预约演示

更新于：2026-03-02

Cabozantinib (s)-Malate

苹果酸卡博替尼

更新于：2026-03-02

概要

基本信息

药物类型

小分子化药

别名

cabozantinib、Cabozantinib Malate、Cabozantinib s-malate (USAN)

+ [10]

靶点

AXL x RET x ROS1 x TYRO3 x Tie-2 x TrkB x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit x c-Met

作用方式

抑制剂、拮抗剂

作用机制

AXL抑制剂(AXL受体酪氨酸激酶抑制剂)、RET抑制剂(酪氨酸蛋白激酶受体RET抑制剂)、ROS1抑制剂(原癌基因酪氨酸蛋白激酶ROS抑制剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [11]

在研适应症

神经内分泌肿瘤高分化胰腺内分泌肿瘤胰腺外神经内分泌肿瘤+ [194]

非在研适应症

晚期胆管癌晚期乳腺癌甲状腺未分化癌+ [48]

原研机构

Exelixis, Inc.

在研机构

Bristol Myers Squibb Co.Ipsen Pharma SAS

National Cancer Institute

+ [20]

非在研机构

University of WashingtonIpsen Pharma GmbHMerck KGaA

+ [3]

权益机构

Ipsen SA

Takeda Pharmaceutical Co., Ltd.

Chugai Pharmaceutical Co., Ltd.

+ [7]

最高研发阶段批准上市

首次获批日期

美国 (2012-11-29),

甲状腺髓样癌

最高研发阶段(中国)临床3期

特殊审评快速通道 (美国)、孤儿药 (美国)、优先审评 (美国)、突破性疗法 (美国)

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结构/序列

分子式C32H30FN3O10

InChIKeyHFCFMRYTXDINDK-WNQIDUERSA-N

CAS号1140909-48-3

关联

282

项与苹果酸卡博替尼相关的临床试验

NCT07383441

/ Not yet recruiting临床3期IIT

Phase III Double Blinded Trial of Immune-Based Therapy With a Live Biotherapeutic MO-03 or Placebo for Frontline Therapy of Advanced Clear Cell Renal Cell Carcinoma [BioFront Trial]

This phase III trial compares the effect of adding live biotherapy, MO-03, to standard of care (SOC) immunotherapy, including ipilimumab, nivolumab, axitinib, pembrolizumab, cabozantinib, and lenvatinib, to SOC immunotherapy alone in treating patients with clear cell renal cell cancer that may have spread from where it first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started to other places in the body (metastatic). Studies have shown that gut health (the gut microbiome) may impact the effectiveness of immunotherapy. The microbiome includes all of the bacteria and organisms naturally found in the digestive tract. MO-03, a type of biotherapy, contains material from living organisms that may help keep the digestive tract healthy and may help to increase the effect of immunotherapy. Immunotherapy with monoclonal antibodies, such as ipilimumab, nivolumab, pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are a type of angiogenesis inhibitor and tyrosine kinase inhibitor (TKI) that block certain proteins which may help keep tumor cells from growing and may also help prevent the growth of new blood vessels that tumors need to grow. Adding MO-03 to SOC immunotherapy may be more effective than SOC immunotherapy alone in treating patients with advanced or metastatic clear cell renal cell cancer.

开始日期2026-06-10

申办/合作机构

SWOG

[+1]

NCT07187869

/ Not yet recruiting临床1期IIT

Modulation of the Bone Immune Microenvironment Following Cabozantinib Treatment of Bone Metastatic Clear Cell Renal Cell Carcinoma: Proof of Concept Study

The goal of our study is to explore how treatments affect the bone immune microenvironment and determine the best treatment options for patients with metastatic kidney cancer to the bone. This could prevent skeletal complications and improve patient outcomes.

开始日期2026-03-31

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

NCT07293351

/ Not yet recruiting临床1/2期

ROSETTA RCC-208: A Phase 1/2 Open-label, Multi-center, Randomized Study of Pumitamig Alone or in Combination With Ipilimumab or Cabozantinib in Participants With Advanced Renal Cell Carcinoma (RCC)

The purpose of this study is to evaluate the safety, tolerability, and efficacy of Pumitamig alone or in combination with Ipilimumab or Cabozantinib in participants with advanced Renal Cell Carcinoma (RCC)

开始日期2026-03-26

申办/合作机构

Bristol Myers Squibb Co.

[+1]

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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2,082

项与苹果酸卡博替尼相关的文献（医药）

2026-04-01·LUNG CANCER

RET Fusion–Positive Lung Adenocarcinoma: Partner-Specific Clinicopathological Characteristics, Co-Mutation Profiles, and Implications for Targeted and Immunotherapy

Article

作者: Wang, Bingzhi ; Gao, Lina ; Ying, Jianming ; Liu, Tianyi ; Li, Weihua ; Guo, Lei ; Zhao, Zuxuan ; Sun, Zihan ; Xu, Jiaxi

BACKGROUND:

RET fusions represent actionable oncogenic drivers in lung adenocarcinoma (LUAD). However, the clinicopathological features, co-mutation landscape, and therapeutic outcomes across different fusion partners remain incompletely characterized.

METHODS:

We retrospectively analyzed 268 patients with RET fusion-positive LUAD diagnosed between July 2017 and December 2024. Clinicopathological features, metastatic patterns, and concomitant genomic alterations were compared between KIF5B and non-KIF5B subgroups. Treatment outcomes of selective RET inhibitors, multikinase inhibitors (MKIs), and immunotherapy combined with chemotherapy were evaluated, with subgroup analyses according to fusion partners.

RESULTS:

The median age at diagnosis was 58 years; most patients were female (57.0%) and never/light smokers (60.8%). Bone (12.3%), pleural (11.9%), and brain metastases (6.7%) were the most common metastatic sites. KIF5B-RET fusions were more frequently detected in earlier disease stages compared with non-KIF5B (p = 0.0531). Among 274 RET fusion events, KIF5B-RET was predominant (65%), followed by CCDC6-RET (16%) and NCOA4-RET (1%). Concomitant mutations were identified in 28.7% of patients, most commonly TP53 (39.0%) and CDKN2A (13.0%), with CDKN2A alterations predominantly consisting of functionally inactivating SNVs concurrent with shallow deletions more enriched in non-KIF5B (p = 0.0393). Nineteen patients received targeted therapy, including pralsetinib, selpercatinib, and cabozantinib, achieving an overall ORR of 57.9% and mPFS of 12.0 months. Notably, non-KIF5B patients demonstrated longer median PFS than KIF5B patients under pralsetinib (17.0 vs. 5.5 months, p = 0.0473). Fifteen patients received first-line immunochemotherapy, achieving a median PFS of 17.0 months, ORR of 40.0%, and DCR of 80.0%, comparable to targeted therapy (p = 0.3871).

