to differ materially from those expressed or implied. Such factors include, but are not limited to, price fluctuations, actual demand, exchange rate movements, market share, competitive conditions, changes in the legal, financial, and regulatory environment, international economic and financial market conditions, political risks, cost estimates, and other risks and variables beyond Handa's control. These forward-looking statements are based on current forecasts and assessments, and Handa assumes no obligation to update them. Contact: Email: info@handapharma.com Phone: +1 (510) 354-2888 CABOMETYX ® is a registered trademark of Exelixis, Inc. Handa is not affiliated with Exelixis, Inc. References 1 CABOMETYX ® (cabozantinib) tablets, prescribing information 2 Exelixis, Inc. annual report / Form 10-K SOURCE: Handa Pharma, Inc. View the original press release on ACCESS Newswire

上市批准加速审批临床结果

2026-07-30

·会康临研

肝癌（肝细胞癌）热门靶点与2/3期临床试验进展

会康临研，You will be fine ❤️ 欢迎转发，让更多人有机会得到帮助 💞 ☆ 主题：肝细胞癌（HCC）系统治疗、局部联合治疗与细胞治疗的热门方向、2/3期临床试验进展及国内企业在研格局数据截至：2026年7月30日文中所列大部分临床试验，如果有需求，都可以联系转发本文的分享者帮忙对接！ ☆ 引言原发性肝癌是全球第六大常见恶性肿瘤、第三大癌症相关死因。据GLOBOCAN 2022统计，全球年新发病例约86.5万例、死亡约75.8万例；中国年新发病例约37万例，约占全球四成，且约80%与乙型肝炎病毒（HBV）感染相关，疾病负担远超欧美。肝细胞癌（HCC）占原发性肝癌的75%～85%，是临床研究的主体。 HCC的治疗按分期分层：早期以手术切除、消融和肝移植为主，中期以经肝动脉化疗栓塞（TACE）为标准，晚期则以系统治疗为主。 2020年IMbrave150研究确立免疫联合抗血管生成的一线地位后，HCC系统治疗进入"免疫联合+"时代；2024—2026年，双免疫联合、免疫联合TKI、TACE联合系统治疗、FGF19/FGFR4精准靶向以及GPC3靶向细胞治疗相继取得突破，同时辅助治疗领域也经历了阳性信号与阴性教训的反复。本文梳理当前HCC 2/3期临床试验的热门方向、关键研究数据及国内创新药企业的代表性在研项目。 ☆ 一、一线治疗：免疫联合方案重塑格局免疫联合抗血管/TKI：多方案并立 IMbrave150（阿替利珠单抗+贝伐珠单抗）：首个击败索拉非尼的免疫联合方案，更新数据中位总生存（mOS）19.2个月对13.4个月，客观缓解率（ORR）约30%对11%，长期被视为全球一线标准。 CARES-310（卡瑞利珠单抗+阿帕替尼，"双艾"组合）：发表于《柳叶刀》的国际多中心III期，最终分析显示mOS 23.8个月对15.2个月（HR=0.64），2年OS率49.0%对36.2%，3年OS率37.7%对24.8%，ORR 26.8%对5.9%，是目前一线III期中最长的OS纪录；2025年获ESMO指南和BCLC指南收录推荐。该方案已获中国国家药监局（NMPA）批准，并被列为我国《原发性肝癌诊疗指南（2026年版）》一线治疗1类证据、A级推荐。 HIMALAYA（度伐利尤单抗+曲美木单抗，STRIDE方案）：mOS 16.4个月对13.8个月（HR=0.78），2022年获FDA批准，是首个双免疫一线方案。 CheckMate 9DW（纳武利尤单抗+伊匹木单抗）：发表于《柳叶刀》（2025），mOS 23.7个月对20.6个月（HR=0.79），ORR 36.1%对13.2%，中位缓解持续时间30.4个月对12.9个月；2025年4月获FDA批准一线适应症，双免疫路线的深度缓解优势突出。阴性参照——LEAP-002（仑伐替尼+帕博利珠单抗）：mOS 21.2个月对19.0个月（HR=0.84），未达预设统计学界值。提示并非所有"免疫+TKI"组合都能复现成功，方案间的药物选择与剂量设计至关重要。监管动态：国产方案出海的喜与忧 "双艾"组合的美国上市之路一波三折：2024年5月、2025年3月及2026年7月10日三度收到FDA完整回复函（CRL），拒批原因均集中于生产现场核查问题，临床数据本身始终未受质疑。企业表示将完成整改后重新提交。该案例提示：临床证据过硬之外，CMC（化学、生产与控制）与全球合规体系同样是创新药国际化的决定性变量。国内企业代表性在研项目恒瑞医药的"双艾"组合（卡瑞利珠单抗+阿帕替尼）——CARES-310国际III期奠定晚期一线地位，并已向围手术期、TACE联合等全病程场景扩展（见第三、六节）。信达生物的信迪利单抗联合贝伐珠单抗类似物IBI305——ORIENT-32研究OS风险比0.57，2021年6月获NMPA批准，为国内首个肝癌一线免疫联合方案。百济神州的替雷利珠单抗——RATIONALE-301研究证实单药一线治疗非劣于索拉非尼（mOS 15.9个月对14.1个月），已获NMPA批准用于不可切除HCC一线治疗。正大天晴/康方生物的安罗替尼联合派安普利单抗——APOLLO研究（发表于《柳叶刀·肿瘤学》2025）：全国79家中心、649例患者，mPFS 6.9个月对2.8个月（HR=0.52），mOS 16.5个月对13.2个月（HR=0.69，P=0.0014），PFS与OS双主要终点均达阳性，成为国产"免疫+TKI"一线新选项。 ☆ 二、TKI与二线治疗：国产创新守住基本盘小分子酪氨酸激酶抑制剂（TKI）是免疫时代之前HCC系统治疗的基石，至今仍是肝功能不佳、免疫禁忌患者的重要选择，也是联合方案的核心组分。一线TKI：索拉非尼（SHARP研究）与仑伐替尼（REFLECT研究，非劣于索拉非尼）沿用十余年；多纳非尼在ZGDH3头对头III期中mOS 12.1个月对10.3个月（HR=0.83）优效于索拉非尼，2021年获NMPA批准，为中国首个自主研发的一线肝癌TKI。二线治疗：瑞戈非尼（RESORCE研究，mOS 10.6个月对7.8个月）、卡博替尼（CELESTIAL研究，mOS 10.2个月对8.0个月）、雷莫西尤单抗（REACH-2研究，限定AFP≥400 ng/mL人群，mOS 8.5个月对7.3个月）为国际三大二线标准；阿帕替尼基于AHELP研究（mOS 8.7个月对6.8个月）于2020年12月获NMPA批准，为国内首个肝癌二线靶向药物。国内企业代表性在研项目泽璟制药的多纳非尼——ZGDH3研究以头对头优效设计击败索拉非尼，是中国首个自主一线肝癌TKI，已纳入国家医保。恒瑞医药的阿帕替尼——AHELP研究确立二线地位，并以"双艾"组合延伸至一线（见第一节），同时以联合TACE的随机III期拓展中期人群（见第三节），实现单药价值的全病程开发。需要指出的是，瑞戈非尼、卡博替尼、雷莫西尤单抗等国际二线标准均已进入国内临床指南，而国产二线靶向格局目前仍以阿帕替尼为主，新型二线小分子尚存空白。 ☆ 三、中期肝癌：TACE联合系统治疗确立新标准中期（BCLC B期）及不可切除HCC长期依赖单纯TACE，但重复栓塞损伤肝功能，且栓塞后VEGF升高促进血管新生与复发转移。2024—2026年，多项III期研究确立了"TACE+免疫+抗血管"三联策略的标准地位。 EMERALD-1（度伐利尤单抗+贝伐珠单抗+TACE）：发表于《柳叶刀》（2025），三联组mPFS 15.0个月对8.2个月（HR=0.77），ORR 43.6%对29.6%；值得注意的是，度伐利尤单抗+TACE（不含贝伐珠单抗）组HR=0.94为阴性，提示"免疫+抗血管"双阻断缺一不可。这是全球首个TACE联合治疗阳性III期。 LEAP-012（仑伐替尼+帕博利珠单抗+TACE）：发表于《柳叶刀》（2025），mPFS 14.6个月对10.0个月（HR=0.66），ORR 46.8%对33.3%；但OS期中分析HR=0.80未达显著，且3—4级治疗相关不良反应达71.3%、出现4例治疗相关死亡。该方案2025年6月获NMPA批准，但全球开发于2025年10月因OS无效性分析而终止——PFS获益、毒性负担与OS金标准之间的权衡，为后续方案设计提供了重要镜鉴。 TALENTACE（阿替利珠单抗+贝伐珠单抗+按需TACE）：2025年ESMO-GI大会LBA报告的中国III期，针对高肿瘤负荷不可切除HCC，TACE-PFS 11.30个月对7.03个月（HR=0.71）。国内企业代表性在研项目恒瑞医药的"双艾"联合TACE（CARES-336/SHR-1210-III-336研究）——全国34家中心、423例的随机对照III期，2026年ASCO大会口头报告：较单纯TACE，BIRC评估PFS取得具有临床意义和统计学显著性的改善，并已观察到OS获益趋势；该适应症上市申请已于2026年初获NMPA受理。恒瑞医药的CARES-005/CHANCE2005研究——TACE联合"双艾"的随机II期（发表于《临床肿瘤学杂志》2026），为III期的剂量与方案设计奠定基础，证据链完整连贯。恒瑞医药阿帕替尼联合TACE随机III期（发表于《BMC医学》2025，ChiCTR1800018621）——mPFS 6.1个月对3.4个月，mOS 28.9个月对24.0个月，ORR 58.1%对31.5%，支持"局部+抗血管"策略。 CHANCE2211全国多中心真实世界研究（发表于《欧洲放射学》2023）——倾向评分匹配后，TACE联合卡瑞利珠单抗+阿帕替尼较单纯TACE显著延长mOS（24.1个月对15.7个月，校正HR=0.41）和mPFS（13.5个月对7.7个月），ORR 59.5%对37.4%，为三联策略提供真实世界佐证。 ☆ 四、新靶点与新机制：FGF19/FGFR4、TIGIT与双功能抗体 HCC长期被视为"无驱动基因可用"的瘤种，精准治疗进展缓慢。2024—2026年，分子分型指导的靶向治疗开始出现实质性突破。 FGF19/FGFR4：HCC首个可成药的分子分型方向约30%的HCC存在FGF19过表达/扩增，通过FGFR4驱动肿瘤增殖。第一代FGFR4选择性抑制剂fisogatinib（BLU-554）在FGF19阳性HCC中验证通路成药性（I期ORR约17%）；新一代高选择性FGFR4抑制剂irpagratinib（ABSK-011）在经免疫治疗的FGF19阳性患者中单药ORR达44.8%（2025年ESMO-GI报告），联合阿替利珠单抗在初治患者ORR 50.0%、免疫经治患者ORR 52.9%，中位PFS均不低于7.0个月。该药2025年5月获CDE突破性治疗认定、2026年2月获FDA快速通道资格、2026年4月获EMA孤儿药资格，注册性研究正在推进。TIGIT与双功能抗体 TIGIT：SKYSCRAPER-14研究（替瑞利尤单抗+阿替利珠单抗+贝伐珠单抗对阿替利珠单抗+贝伐珠单抗）III期正在进行中，II期IMbrave152研究已显示加入TIGIT单抗后ORR提升的信号。双功能抗体：PD-1/CTLA-4组合抗体QL1706的DUBHE-H-308研究（II/III期，NCT05976568）一线治疗晚期HCC，2024年ESMO报告显示QL1706联合贝伐珠单抗组ORR 35.5%、疾病控制率87.1%。国内企业代表性在研项目和誉医药的irpagratinib（ABSK-011）——全球进度领先的高选择性FGFR4抑制剂，一年内连获中、美、欧三项资格认定，有望填补FGF19阳性HCC精准治疗的空白。齐鲁制药的QL1706（艾帕洛利托沃瑞利单抗）——PD-1/CTLA-4双功能单分子抗体，肝癌一线II/III期推进中；该药已于2024年在国内获批宫颈癌适应症。基石药业的fisogatinib（BLU-554，大中华区权益）——全球首个进入临床的FGFR4抑制剂，完成通路概念验证，为后续国产FGFR4抑制剂的开发铺路。 ☆ 五、细胞治疗：GPC3 CAR-T与HBV TCR-T领跑实体瘤细胞治疗 GPC3（磷脂酰肌醇蛋白聚糖3）在70%～80%的HCC中特异性高表达，HBV慢性感染则为TCR-T提供了病毒抗原靶点，使肝癌成为实体瘤细胞治疗最活跃的领域之一。当前管线以国内企业和中国研究者为主导，覆盖I期至确证性III期。西比曼生物/阿斯利康的C-CAR031（装甲型GPC3 CAR-T）——2024年ASCO报告：24例末线患者ORR 56.5%、疾病控制率91.3%，最高剂量组ORR达75%；2025年更新中位OS达11.14个月。2026年1月，阿斯利康以最高6.3亿美元收购该药中国区全部权益份额，成为国产实体瘤CAR-T出海的标志性交易。科济药业的CT011（GPC3 CAR-T）——研究者发起试验长期随访中，1例患者经治疗后无瘤生存超过8年；2024年1月获NMPA批准开展GPC3阳性高复发风险HCC术后辅助III期，为全球首个进入确证性III期的实体瘤CAR-T，实现从末线挽救向治愈性场景的跨越。原启生物的Ori-C101（GPC3 CAR-T）——I期研究ORR 44.4%（4/9）、疾病控制率77.8%，已进入确证性II期，为国内注册进度最快的GPC3 CAR-T之一。星汉德生物的SCG101（HBV特异性TCR-T）——2024年AASLD报告：92%的患者乙肝表面抗原（HBsAg）下降1.0～4.6 log10，约三分之一实现HBsAg持续清除（≥9个月），并观察到肿瘤缓解，呈现"抗病毒+抗肿瘤"双重机制，对HBV相关肝癌具有源头治疗潜力。来恩生物的LioCyx-M004（HBV特异性TCR-T）——I/II期研究初步显示抗病毒与抗肿瘤双重活性，尚待更大样本验证。其他方向如肿瘤浸润淋巴细胞（TIL）与新抗原疫苗在HCC中尚处于I期探索阶段，暂无随机对照数据。 ☆ 六、围手术期与辅助治疗：阳性信号与阴性教训并存 HCC术后5年复发率超过70%，辅助治疗需求迫切，但该领域迄今无任何方案获批，且近年多项大型研究相继受挫，教训与希望并存。 CARES-009（围手术期"双艾"组合）：发表于《柳叶刀》（2025）的中国随机2/3期（294例），围手术期卡瑞利珠单抗+阿帕替尼较单纯手术显著延长中位无事件生存（42.1个月对19.4个月，HR=0.59，P=0.004），3级及以上不良反应38%，OS随访中。这是可切除HCC围手术期免疫联合治疗的首个随机阳性证据。 IMbrave050（阿替利珠单抗+贝伐珠单抗辅助）：初期RFS分析HR=0.72（P=0.012）一度被视为突破，但35个月随访更新后HR=0.90（无统计学意义），OS风险比1.26，获益未能维持，未获指南采纳——提示辅助治疗短期RFS阳性不等于长期获益。 KEYNOTE-937与CheckMate 9DX：帕博利珠单抗单药辅助（959例，mRFS 46.7个月对45.5个月）与纳武利尤单抗单药辅助均未达到RFS终点。单药免疫辅助策略接连阴性，提示联合方案（免疫+抗血管）与人群筛选可能是辅助治疗的必要条件。国内企业代表性在研项目恒瑞医药的"双艾"围手术期方案——CARES-009为可切除HCC提供首个随机阳性证据，OS数据值得期待。信达生物的信迪利单抗——针对微血管侵犯（MVI）阳性患者的辅助随机II期（198例，发表于《自然·医学》2023）：mRFS 27.7个月对15.5个月（HR=0.534），3—4级不良反应仅12.4%，开创了"生物标志物筛选+辅助治疗"的中国路径，III期验证待开展。君实生物的特瑞普利单抗——JUPITER-04辅助III期（402例）正在进行中。科济药业的CT011——GPC3阳性高复发风险HCC术后辅助III期（见第五节），细胞治疗向辅助场景前移的代表。 ☆ 七、结语过去五年，HCC治疗完成了从"TKI单药时代"向"免疫联合+时代"的整体切换：一线OS纪录被刷新至23.8个月，双免疫、免疫+TKI、免疫+抗血管多条路线并存；TACE联合系统治疗确立中期新标准；FGF19/FGFR4使HCC首次拥有可成药的分子分型方向；GPC3 CAR-T与HBV TCR-T则让肝癌站上了实体瘤细胞治疗的最前沿。同时也应清醒地看到：辅助治疗仍是"无人区"，KEYNOTE-937、CheckMate 9DX的阴性与IMbrave050获益的衰减提示，短期RFS阳性并不等于长期生存获益，OS仍是不可动摇的金标准；LEAP-012的高毒性教训警示联合方案需审慎权衡获益与负担；而"双艾"组合三遇FDA CRL则说明，临床数据之外，生产质量体系与国际合规能力同样决定中国创新药能走多远。下一阶段，生物标志物指导的人群筛选、全病程序贯策略的优化，以及细胞治疗向治愈性场景的前移，将是HCC研究最值得期待的方向。风险提示：本文内容仅供学术交流参考，不构成任何诊疗建议。文中涉及的研究数据均来自公开发表的文献与学术会议报告，具体治疗请遵循临床指南与专科医生意见。 ☆ 参考文献 Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905（IMbrave150）. Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310). Lancet. 2023;402:1133-1146. Qin S, Gu S, Chan SL, et al. CARES-310最终分析. Lancet Oncol. 2025;26(12):1598-1611. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma（HIMALAYA）. NEJM Evid. 2022;1(8). Galle PR, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma（CheckMate 9DW）. Lancet. 2025;405:1851-1864. Llovet JM, et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma（LEAP-002）. Lancet Oncol. 2023;24:1399-1410. Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma（ORIENT-32）. Lancet Oncol. 