CONCLUSIONS:

RET fusion-positive LUAD comprises biologically heterogeneous subsets defined by fusion partners. KIF5B-RET tend to occur at earlier stages, whereas non-KIF5B are more frequently associated with CDKN2A co-mutations and may derive greater benefit from selective RET inhibition. Immunochemotherapy demonstrates comparable efficacy regardless of fusion partner, highlighting the need for partner-specific therapeutic strategies in RET fusion-positive LUAD.

2026-03-01·DRUG RESISTANCE UPDATES

UBL3 governs VEGFR inhibitor resistance by activating NOTCH signaling in renal cell carcinoma

Article

作者: Zhang, Xiaoping ; Fang, Kanglin ; Shi, Jian ; Yang, Hongmei ; Miao, Daojia ; Gong, Jinshuo ; Tan, Diaoyi ; Xiong, Zhiyong ; Wu, Songming ; Zhao, Chuanyi ; Yang, Junkai ; Ruan, Hailong ; Xiao, Wen ; Ye, Yuzhong ; Lv, Qingyang ; Lu, Feiyi

BACKGROUND:

Targeted therapy is the first-line treatment for patients with metastatic renal cell carcinoma (RCC), with vascular endothelial growth factor receptor inhibitors (VEGFRis) constituting the bulk of regimens used. Although the repertoire of VEGFRis for RCC now spans from sunitinib to cabozantinib, resistance to treatments has emerged as a common and prominent challenge. Thus, identifying novel therapeutic targets has become essential for enhancing the antitumor efficacy of current treatments and inhibiting RCC progression.

METHOD:

To investigate the potential mechanisms underlying VEGFRi resistance in RCC, we performed a genome-wide CRISPR/Cas9 library screen under sunitinib and cabozantinib treatment and identified UBL3 as a key driver of VEGFRi resistance in RCC cells. The critical role of UBL3 in promoting VEGFRi resistance was validated using CCK8 assays, flow cytometry, TUNEL assays, and bioinformatics analyses. To elucidate the molecular mechanisms underlying UBL3, we utilized western blotting, RNA sequencing, chromatin immunoprecipitation, small extracellular vesicles (sEVs) isolation, and Astral-DIA proteomics. The contribution of UBL3 to VEGFRi resistance was further confirmed through comprehensive in vitro and in vivo experiments.

RESULTS:

UBL3 was confirmed to suppress apoptosis and promote VEGFRi resistance through NOTCH signaling activation. Further investigations highlighted the importance of NOTCH signaling in VEGFRi resistance in RCC via the NOTCH-PTEN-AKT and NOTCH-FOS pathways and revealed the mechanisms by which UBL3 activated NOTCH signaling. On the one hand, UBL3 formed complex with NOTCH2 and ADAM17 simultaneously, accelerating ADAM17-mediated cleavage of NOTCH2. On the other hand, UBL3-modified NOTCH2 was sorted into sEVs, which were taken up by recipient cells, activating NOTCH signaling and thereby transmitting VEGFRi resistance. Finally, lipid nanoparticle-mediated delivery of the CRISPR/Cas9 knockout system targeting UBL3 effectively restored the sensitivity of RCC tumors to VEGFRis.

CONCLUSION:

This study emphasized the importance of UBL3 in VEGFRi resistance in RCC and proposed that UBL3 activated NOTCH signaling through two distinct pathways, thereby suppressing cancer apoptosis and promoting resistance to VEGFRis. These findings provided a solid scientific foundation and paved the way for the development of novel therapeutic strategies for patients with advanced RCC.

2026-03-01·LIFE SCIENCES

Cabozantinib induces NLRP3-CASP1-GSDMD-dependent pyroptosis in hepatocellular carcinoma

Article

作者: Ou, Da-Liang ; Chang, Hsin-Yi ; Feng, Zhi-Rui ; Hsu, Chiun ; Chung, Chih-Hung ; Lin, Li ; Yang, Muh-Hwa ; Cheng, Ann-Lii ; Cheng, Han-Ying ; Jian, Cheng-Zhe ; Hsu, Chia-Lang

AIMS:

Cabozantinib is a multi-target tyrosine kinase inhibitor approved for second-line treatment of advanced hepatocellular carcinoma (HCC). While its antiangiogenic and antiproliferative effects are well known, its immunomodulatory mechanisms remain incompletely understood. Here, we aimed to investigate the novel immunomodulatory mechanism of cabozantinib, focusing on its role in inducing pyroptotic cell death in HCC cells and myeloid-derived suppressor cells (MDSCs).

MATERIALS AND METHODS:

Cabozantinib-induced pyroptosis was evaluated in HCC cell lines and MDSCs. The involvement of the canonical NLRP3-CASP1-GSDMD pathway was validated using MDSCs induced from Nlrp3 knockout mice and Gsdmd knockout HCC cells. In vivo efficacy and immunomodulation were assessed using Gsdmd knockout Hepa1-6 tumors in immunocompetent mice, analyzed via flow cytometry, single-cell RNA sequencing, and phosphoproteomics.

KEY FINDINGS:

We show that cabozantinib induces pyroptotic cell death in both HCC cells and MDSCs via the canonical NLRP3-CASP1-GSDMD pathway. Disruption of this pathway using MDSCs induced from Nlrp3 knockout mice or Gsdmd knockout HCC cells abrogated cabozantinib-induced pyroptosis. Critically, implantation of Gsdmd knockout tumors in vivo abolished the antitumor and immunomodulatory effects of cabozantinib, confirming the necessity of GSDMD-mediated pyroptosis. Furthermore, cabozantinib reduced MDSC accumulation and enhanced cytotoxic CD8⁺ T cell responses, findings further supported by phosphoproteomic analysis showing pyroptosis-associated signaling alterations.