2021;22:977-990. Qin S, et al. Tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma（RATIONALE-301）. Lancet Oncol. 2023;24:1311-1324. Zhou J, Bai L, Luo J, et al. Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma（APOLLO）. Lancet Oncol. 2025;26(6):719-731. Qin S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma（ZGDH3）. J Clin Oncol. 2021;39:3002-3011. 阿帕替尼二线治疗晚期肝细胞癌的随机、双盲、安慰剂对照III期研究（AHELP）. Liver Cancer. 2021. Zhu AX, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations（REACH-2）. Lancet Oncol. 2019;20:282-296. Bruix J, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment（RESORCE）. Lancet. 2017;389:56-66. Abou-Alfa GK, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma（CELESTIAL）. N Engl J Med. 2018;379:54-63. Sangro B, et al. Durvalumab plus bevacizumab with transarterial chemoembolisation in unresectable hepatocellular carcinoma（EMERALD-1）. Lancet. 2025;405:216-232. Llovet JM, et al. Transarterial chemoembolization combined with lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma（LEAP-012）. Lancet. 2025;405:203-215. Jia W, et al. Camrelizumab plus rivoceranib with TACE vs TACE alone in unresectable hepatocellular carcinoma（CARES-336/SHR-1210-III-336）. 2026 ASCO年会口头报告（摘要号4001）；恒瑞医药公告，2026年6月. Zhu HD, Teng GJ, et al. Transarterial chemoembolization combined with camrelizumab and rivoceranib for unresectable hepatocellular carcinoma（CHANCE2005/CARES-005）. J Clin Oncol. 2026;44(11):959-969. Jin ZC, Zhong BY, Chen JJ, et al. Real-world efficacy and safety of TACE plus camrelizumab and apatinib in patients with HCC（CHANCE2211）. Eur Radiol. 2023;33(12):8669-8681. Kan XF, et al. Transarterial chemoembolization plus apatinib for unresectable hepatocellular carcinoma: a multicenter, randomized, open-label, phase III trial. BMC Med. 2025（ChiCTR1800018621）. 围手术期卡瑞利珠单抗联合阿帕替尼治疗可切除肝细胞癌的随机2/3期研究（CARES-009）. Lancet. 2025;406:2089-2099. Perioperative immunotherapy for hepatocellular carcinoma（围手术期免疫治疗综述，含KEYNOTE-937、CheckMate 9DX、IMbrave050更新数据）. 2026. 信迪利单抗辅助治疗微血管侵犯阳性肝细胞癌的随机II期研究. Nat Med. 2023. 和誉医药公告：irpagratinib（ABSK-011）获CDE突破性治疗认定（2025年5月）、FDA快速通道资格（2026年2月）、EMA孤儿药资格（2026年4月）；2025 ESMO-GI大会报告. C-CAR031在晚期肝细胞癌中的I期研究. 2024 ASCO年会；西比曼生物/阿斯利康公告（2026年1月）. SCG101（HBV特异性TCR-T）治疗HBV相关肝细胞癌的I期研究. 2024 AASLD年会. 国家卫生健康委员会. 原发性肝癌诊疗指南（2026年版）. 2026年4月. ☆ 重要声明与提示 1，本研究严格遵循《赫尔辛基宣言》和 GCP（药物临床试验质量管理规范）要求，所有入组患者的权益都将得到充分保障； 2，本研究已获得国家药品监督管理局批准（登记号：），并通过各中心伦理委员会审查研究为开放标签设计，患者知晓所接受的治疗方案参与研究为自愿行为，可随时退出，不影响后续正常医疗最终入组资格需经研究医生全面评估后确定。 3，本文信息来源于药物临床试验登记与信息公示平台及公开学术资料，仅供医学科普和招募信息传播使用，不构成具体医疗建议。具体诊疗方案请遵医嘱。 ☆ 关于我们会康临研是由一群有着相同初心的生物医药人共同搭建的一个公益性质的临床试验项目聚合信息与咨询平台。致力于分享新的前沿的临床试验招募信息，为有需求且符合条件的患者寻找新的希望，同时能得到免费的救治。也欢迎大家动动小手，转发给更多有需要的人，每一次转发，都是一次希望的传递！❤️❤️ ☆ 1. 胰腺癌的临床试验概况：热点靶点、最新进展与细胞治疗/疫苗探索 2. 胃癌的临床试验概况：热门靶点、最新进展与细胞治疗突破 3. 结直肠癌的临床试验概况：热门靶点、最新进展与细胞治疗探索