SIGNIFICANCE:

These findings reveal a mechanistic link between cabozantinib-induced pyroptosis and immune activation. Our results provide a strong rationale for the clinical combination of cabozantinib with immunotherapy in the treatment of HCC.

897

项与苹果酸卡博替尼相关的新闻（医药）

2026-03-02

·Firstwordpharma

Merck & Co.'s Welireg bags priority FDA review in early RCC with pivotal DFS data

A preliminary interim analysis from a late-stage study of Merck & Co.'s Welireg (belzutifan) in earlier-stage clear cell renal cell carcinoma (RCC) showed that the oral HIF-2α inhibitor significantly boosting disease-free survival (DFS) when combined with the PD-1 inhibitor Keytruda (pembrolizumab) as adjuvant therapy following nephrectomy. The latest readout — building on findings highlighted last October — prompted a priority review by the FDA, with a target action date of June 19. The LITESPARK-022 trial randomised 1841 patients to receive either Welireg plus Keytruda for approximately one year, or Keytruda plus placebo, with the primary endpoint being DFS. Results presented Saturday at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) showed that Welireg plus Keytruda lowered the risk of disease recurrence or death by 28% compared with Keytruda plus placebo at a median follow-up of 28.4 months. While the estimated 24-month DFS rate was 80.7% for the combination arm versus 73.7% for the control arm, median DFS was not reached in either group. The trial's key secondary endpoint of overall survival (OS) continues to be evaluated. "These findings represent the first positive Phase III data for Welireg in earlier stages of disease, as well as the first positive Phase III results for a HIF‑2α inhibitor and immunotherapy combination," said M Catherine Pietanza, VP of global clinical development at Merck Research Laboratories. Welireg is approved in multiple regions for advanced RCC following prior PD-(L)1 and VEGF-targeted therapies, whereas Keytruda is authorised across the US, EU, Canada and Japan in the adjuvant RCC setting. Merck's pivotal LITESPARK programme in RCC also includes LITESPARK-011, wherein Welireg plus Eisai's oral tyrosine kinase inhibitor Lenvima (lenvatinib) improved progression-free survival (PFS) versus Exelixis' Cabometyx (cabozantinib) in the post-immunotherapy setting. Having been top-lined as positive last year, data presented at ASCO GU showed that with a median follow-up of 29 months, Welireg in combination with Lenvima reduced the risk of disease progression or death by 30% compared to Cabometyx, with median PFS in the two groups of 14.8 months and 10.7 months, respectively. The trial also demonstrated a trend toward improvement in survival, with median OS of 34.9 months for Welireg plus Lenvima, versus 27.6 months for Cabometyx. Based on the findings, submissions to expand the use of Welireg in combination with Lenvima have been accepted by the FDA, with a target review data of October 4. Meanwhile, the ongoing LITESPARK-012 trial, due to read out later this year, is evaluating the addition of Welireg to Keytruda plus Lenvima in first-line advanced RCC. For more, see – Spotlight On: Evolving treatment trends in RCC and Spotlight On: Rising use of adjuvant Keytruda among major RCC treatment trends. The content above comes from the network. if any infringement, please contact us to modify.