2026-07-30

·今日头条

2026肝癌新药研发模型怎么选？皮下、原位、人源化分层决策全攻略

关键要点肝癌（HCC）约 80%–90% 继发于肝硬化背景，肿瘤生长在已纤维化、免疫失衡的"病肝"微环境中，脱离这一背景的模型药效数据极易与临床脱节。常规皮下模型对免疫检查点抑制剂（ICI）常出现假阳性疗效，无法预测肝癌真实的低客观缓解率（ORR）。模型选择应遵循"分层递进"逻辑：早期 CDX 快筛 → 靶点阳性/通路依赖模型 → 同基因原位/人源化/转移模型 → PDX/PDO 患者分层。 FDA 2020年批准 T+A 方案（阿替利珠单抗+贝伐珠单抗）以来，肝癌一线治疗已进入免疫联合时代，对模型免疫背景完整性提出更高要求。云桥璞瑞（ClinBridge Biotech）已布局覆盖"肝病背景+免疫微环境"的肝癌模型体系，同基因原位、人源化原位、伴纤维化/硬化原位（开发中）、普通 CDX，支撑从早期筛选到免疫完整背景 POC 的全链路研究。一组数据，看清肝癌新药研发的"模型困局" 肝癌有多难治？全球每年新发肝癌病例约 90万例，中国占 45% 以上。肝细胞癌（HCC）占原发性肝癌的 75%–85% ，是最主要的病理类型。更棘手的是——约 80%–90% 的 HCC 继发于肝硬化背景。也就是说，肿瘤不是长在"好肝"上，而是长在已经纤维化、免疫失衡的"病肝"里。这种独特的肿瘤微环境（TME），是肝癌区别于多数实体瘤的核心特征。也正因为此，常规的动物模型"搞不定"肝癌。 2020年以来，随着免疫联合疗法接连获批，临床前模型的选择正在成为新药研发成败的关键变量。这篇文章，我们把肝癌动物模型的选择逻辑讲透。一、肝癌治疗进入"免疫联合时代"，模型跟上了吗？ 1.1 一线治疗格局巨变先看临床端发生了什么：阿替利珠单抗+贝伐珠单抗（T+A）： FDA 2020年批准用于不可切除 HCC 一线，凭借显著 OS 获益确立标准地位。卡瑞利珠单抗+阿帕替尼（"双艾"组合）： NMPA 2023年1月批准晚期 HCC 一线，成为首个国产"PD-1+小分子抗血管"组合。度伐利尤单抗+曲美木单抗（STRIDE）： FDA 2022年批准， NMPA 2026年4月批准在华一线治疗。纳武利尤单抗+伊匹木单抗（O+Y）： FDA 2025年4月批准， NMPA 2025年3月批准在华一线。一句话总结：肝癌一线治疗，已经从"单药独大"变成了免疫联合、双免治疗多条路线并行。 1.2 临床进步给模型出的"考题" 治疗格局变化意味着什么？意味着临床前研究要回答的问题变了。不再只是"肿瘤能不能缩小"，而是：免疫细胞能不能浸润进去？抗血管生成的机制是否验证了？肝内微环境的影响考虑了吗？联合治疗的机制说清楚了吗？这些问题，靠一株肝癌细胞打到皮下，远远不够。 1.3 后线治疗和新兴靶点同样重要多纳非尼 NMPA 2021年批准一线；瑞戈非尼、卡博替尼、雷莫芦单抗构成后线选择。其中，雷莫芦单抗是首个获 FDA 批准的 HCC 生物标志物驱动疗法，适用于 AFP ≥ 400 ng/mL 的特定人群。新兴靶点方面， GPC3 是 CAR-T 细胞治疗热门靶点， FGFR4 、 c-MET 、 CD147 等方向也在持续探索。这些药物的模型选择，不是"随便挑一株肝癌细胞系"就能解决的。二、为什么常规皮下模型"搞不定"肝癌？这是很多研发团队容易踩的坑。皮下模型构建简单、成本低、稳定性高——这些优点不假。但用在肝癌免疫治疗评价上，存在三大致命缺陷：表格维度皮下模型原位模型解剖部位皮下疏松结缔组织，与肝脏微环境天差地别肝脏原位，保留 Kupffer 细胞、肝窦内皮细胞等特异性免疫细胞纤维化/基质背景无法重现"因病致癌"的慢性炎症/肝硬化背景可结合纤维化诱导，还原"病肝"病理特征免疫应答缺乏肝脏特有的免疫耐受，对 ICI 常出现假阳性保留肝脏免疫抑制网络，更真实预测临床 ORR 氧分压/代谢皮下氧分压与肝脏显著不同更接近肝脏缺氧、酸中毒的微环境特征药物递送无法模拟肝内异常血管导致的递送障碍可再现物理屏障与代谢屏障简单说：皮下模型对免疫治疗"过于乐观" ，给出的药效数据放到临床上往往兑现不了。这也是为什么，行业正在加速转向原位模型、人源化模型、伴纤维化背景模型等更复杂的系统。三、肝癌模型到底怎么选？一张表说清楚 3.1 先按靶点选细胞系模型选择的第一步，不是选"模型类型"，而是选细胞系。核心逻辑：药物需要什么生物学背景，就选什么细胞系。表格靶点方向常用细胞系关键提示 GPC3 靶向 Hep3B、HepG2、Huh7（均 GPC3 阳性）先用流式/IHC 确认表达水平和抗原密度 FGFR4 靶向 HepG2、Huh7 确认 FGF19–FGFR4–β-Klotho 通路可检测 c-MET /侵袭转移 HCCLM3、MHCC97-H、MHCC97-L 建议结合原位或转移模型 HBV 相关 PLC/PRF/5 基因组整合 HBV DNA，分泌 HBsAg 间质样/EMT/耐药 SNU-449、SNU-475 、SNU-182、SNU-398、SNU-387 探索异质性、耐药和信号通路机制特别注意： HepG2 虽广泛用于肝源性肿瘤研究，但目前被认为更符合肝母细胞瘤来源，不宜作为典型成人 HCC 唯一代表。 3.2 再按药物类型选模型路径表格药物类型优先模型路径核心 readout 多靶点 TKI / 小分子皮下 CDX → 原位 CDX TGI、剂量反应、PK/PD 抗血管生成 CDX 初筛 → 原位/高血管生成模型 TGI、血管生成标志物、坏死 ADC / 双抗 / TCE 靶点阳性 CDX → 原位/人源化抗原密度、内吞、体内药效 CAR-T / 细胞治疗靶点阳性 CDX → 原位/PDX/人源化肿瘤清除、细胞浸润扩增、抗原逃逸 IO 或 IO 联合同基因模型 → 人源化模型 CD8+ T 细胞、Treg、MDSC、细胞因子抗转移/PVTT 高转移细胞系 → 原位/转移模型肝内播散、肺转移、血管侵犯核心原则：模型不是越复杂越好，而是要与药物问题相匹配。早期项目要效率，转化项目要相关性，免疫项目要免疫背景。四、云桥璞瑞的解题思路：分层递进的模型体系云桥璞瑞围绕肝癌疾病生物学特征和行业痛点，已布局一系列临床前转化模型，适合处于不同开发阶段的新分子药物评估。除常用肝癌 CDX 模型外，云桥重点打造了可模拟肝脏免疫抑制 TME 的动物模型，包括同基因肝癌原位肿瘤模型、人源化肝癌原位肿瘤模型，以及转移型肝癌肿瘤模型，支持候选药物从早期体内药效筛选、靶向机制验证，到原位评价和免疫完整背景 POC 的分层研究。 4.1 四层模型能力第一层：普通人肝癌 CDX 模型包括 Huh-7、HCCLM3、HepG2、Hep3B、PLC/PRF/5、MHCC97-H、SNU-878 等。构建简单、时间线短、成本低，适合 TKI/抗血管/ADC 等早期药理药效评估。第二层：荧光标记原位/转移模型 HepG2-LG、HCCLM3-LG、Huh-7-LG、Hep3B-LG、H22-LG 等。支持活体成像追踪，适合微环境靶向和代谢靶向研究。第三层：鼠源同基因+人源化模型 H22、Hepa1-6 同基因模型；Hu-PBL/Hu-CD34+ 免疫系统人源化 CDX 模型。支持人源靶点 ADC/双抗/TCE、IO 联合、CAR-T 细胞治疗评价。第四层：伴纤维化/硬化原位模型（开发中）+GEMM 先通过长期注射四氯化碳或饮食诱导使小鼠产生肝纤维化/肝硬化，再进行原位成瘤。极高还原临床"病肝"特征，天然具备强免疫抑制微环境。GEMM 通过基因敲除或突变在免疫功能完整小鼠体内自发诱导肝癌。四类建模策略说明 1. 同源原位肝癌模型（Orthotopic Syngeneic）：将小鼠肝癌细胞（如 H22、Hepa1-6）直接注射或植入具有正常免疫系统的小鼠肝包膜下或肝实质内。优势：肿瘤在自然的肝脏微环境中生长，能较好招募宿主免疫细胞，并部分重现肝脏特有的免疫抑制微环境，是评估免疫联合疗法（如 PD-1 抗体联合靶向药/ADC）比较理想的动物模型。 2. 人源化小鼠模型与 GEMMs ：在免疫缺陷小鼠（NOG/NSG）体内重建人类造血/免疫系统（Hu-PBL / Hu-CD34+），并接种人源肝癌 CDX，允许直接评估针对人类靶点的免疫新药（如靶向人源抗原的 BsADC 或 CAR-T/CAR-NK）；GEMM 则在免疫完整小鼠体内自发诱导肝癌。 3. 伴肝纤维化 / 硬化的原位模型（开发中）：先诱导肝纤维化/硬化再原位成瘤，还原"病肝"的强免疫抑制微环境。 4. 普通人肝癌 CDX 模型：构建简单、稳定性高，适用于细胞毒类、细胞周期阻断剂、化疗药及明确靶向小分子药物的药理药效评估。 4.2 数据说话云桥璞瑞已积累多个标准模型的药效数据： Huh-7 皮下模型： HepG2-LG 原位模型：建立生长曲线和活体成像追踪体系。 H22-LG 同基因原位模型：五、结论：从"模型展示"到"证据链设计" 一句话概括趋势：肝癌临床前模型选择，正在从"我有什么模型"转向"我的药物需要什么证据链"。分层递进逻辑很清晰：早期筛选：CDX 快速拿体内药效信号靶点验证：进入靶点阳性/通路依赖模型免疫/微环境/转移：升级至同基因、原位、人源化、病因背景模型患者分层：PDX/PDO/PDOX 转化验证肝癌新药研发的成败，很大程度取决于模型能不能"说实话"。只有在更贴近临床的微环境中严格筛选，才能有效降低临床试验的失败率。你怎么看？你所在的团队在肝癌模型选择上踩过哪些坑？欢迎留言讨论。 FAQ Q1：肝癌药物临床前模型为什么不能只用皮下模型？ A：皮下模型存在三大缺陷——解剖部位错位（皮下组织与肝脏微环境天差地别）、缺乏纤维化/基质背景（无法重现"因病致癌"）、免疫应答失真（对 ICI 常出现假阳性，无法预测肝癌真实低 ORR）。 Q2：评价 PD-1/PD-L1 抗体该用什么肝癌模型？ A：评价鼠源 PD-1/PD-L1 抗体可用 H22、Hepa1-6 等同基因模型做早期 IO POC；评价人源 PD-1/PD-L1 抗体则需人源化体系（Hu-PBL/Hu-CD34+），并应先行确认其与鼠源靶点的种属交叉反应。 Q3：云桥璞瑞有哪些肝癌临床前模型？ A：覆盖四类——普通人肝癌 CDX（Huh-7、HCCLM3、HepG2、Hep3B、PLC/PRF/5、MHCC97-H、SNU-878）、荧光标记原位/转移模型（HepG2-LG 等）、鼠源同基因+人源化模型（H22、Hepa1-6、Hu-PBL/Hu-CD34+）、伴纤维化/硬化原位模型（开发中），以及 GEMM。 Q4：GPC3 ADC 或 CAR-T 项目该选什么模型？ A：先确认模型中的 GPC3 表达和抗原密度（Hep3B/HepG2/Huh7 均为 GPC3 阳性），用 GPC3 阳性 CDX 做基础验证，再升级至原位或人源化模型评估体内药效与效应细胞参与；必要时设置低表达或阴性对照。 Q5：皮下模型和原位模型到底有什么区别？ A：核心区别在于微环境真实性。皮下模型在疏松结缔组织中生长，缺乏肝脏特有的 Kupffer 细胞、肝窦内皮细胞和免疫耐受网络；原位模型将肿瘤细胞直接种植于肝实质内，保留了肝脏的免疫抑制特征、纤维化背景和异常血管生成，药效数据更贴近临床。参考文献 [1] U.S. FDA. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. 2020-05-29. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma [2] 新华财经（新华网）. 恒瑞医药创新药获批新适应症：卡瑞利珠单抗联合阿帕替尼获 NMPA 批准一线治疗晚期肝癌. 2023-01-31. https://www.cnfin.com/gs-lb/detail/20230131/3795008_1.html [3] 恒瑞医药公告（载《中国证券报》）. 关于注射用卡瑞利珠单抗收到 FDA 完整回复信（CRL）. 2026-07-11. https://epaper.cs.com.cn/zgzqb/wap/html/2026-07/11/nw.D110000zgzqb_20260711_7-B018.htm [4] U.S. FDA. Drug Trials Snapshots: IMJUDO（tremelimumab + durvalumab）. Original approval 2022-10-21. https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-imjudo [5] 阿斯利康中国官网. 英飞凡®联合英卓凡®在华获批一线治疗晚期或不可切除肝细胞癌（HCC）. 2026-04-27. https://www.astrazeneca.com.cn/zh/media/press-releases/2026/04-27-01.html [6] U.S. FDA. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. 2025-04-11. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma [7] 新华网. 欧狄沃联合逸沃成为中国目前唯一获批的肝细胞癌一线双免疫联合疗法（NMPA 批准，2025-03-31）. https://app.xinhuanet.com/news/article.html?articleId=91bd3ba3c08b7cdbf58d1198f178d57c [8] 泽璟制药官网. 甲苯磺酸多纳非尼片（泽普生®）获 NMPA 批准用于不可切除肝细胞癌一线（批准日期 2021-06-09）. 2021-07-11. https://www.zelgen.com/xinwenzhongxin/2021/07-11/228.html [9] Eli Lilly and Company. Lilly's CYRAMZA®（ramucirumab）成为首个获 FDA 批准的 HCC 生物标志物驱动疗法（AFP ≥400 ng/mL）. 2019-05-10. https://investor.lilly.com/news-releases/news-release-details/lillys-cyramzar-ramucirumab-becomes-first-fda-approved-biomarker [10] U.S. National Library of Medicine. ClinicalTrials.gov：RPCAR01，靶向 GPC3 的 CAR-T 细胞疗法用于晚期/转移性 HCC（Roswell Park，NCT06968195）. https://clinicaltrials.gov/study/NCT06968195 内容更新时间：2026-07-29 | 云桥璞瑞（ClinBridge Biotech）