临床结果优先审批ASCO会议上市批准

2026-03-01

·Briinsight

默沙东的“王炸”组合：Welireg 连下两城，能否终结肾癌化疗时代的折磨？

在 2026 年的美国临床肿瘤学会泌尿生殖系统癌症研讨会（ASCO GU）上，默沙东（Merck & Co.）毫无疑问是全场的焦点。当同行们还在单药或传统方案中苦苦挣扎时，默沙东祭出了其管线中的“明日之星”——Welireg (belzutifan)。通过两项重磅三期临床试验（Litespark-011 和 Litespark-022）的联手出击，默沙东向肾细胞癌（RCC）治疗领域投下了一枚深水炸弹：Welireg 的组合疗法，正在重塑肾癌从术后辅助到晚期治疗的全线格局。但这枚“炸弹”在带来希望的同时，也抛出了一个行业绕不开的终极命题：如果没有“金标准”的总生存期（OS）数据，仅凭无进展生存期（PFS）的胜利，真的够吗？一、双拳出击：Welireg 的 1-2 组合拳默沙东这次带来的数据，分别覆盖了肾癌患者旅程中的两个关键阶段，可谓“精准打击”。二线逆袭（Litespark-011）：针对既往免疫治疗后进展的晚期透明细胞肾细胞癌（ccRCC）患者，Welireg 联合仑伐替尼（Lenvima）表现出了惊人的战斗力。数据显示，相比于目前临床常用的卡博替尼（Cabometyx），该组合显著降低了患者 30% 的疾病进展或死亡风险。这是首个在免疫治疗后进阶阶段改善临床获益的三期试验，挑战意味极强。术后防线（Litespark-022）：在术后复发风险增加的患者中，Welireg 联合“药王”帕博利珠单抗（Keytruda）同样表现优异，将患者的复发或死亡风险降低了 28%。这是首个在术后辅助治疗中证明“联合用药优于单药 PD-1”的三期试验。默沙东研究实验室全球临床开发副总裁 Cathy Pietanza 博士在接受采访时直言： “这两项研究的数据非常令人信服，在各自的主要终点上都表现出了统计学和临床意义上的双重改善。”二、生存期的悬念：是“新标准”还是“暂时选项”？尽管数据耀眼，但在肿瘤领域，所有的胜利都必须经过 OS（总生存期）的考验。目前，这两项研究最大的争议点在于——缺乏成熟、决定性的 OS 数据。市场的审视：虽然早期 OS 趋势看起来有利（比如 Litespark-011 显示出了 15% 的死亡风险降低，Litespark-022 显示出 22% 的改善），但这些数据目前均未达到统计学显著性。副作用的代价：天下没有免费的午餐。联合用药意味着副作用的叠加。贫血、缺氧、心脏功能障碍……这些在 Welireg 组合中更为明显的副作用，需要医生在治疗方案中精细考量。 ASCO GU 的专家们给出了一个微妙的评价：这是一个潜在的“新治疗选项”，而非“全能标准”。在没有 definitive OS（决定性总生存期）获益的情况下，Welireg 在二线治疗中的市场销售压力，可能比在术后辅助阶段要大得多。三、战略意义：默沙东的“Keytruda 护城河” 为什么默沙东如此急切地推动 Welireg？这背后其实是默沙东的一场“时间赛跑”。随着 Keytruda（帕博利珠单抗）未来专利到期（LOE）的阴影步步逼近，默沙东急需新的支柱产品来接力。 Welireg 作为首个 HIF-2α 抑制剂，其独特的机制（通过阻断低氧诱导因子 2α 信号通路来扰乱肿瘤的“呼吸”和供血）为默沙东提供了一把差异化的武器。通过将 Welireg 与现有的“王牌”联合，默沙东实际上是在构建一条坚固的临床护城河：通过高门槛的组合方案，锁定患者的使用时间，并在此基础上不断拓展适应症。四、未来之路：FDA 的态度才是风向标好消息是，数据已经足够让默沙东敲开 FDA 的大门。据了解，FDA 已经接受了 Welireg 这两项组合疗法的补充上市申请（sNDA），全球各地的监管机构提交工作也在如火如荼地进行中。 Brian Rini 博士指出： “虽然我们还在等待长期生存获益的确认，但疾病无进展生存期的显著延长，对于临床医生来说已经是极大的诱惑。” 对于患者而言，预防复发和延缓进展，意味着他们能有更多时间告别化疗室，回到正常生活中去。这本身就是一种极具意义的“临床获益”。结语：在不确定性中博弈未来从 Litespark 的系列试验中，我们看到了默沙东清晰的野心——它不满足于仅仅作为免疫治疗的王者，更要在 HIF-2α 这一全新靶点上定义未来的标准。虽然 OS 数据尚需时间打磨，但 Welireg 已经用强有力的数据证明了它不仅仅是 Keytruda 的“副手”，它完全有能力成为独当一面的核心。 2026 年的 ASCO GU 大会，或许就是肾癌治疗从“单一免疫时代”跨向“靶向联合时代”的分水岭。至于最终谁能称王，时间会给出最后的判决。欢迎在评论区留下你的评论。高质量观点，我们会精选置顶。我们将持续输出：洞察行业变局，预判未来先机。我们持续深耕医疗健康赛道，为您提供：深度解读：穿透表象，还原商业底层逻辑。标的拆解：拆解并购核心，寻找估值锚点。趋势研判：捕捉投融资风向，预警行业巨震。把复杂问题，讲清楚。【互动环节】你如何看待这种“只看 PFS 不等 OS”的研发策略？在肾癌治疗中，你是更看重眼下的“疾病不进展”，还是更看重长远的“总生存期”？评论区留下你的深度见解！ 👇 访问网站：https://www.briinsight.com 了解更多👇 👇 商务合作与咨询，敬请扫描二维码 👇 生物医药前沿洞察｜职业成长加速器聚焦创新药、制剂技术、CDMO、AI药物研发等领域的最新突破；专注生物医药研发、注册申报、临床进展与市场趋势解析；汇聚业内声音、人才资讯与实战经验，打造最具价值的行业交流平台。 👇 更多精彩内容，敬请关注“Briinsight” 👇 天价“插队券”！2.05亿美元一张，FDA“黄牛票”凭什么这么贵？千亿豪赌再加码！艾伯维砸3.8亿美元新建两座API工厂，美国制造“回流”剑指何方？疫苗巨头的集体“败退”！Moderna 遭拒背后：RFK Jr. 掌舵 HHS 的第一把火，正在烧毁美国疫苗工业的根基医药圈地震！赛诺菲 CEO 突然下课：功勋主帅为何在黎明前被弃？默克“铁娘子”空降巴黎，能否拯救 2031 专利悬崖？