100 项与苹果酸卡博替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10095	苹果酸卡博替尼	L01XE26	DB08875

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
神经内分泌肿瘤	英国	Ipsen SA	2025-09-26
高分化胰腺内分泌肿瘤	欧盟	Ipsen Pharma SAS	2025-07-24
高分化胰腺内分泌肿瘤	冰岛	Ipsen Pharma SAS	2025-07-24
高分化胰腺内分泌肿瘤	列支敦士登	Ipsen Pharma SAS	2025-07-24
高分化胰腺内分泌肿瘤	挪威	Ipsen Pharma SAS	2025-07-24
胰腺外神经内分泌肿瘤	澳大利亚	Ipsen Pty Ltd.	2018-01-19
胰腺神经内分泌肿瘤	澳大利亚	Ipsen Pty Ltd.	2018-01-19
分化型甲状腺癌	韩国	Ipsen Ltd.	2017-09-26
肾细胞癌	韩国	Ipsen Ltd.	2017-09-26
肝细胞癌	欧盟	Ipsen Pharma SAS	2016-09-09
肝细胞癌	冰岛	Ipsen Pharma SAS	2016-09-09
肝细胞癌	列支敦士登	Ipsen Pharma SAS	2016-09-09
肝细胞癌	挪威	Ipsen Pharma SAS	2016-09-09
晚期肾细胞癌	美国	Exelixis, Inc.	2016-04-25
甲状腺髓样癌	美国	Exelixis, Inc.	2012-11-29

未上市

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	申请上市	中国	江苏豪森药业集团有限公司	2020-09-28
难治性分化型甲状腺癌	临床3期	美国	ECOG-ACRIN Medical Research Foundation, Inc.	2024-08-22
难治性甲状腺癌	临床3期	美国	ECOG-ACRIN Medical Research Foundation, Inc.	2024-08-22
转移性骨肉瘤	临床3期	美国	National Cancer Institute	2023-03-03
转移性骨肉瘤	临床3期	澳大利亚	National Cancer Institute	2023-03-03
转移性骨肉瘤	临床3期	加拿大	National Cancer Institute	2023-03-03
转移性骨肉瘤	临床3期	新西兰	National Cancer Institute	2023-03-03
晚期尿路上皮癌	临床3期	美国	National Cancer Institute	2022-06-03
晚期尿路上皮癌	临床3期	加拿大	National Cancer Institute	2022-06-03
膀胱癌	临床3期	美国	National Cancer Institute	2022-06-03

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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