2026-02-28

·大橡科技

Clin Mol Hepatol(IF16.9)类器官研究：肝癌一线TKI耐药后序贯治疗的全新预测标志物

点击蓝字关注我们肝细胞癌（HCC）是原发性肝癌的主要病理类型，多数患者确诊时已处于晚期，治疗手段有限。临床指南及临床试验推荐Regorafenib（瑞戈非尼）作为HCC患者一线Sorafenib（索拉非尼）或Lenvatinib（仑伐替尼）治疗耐药后的二线序贯治疗药物，但疗效依然有限。因此，阐明Regorafenib的耐药机制并探索联合治疗策略以提升其疗效至关重要。为探究导致Regorafenib序贯治疗疗效受限的潜在靶点，复旦大学附属华山医院陈进宏研究团队通过HCC体内（细胞、类器官）和体外（异种移植瘤）建模进行了研究，并于2026年1月20日在国际知名期刊Clinical And Molecular Hepatology 上发表了题为ERBB3 blockade sensitizes HCC to regorafenib after first-line TKI resistance by inhibiting HIF1A-ABCB1 signaling的高水平研究论文。该研究通过构建Sorafenib或Lenvatinib耐药（SR/LR）的体内和体外模型，揭示ERBB3是导致Regorafenib序贯治疗疗效受限的关键耐药因子，同时也是有效的治疗靶点，阐明ERBB3抑制剂可通过ERBB3-HIF1A-ABCB1通路显著增强SR/LR后肝癌细胞对Regorafenib的敏感性，ERBB3低表达可作为筛选Regorafenib序贯治疗获益人群的预测性生物标志物，而ERBB3高表达的SR/LR-HCC可从Regorafenib联合Seribantumab（瑟瑞妥单抗）治疗中获益。该研究提出了一种新型ERBB3指导的个体化治疗分层策略，为HCC序贯治疗提供了新见解。缩写词全称 HCC 肝细胞癌 Regorafenib 瑞戈非尼 Sorafenib 索拉非尼 Lenvatinib 仑伐替尼 SR 索拉非尼耐药 LR 仑伐替尼耐药 SR/LR-HCC 索拉非尼/仑伐替尼耐药肝细胞癌 CRISPR 成簇规律间隔短回文重复序列 ERBB3 Erb-B2受体酪氨酸激酶3 HIF1A 缺氧诱导因子1α ABCB1 ATP结合盒亚家族B成员1 CDX 细胞来源异种移植 PDX 患者来源异种移植 Seribantumab 瑟瑞妥单抗，靶向ERBB3的单克隆抗体 01 研究亮点 Research Highlights 1. 靶点筛选突破：明确了ERBB3是Sorafenib（索拉非尼）或Lenvatinib（仑伐替尼）耐药肝癌细胞及类器官中，与Regorafenib（瑞戈非尼）具有合成致死效应的关键靶点。 2. 耐药机制阐明：揭示了耐药后ERBB3-HIF1A-ABCB1信号通路的反馈激活机制，该通路会促进Regorafenib的细胞外排，进而导致药物疗效受限。 3. 预测标志物发现：证实了ERBB3低表达可作为预测性生物标志物，用于筛选Sorafenib或Lenvatinib-Regorafenib序贯治疗的获益人群。 4. 联合疗法验证：验证了ERBB3靶向单克隆抗体Seribantumab（瑟瑞妥单抗）与Regorafenib联用，对ERBB3高表达的耐药肝癌具有显著协同抗肿瘤效果，且耐受性良好。 02 研究内容 Research Content 1. 全基因组CRISPR筛选鉴定ERBB3为SR/LR后Regorafenib的合成致死靶点 Regorafenib是HCC一线靶向药耐药后的首选序贯治疗药物，但疗效待进一步提升（图1A）。为模拟治疗过程，研究团队构建了SR-HCC和LR-HCC细胞株，SR/LR细胞对药物敏感性均显著下降、迁移能力增强，而增殖能力无变化（图1B）。在构建的SR/LR细胞模型中，短期细胞活力实验显示Regorafenib抑制效果优于卡博替尼（Cabozantinib）、阿帕替尼（Apatinib），但其半数抑制浓度（IC₅₀）仍偏高。随后，研究团队通过全基因组CRISPR-Cas9筛选，发现ERBB3是Regorafenib的合成致死（指两个基因同时被抑制时导致细胞死亡，而单独抑制其中一个基因则不会）靶点，在SR/LR模型中均排名靠前（图1C）。ERBB3敲低联合Regorafenib可显著抑制SR/LR细胞增殖，过表达则降低药物敏感性（图1D）。进一步，在SR/LR-HCC类器官模型中，ERBB3敲低联合Regorafenib同样产生合成致死效应（图1E、F）。综上表明，ERBB3是SR/LR后Regorafenib序贯治疗疗效受限的关键因子，抑制该靶点可增敏耐药细胞/类器官对Regorafenib的敏感性。图1. 全基因组CRISPR筛选鉴定出ERBB3是SR/LR后Regorafenib的合成致死靶点。(A)美国和日本多中心试验显示，序贯Regorafenib在SR/LR后有效，但低ORR（11%和13.6%）时疗效有限。(B)HuH7、HuH7-SR、PLC/PRF/5和PLC/PRF/5-SR细胞对Sorafenib的半抑制浓度（IC₅₀）值。HuH7、HuH7-LR、PLC/PRF/5和PLC/PRF/5-LR细胞对Lenvatinib的半抑制浓度（IC₅₀）值。(C)HuH7-SR或HuH7-LR细胞株全基因组CRISPR文库筛选的工作流程。HuH7-SR与HuH7-LR中Regorafenib的合成致死靶点交集。应用MAGECK软件通过计算每个基因的RRA评分来评估Regorafenib和载体处理细胞中sgRNA的丰度。在HuH7-SR或HuH7-LR细胞中，Regorafenib存在时靶向ERBB3的三种sgRNA均被耗竭。(D)ERBB3敲低显示SR/LR细胞对Regorafenib的协同反应。(E)已建立的HCC类器官的代表性明场、H&E和免疫组化图像。获得性SR/LR类器官选择的示意图。Sorafenib敏感和耐药类器官的半抑制浓度值。Lenvatinib敏感和耐药类器官的半抑制浓度值。(F)ERBB3敲低显示获得性SR/LR类器官对Regorafenib的协同反应（存活：钙黄绿素AM，绿色；死亡：PI，红色）。 2. SR/LR后激活的ERBB3信号通路可上调HIF1A表达为探究SR/LR后ERBB3信号通路是否存在反馈激活，研究团队开展了蛋白及转录组学分析。