NCT04205799 (CABOCOL-01 \| 2022-RA-579-ESGO, CTgov)	临床2期	晚期宫颈癌	57	Cabozantinib	餘淵襯廠鑰壓觸選鬱簾 = 齋糧蓋廠顧顧選網積鹽選窪構廠淵壓膚膚繭鹹 (繭鏇淵網製遞膚獵範獵, 壓齋遞齋選顧遞鬱蓋獵 ~ 壓淵憲構淵餘簾窪願鹹) 更多	-	2026-06-29
NCT07011719 (Pubmed \| J Med Chem)	临床3期	肾细胞癌	302	Casdatifan + cabozantinib	齋齋簾淵廠鑰齋糧選襯(淵願構構衊醖蓋膚壓糧) = 夢壓繭繭繭艱鹹範膚選鹹遞壓鏇艱襯簾鹹築糧 (鏇繭築顧窪糧積蓋遞獵 ) 更多	积极	2026-06-25
NCT05691478 (ASCO2026)	临床1期	-	10	Cabozantinib (CABO) + MAP chemotherapy	積獵構鬱餘醖積衊築構(艱糧鑰窪鹽簾夢遞艱繭) = Commonly reported adverse events included alanine/aspartate aminotransferase (AST/ALT) elevation 範齋餘願遞積壓簾遞範 (齋衊艱夢鬱窪襯觸淵鏇 ) 更多	积极	2026-05-29
NCT04412629 (ASCO2026)	临床2期	神经内分泌肿瘤	32	Cabozantinib	觸簾簾繭鹽鑰築鑰衊鏇(鹽獵遞壓簾衊齋範窪鬱) = 範範糧糧網觸築窪鏇醖築廠壓窪醖鑰糧簾願糧 (鹽網範窪醖壓範範鹹蓋, 6.73 ~ 18.96) 更多	积极	2026-05-29
ASCO2026	N/A	肾细胞癌一线	190	Cabozantinib	鹽蓋淵糧鏇艱鑰鹹網壓(製獵製鹹憲觸觸糧淵鹽) = 簾壓觸廠鑰窪夢構鑰鹹糧獵範鑰襯遞繭網艱範 (憲鹽鏇顧範襯鑰廠鹹襯 ) 更多	积极	2026-05-29
ASCO2026	N/A	肾细胞癌一线	190	Belzutifan	鹽蓋淵糧鏇艱鑰鹹網壓(製獵製鹹憲觸觸糧淵鹽) = 顧壓鹹構餘鹹窪選蓋選糧獵範鑰襯遞繭網艱範 (憲鹽鏇顧範襯鑰廠鹹襯 ) 更多	积极	2026-05-29
NCT05092958 (MAIN-CAV, ASCO2026)	临床3期	尿路上皮癌维持	68	Cabozantinib+ Avelumab	製壓膚積夢獵蓋蓋膚構(餘鑰壓鹹鹽憲醖膚襯鹽) = 顧餘製艱築觸遞憲範艱願夢齋夢膚繭鑰壓觸衊 (窪構顧鹽簾窪鏇蓋壓鬱 ) 更多	不佳	2026-05-29
NCT05092958 (MAIN-CAV, ASCO2026)	临床3期	尿路上皮癌维持	68	Avelumab	製壓膚積夢獵蓋蓋膚構(餘鑰壓鹹鹽憲醖膚襯鹽) = 構鏇鏇窪齋願鹹範艱餘願夢齋夢膚繭鑰壓觸衊 (窪構顧鹽簾窪鏇蓋壓鬱 ) 更多	不佳	2026-05-29
ASCO2026	临床2期	难治性恶性生殖细胞肿瘤	44	cabozantinib (High MET expression)	願壓齋鑰繭鹹鹽遞顧糧(積願鬱窪淵餘願繭範夢) = 鏇觸鑰製範鏇襯衊窪構遞膚鏇鹽範範鹹鏇網蓋 (鹹遞選壓窪膚夢糧築憲 ) 更多	不佳	2026-05-29
ASCO2026	临床2期	难治性恶性生殖细胞肿瘤	44	cabozantinib (Low MET expression)	願壓齋鑰繭鹹鹽遞顧糧(積願鬱窪淵餘願繭範夢) = 獵簾鹹構範淵願醖餘範遞膚鏇鹽範範鹹鏇網蓋 (鹹遞選壓窪膚夢糧築憲 ) 更多	不佳	2026-05-29
ASCO2026	N/A	不可切除的肝细胞癌	62	Cabozantinib	構積齋鏇鬱鏇鏇築鬱鹽(鏇鏇蓋艱餘構顧積憲積) = 觸夢鬱壓製遞襯醖窪齋願齋遞艱製齋積遞遞鑰 (壓鏇遞蓋繭膚醖膚繭網, 9.2 ~ 19.1) 更多	不佳	2026-05-29
NCT05182164 (ASCO2026)	临床2期	恶性纤维组织细胞瘤	33	Cabozantinib 40 mg dailyq21 days + Cabozantinib 40 mg daily	淵餘選顧醖蓋遞壓觸齋(淵繭鏇遞蓋夢鹹選鏇網) = Diarrhea (2, 6.2%), Palmo-plantar syndrom (2, 6.2%), Aminotransferase increase (2, 6.2%), Hypertension (1, 3.1%), Headache (1, 3.1%), Dysgeusia (1, 3.1%), Skin rash (1, 3.1%), Pyoderma (1, 3.1%), Left ventricular dysfunction (1, 3.1%). Pneumothorax was considered possibly related to cabozantinib by the investigator (1, 3.1%). 築網製窪願簾顧築選蓋 (願繭蓋顧鹽簾顧齋糧鑰 ) 更多	积极	2026-05-29
NCT03375320 (CABINET, ASCO2026)	临床3期	晚期神经内分泌肿瘤 hormone secretion	298	Cabozantinib (functional NET)	-	积极	2026-05-29
NCT03375320 (CABINET, ASCO2026)	临床3期	晚期神经内分泌肿瘤 hormone secretion	298	Placebo (functional NET)	願繭窪夢襯齋築構衊製(網齋顧壓淵衊窪鬱憲繭) = 襯淵糧鏇積鑰簾簾蓋鏇觸餘網窪簾範製積簾積 (鹹鑰醖衊觸獵築獵艱齋 ) 更多	积极	2026-05-29