结果显示，SR/LR-HCC细胞株中，ERBB3的蛋白与mRNA表达显著升高，其信号通路富集，且该上调由SR/LR耐药诱导，与Regorafenib直接作用无关（图2A）。接下来，研究团队将Regorafenib协同致死靶点与ERBB3过表达细胞上调基因进行交集分析，筛选出8个候选靶点，结合基因集富集分析和功能验证实验锁定缺氧诱导因子1α（HIF1A）为下游关键靶点，且实验证实ERBB3通过磷酸化AKT（p-AKT）介导的PI3K/AKT通路调控HIF1A表达，而非MAPK/ERK通路（图2B-D）。进一步细胞增殖实验显示，抑制HIF1A可逆转ERBB3过表达导致的Regorafenib耐药；反之，HIF1A过表达或积累可使对Regorafenib敏感的ERBB3敲低细胞恢复Regorafenib耐药性（图2E、F）。综上表明，SR/LR后激活的ERBB3信号通路通过上调下游HIF1A表达介导肿瘤细胞对Regorafenib的耐药。图2. 激活的ERBB3信号通路在SR/LR后上调HIF1A表达。(A)亲本细胞和耐药细胞中ERBB3蛋白表达的Westernblot分析（左）。RNA-seq分析显示与亲本HuH7细胞相比，HuH7-SR或HuH7-LR细胞中上调和下调的基因（中）。基因集富集分析（GSEA）表明ERBB3信号在SR/LR组中呈正向富集。（右）来自四个公共SR/LRGEO数据集的ERBB3表达差异柱状图。(B)Venn图显示Regorafenib的合成致死靶点与HuH7-SR和HuH7-LR细胞中ERBB3过表达上调基因的交集。(C)GSEA揭示OE-ERBB3组中显著富集的生物学通路。HIF1A在mRNA水平上被ERBB3过表达上调。HIF1A是Regorafenib的另一个协同致死靶点，且在HuH7-SR或HuH7-LR细胞中，靶向HIF1A的三种sgRNA在Regorafenib存在下被耗竭。(D)SR/LR细胞转染ERBB3敲低或过表达质粒后，进行指定抗体的Westernblot分析。细胞在收获前用100μM氯化钴预处理24小时以稳定HIF1A。（E和F）SR/LR细胞在Regorafenib存在下处理（2μM为HuH7-SR和HuH7-LR，4μM为PLC/PRF/5-SR和PLC/PRF/5-LR）。LW6（100μM）抑制HIF1A；DMOG（0.5mM）诱导HIF1A积累。 3. HIF1A转录激活ABCB1表达为研究HIF1A的下游转录靶点ABC转运蛋白家族的作用，研究团队经全基因组筛选发现除ERBB3和HIF1A外，抑制ABCB1在SR/LR-HCC细胞中同样可与Regorafenib产生合成致死效应（图3A）。随后，研究团队发现HIF1A诱导累积或过表达可使ABCB1表达上调，而HIF1A抑制或敲低则降低ABCB1表达，二者表达呈正相关，提示HIF1A对ABCB1的关键调控作用（图3B、C）。进一步，为探究HIF1A是否通过直接结合ABCB1启动子区的转录因子结合位点促进其转录，研究团队通过JASPAR数据库预测发现ABCB1启动子区有3个HIF1A结合位点，荧光素酶报告实验证实HIF1A可转录激活ABCB1表达，3个转录因子结合位点突变后激活作用部分减弱（图3D-F）。此外，HIF1A也可转录激活ERBB3，为其表达上调提供了合理解释。综上表明，ABCB1作为与药物外排密切相关的转运蛋白，是SR/LR-HCC细胞中HIF1A的直接转录靶点。图3. HIF1A转录上调ABCB1表达。(A)ABCB1是Regorafenib的另一协同致死靶点，三种靶向ABCB1的sgRNA在HuH7-SR或HuH7-LR细胞中经Regorafenib处理后表达被耗竭。(B)Westernblot分析显示SR/LR细胞在不同浓度DMOG暴露下HIF1A与ABCB1的表达变化。使用DMOG诱导HIF1A逐步积累。Westernblot分析SR/LR细胞经100μMLW6处理（LW6用于抑制HIF1A表达）或未处理的HIF1A与ABCB1蛋白水平。(C)Westernblot分析稳定转染HIF1A基因敲低或过表达质粒的SR/LR细胞中HIF1A与ABCB1蛋白水平。(D)预测ABCB1启动子区（转录起始位点上游2kb）存在三个潜在HIF1A结合位点。(E)设计图示三个转录因子结合位点（TFBS）的突变序列。Mut表示突变；WT表示野生型。(F)所示细胞中含WT或突变型ABCB1启动子序列的报告基因相对荧光素酶活性。红色圆圈代表野生型HIF1A结合位点，红色“X”标记突变型HIF1A结合位点。 4. ERBB3-HIF1A-ABCB1通路激活促进SR/LR后Regorafenib外排为探究SR/LR后ERBB3-HIF1A-ABCB1通路对Regorafenib外排的作用，研究团队采用绿色荧光标记Regorafenib、红色Dil染料标记细胞膜开展药物外排实验发现，SR/LR细胞内Regorafenib外排速率显著高于亲本细胞，该现象可能由ERBB3-HIF1A-ABCB1通路反馈激活介导（图4A、B）。进一步，研究团队在SR/LR细胞中调控ABCB1或ERBB3表达发现，ABCB1敲低可降低细胞膜表面ABCB1表达、减慢荧光衰减速率，过表达则相反；ERBB3敲低会降低细胞膜表面ABCB1水平、延缓荧光衰减速率，过表达则相反（图4C-F）。同时证实在SR/LR细胞模型中FGFR1/2是Regorafenib主要靶点，ABCB1介导的药物外排会影响其信号活性。综上表明，SR/LR后激活的ERBB3-HIF1A-ABCB1通路可促进Regorafenib外排，降低细胞内药物浓度，导致Regorafenib耐药。图4. ERBB3-HIF1A-ABCB1级联反应的激活促进了SR/LR后的Regorafenib外排。(A)添加绿色FITC荧光标记的Regorafenib分子结构式（纯度95.06%，分子量901.24g/mol）。(B)HuH7-亲本、HuH7-SR和HuH7-LR菌株的Regorafenib外排实验。(C)转染ABCB1敲低和过表达质粒的HuH7-SR或HuH7-LR菌株中ABCB1染色的代表性免疫荧光图像。(D)HuH7-SR或HuH7-LR菌株中shABCB1、载体和OEABCB1组的Regorafenib外排实验。(E)转染ERBB3敲低和过表达质粒的HuH7-SR或HuH7-LR菌株中ABCB1染色的代表性免疫荧光图像。(F)HuH7-SR或HuH7-LR菌株中shERBB3、载体和OE-ERBB3组的Regorafenib外排实验。直方图显示FITC-Regorafenib（绿色）的相对荧光强度。 5. 低ERBB3表达可提升SR/LR后肝癌临床前模型及患者对Regorafenib序贯治疗的疗效为在体内验证ERBB3低表达肿瘤对Regorafenib序贯治疗的敏感性，研究团队构建了SR/LR细胞来源异种移植瘤（CDX）模型和患者来源异种移植瘤（PDX）模型，发现ERBB3低表达组中移植瘤生长受显著抑制，瘤内ERBB3-HIF1A-ABCB1信号通路相关蛋白表达水平显著降低（图5A-D）。此外，临床队列验证发现Sorafenib或Lenvatinib治疗进展的HCC患者中，ERBB3低表达患者对Regorafenib的响应率远高于高表达患者（图5E）。综上表明，ERBB3低表达可作为筛选Regorafenib序贯治疗获益人群的预测性生物标志物。图5. 在HCC临床前模型和患者中，ERBB3低表达可提高SR/LR后序贯Regorafenib的疗效。（A和B）皮下细胞来源异种移植模型的体内示意图。各组皮下小鼠模型的肿瘤外观、生长曲线及重量。(C)各组ERBB3、HIF1A和ABCB1染色的代表性图像及定量分析。(D)HCCPDX肿瘤构建方案及SR/LRPDX肿瘤生成示意图。已建立SR/LRPDX肿瘤中ERBB3低表达与高表达的IHC染色代表性图像。NSG小鼠皮下植入SR/LRPDX肿瘤的示意图（ERBB3低表达组和高表达组）。SR/LRPDX模型中各组的代表性肿瘤图像、生长曲线及重量。(E)Sorafenib难治性HCC患者序贯Regorafenib治疗后靶病灶较基线的变化百分比及疗效参数（左）。Sorafenib进展后ERBB3低表达与高表达患者对序贯Regorafenib治疗应答与无应答的饼图及统计分析（右）。(F)Lenvatinib难治性HCC患者序贯Regorafenib治疗后靶病灶较基线的变化百分比及疗效参数（左）。ERBB3低表达与高表达患者在Lenvatinib进展后序贯Regorafenib治疗的应答与无应答情况的饼图及统计分析（右图）。 6. Seribantumab与Regorafenib联用对SR/LR的ERBB3高表达肿瘤具有协同抗肿瘤作用 ERBB3过表达的SR/LR-HCC细胞及肿瘤，均对Regorafenib序贯治疗不敏感。为开发联合治疗策略，研究团队将ERBB3单克隆抗体Seribantumab与Regorafenib联用，发现该方案可显著抑制ERBB3过表达SR/LR细胞增殖（图6A）。体内实验中，联合用药能有效抑制SR/LR-ERBB3过表达裸鼠移植瘤生长，显著下调瘤内ERBB3-HIF1A-ABCB1通路蛋白表达，且无明显的肝肾功能损伤及组织病理学毒性（图6B-E）。在SR/LR-ERBB3高表达的PDX模型中，联合治疗的抑瘤效果显著优于单药，其机制为Seribantumab阻断ERBB3-HIF1A-ABCB1通路介导的Regorafenib外排（图6F）。综上表明，ERBB3高表达的SR/LR-HCC可从Regorafenib联合Seribantumab治疗中获益。图6. Regorafenib与Seribantumab在SR/LR后对ERBB3高表达肿瘤的协同抗肿瘤作用（体外及体内实验）。(A)在指定浓度下，Regorafenib与Seribantumab联合治疗对ERBB3OESR/LR细胞的协同效应。（B和C）皮下肿瘤模型中Regorafenib联合Seribantumab的体内抗癌作用示意图。治疗结束时各组HuH7-SR-ERBB3OE和HuH7-LR-ERBB3OE异种移植瘤的肿瘤形态、生长曲线及重量。（D和E）各组ERBB3、HIF1A及ABCB1染色的代表性图像与定量分析。(F)NSG小鼠皮下植入ERBB3高表达SR/LRPDX肿瘤的示意图。ERBB3高表达SR/LRPDX模型中各组的代表性肿瘤图像、重量及生长曲线。 03 总结与展望 Summary and Outlook 该研究通过肝细胞癌（HCC）体内（细胞、类器官）和体外（异种移植瘤）模型明确ERBB3是HCC一线Sorafenib/Lenvatinib耐药（SR/LR）后，Regorafenib序贯治疗疗效受限的关键因素，其机制是SR/LR会反馈激活ERBB3-HIF1A-ABCB1通路，加速Regorafenib外排，降低胞内药物浓度。临床层面，ERBB3低表达可作为预测标志物，筛选适合Regorafenib单药治疗的患者；ERBB3高表达患者则可通过Regorafenib联合ERBB3靶向单抗Seribantumab提升治疗疗效，该联合方案在体内外均展现出协同抗肿瘤效果。然而该研究还存在局限性，比如临床样本量相对较小；未深入探索ERBB3通路与其他耐药相关信号通路的交叉调控机制；缺乏长期临床随访数据，联合治疗的远期疗效和安全性有待进一步确认。未来需扩大临床队列，开展多中心研究验证ERBB3作为标志物的普适性，推动其进入临床诊疗指南；深入探究ERBB3通路与其他耐药机制的关联，开发多靶点联合治疗方案；推进Seribantumab联合Regorafenib的临床试验，优化给药剂量和方案，同时探索ERBB3抑制剂与免疫治疗的联合潜力，为肝癌耐药患者提供更多精准治疗选择。扫描二维码可下载原文大橡科技肿瘤类器官药物评价大橡科技依托肿瘤类器官样本库，打造精准药物评价解决方案。高度还原肿瘤微环境与异质性，突破传统模型局限，可高效支持小分子、抗体药物、ADC、CGT等候选药物的敏感性检测与耐药研究，助力药企加速筛选进程，降低研发成本与试错风险，同时为临床个体化用药赋能，推动肿瘤药物研发与精准医疗落地。（详情请点击下方链接）客户文章解读系列｜IF40.8的前列腺癌治疗突破研究！eRNA驱动铁死亡，联合疗法攻克去势抵抗性难题客户文章解读系列｜Cancer Research从预测到增效：肿瘤类器官免疫模型助力免疫亚型分类系统创新客户文章解读｜类器官模型验证TFE3重排肾细胞癌治疗新机制珍芯严®全场景解决方案你有思路，我来想！你出方案，我来做！以专业眼光洞察数据，让决策更加清晰！珍芯严®面向药企药物早期研发与高校、医院的基础科研，我们倾力打造类器官芯片全场景解决方案。凭借创新的类器官芯片技术，打破传统细胞与动物研究瓶颈，高效产出优质数据，从实验室到临床，我们与您并肩作战！客服电话/微信:18610798010 扫描二维码可联系我们小红书设计: Summer、Rebecca｜封面: Rebecca 求点赞求分享求喜欢

临床结果放射疗法临床研究

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

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
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


NCT01068782 (CTgov)	临床2期	胶质母细胞瘤	19	cabozantinib (Arm 1)	願壓繭積選艱簾願顧夢 = 鑰構醖齋醖選積壓築繭襯鹽廠醖繭蓋餘壓衊廠 (鹽糧選網艱醖遞衊窪鹽, 糧糧襯壓範餘蓋鹹憲鑰 ~ 簾壓鏇鏇範鹹觸壓範願) 更多	-	2026-02-25
				cabozantinib (Arm 2)	願壓繭積選艱簾願顧夢 = 鏇窪製鏇壓齋範醖願廠襯鹽廠醖繭蓋餘壓衊廠 (鹽糧選網艱醖遞衊窪鹽, 糧積獵構遞膚簾範襯簾 ~ 鏇鏇衊夢衊鑰夢夢顧廠) 更多
NCT04200443 (Pubmed \| Lancet Oncol)	临床2期	平滑肌肉瘤 \| 软组织肉瘤	72	Cabozantinib 40 mgTemozolomide 40 mg + Cabozantinib 40 mgTemozolomide	衊襯齋製艱鑰糧積顧鏇(鏇憲鏇膚醖鏇觸鏇觸窪) = 淵願糧範繭鏇醖齋鹹選淵鹽觸範顧鏇壓觸壓淵 (製築顧構遞廠願簾選遞 ) 更多	积极	2026-02-01
				Temozolomide (Cohort 1)	鏇膚壓壓蓋願網壓憲齋(構鏇餘獵醖鹹蓋襯積繭) = 鏇糧鏇網製襯積選糧繭鹹艱夢鹹壓鑰製夢構獵 (獵範鬱膚襯窪獵淵顧窪 ) 更多
NCT00596648 (CTgov)	临床1/2期	非小细胞肺癌	92	erlotinib+cabozantinib (Phase 1 - Cohort 1)	繭鹽淵獵積鹹鹹選衊衊(築鹽築獵製觸糧構願觸) = 鏇網憲願鑰艱壓餘網夢簾憲壓憲觸築糧艱簾膚 (壓範願築繭艱醖蓋願範, 範製繭網廠願憲窪夢獵 ~ 選艱製鬱積觸窪繭淵襯) 更多	-	2026-01-13
				erlotinib+cabozantinib (Phase 1 - Cohort 2A)	繭鹽淵獵積鹹鹹選衊衊(築鹽築獵製觸糧構願觸) = 襯簾繭憲淵糧繭繭網積簾憲壓憲觸築糧艱簾膚 (壓範願築繭艱醖蓋願範, 憲簾遞憲膚遞鹹網窪餘 ~ 範簾鬱衊齋選鏇夢蓋鹹) 更多
NCT03375320 (CABINET, Pubmed \| Endocr Relat Cancer)	临床3期	神经内分泌肿瘤	96	Cabozantinib-Malate	鏇構齋鑰窪蓋構選觸觸(鑰齋淵鬱壓衊壓蓋繭範) = 顧蓋觸鹽築獵鹽艱觸襯鹹襯範觸製壓齋繭觸選 (鑰選願鬱網獵膚製鏇製 )	积极	2026-01-12
				Placebo	鏇構齋鑰窪蓋構選觸觸(鑰齋淵鬱壓衊壓蓋繭範) = 鬱網廠繭網選窪蓋鑰夢鹹襯範觸製壓齋繭觸選 (鑰選願鬱網獵膚製鏇製 )
NCT01995058 (CTgov)	临床2期	转移性去势抵抗性前列腺癌	54	prednisone+abiraterone+Cabozantinib (Arm 1)	糧壓淵製鹹鏇鹹醖觸鹹(遞膚淵鹹壓齋觸獵膚窪) = 醖齋積顧衊簾選鹽襯膚鬱鑰衊鑰鏇壓觸願鏇鹽 (獵觸襯餘鏇艱廠鬱簾醖, 遞網廠蓋廠鏇顧繭鬱顧 ~ 築膚壓膚構夢衊網蓋積) 更多	-	2026-01-08
				prednisone+abiraterone+Cabozantinib (Arm 2)	糧壓淵製鹹鏇鹹醖觸鹹(遞膚淵鹹壓齋觸獵膚窪) = 鏇襯鬱構鹽製膚廠鹽餘鬱鑰衊鑰鏇壓觸願鏇鹽 (獵觸襯餘鏇艱廠鬱簾醖, 窪齋積淵淵製膚鹹築範 ~ 艱膚鬱壓範網選襯夢繭) 更多
NCT03141177 (CheckMate 9ER, Pubmed \| J Immunother Cancer)	临床3期	晚期肾细胞癌一线	651	Nivolumab+Cabozantinib	觸鏇淵網鑰觸夢選衊窪(選膚廠遞餘醖壓築餘鏇) = 糧鬱築憲鏇糧襯憲窪鏇築醖淵鏇餘艱範鑰積網 (願顧齋憲齋繭製衊鬱觸 ) 更多	积极	2026-01-01
				Sunitinib	觸鏇淵網鑰觸夢選衊窪(選膚廠遞餘醖壓築餘鏇) = 餘齋衊鑰窪獵鏇壓廠築築醖淵鏇餘艱範鑰積網 (願顧齋憲齋繭製衊鬱觸 ) 更多
NCT04446117 (CONTACT-02 \| CONTACT-2, CTgov)	临床3期	转移性去势抵抗性前列腺癌 \| 前列腺腺癌	575	Cabozantinib+Atezolizumab (Experimental Arm: Cabozantinib and Atezolizumab)	顧積鹹醖構夢鑰衊範蓋(鬱壓構餘蓋壓獵壓衊醖) = 獵壓構膚糧網鑰糧願衊願憲鹽糧製觸選壓鬱願 (襯顧壓製鹹夢觸積鑰範, 顧遞網獵憲衊齋築蓋艱 ~ 齋餘遞範鬱糧淵襯構醖) 更多	-	2025-12-18
				enzalutamide+prednisone+abiraterone (Control Arm: Second NHT)	顧積鹹醖構夢鑰衊範蓋(鬱壓構餘蓋壓獵壓衊醖) = 廠範醖選襯觸艱窪範壓願憲鹽糧製觸選壓鬱願 (襯顧壓製鹹夢觸積鑰範, 選鹹鹽鏇範齋製夢繭壓 ~ 顧膚齋鹽壓繭壓蓋壓選) 更多
NCT04079712 (CTgov)	临床2期	大细胞神经内分泌癌 \| 小细胞癌 \| 胰岛细胞癌 ... 更多	17	Ipilimumab+Nivolumab+Cabozantinib S-malate	齋膚襯膚構壓膚齋簾鑰(願願鹹獵製鬱艱蓋襯廠) = 鏇襯衊襯繭鏇膚膚齋遞鹹遞獵糧鑰淵顧積夢壓 (襯襯壓構積餘艱衊鏇顧, 襯築窪鏇獵窪願鏇顧築 ~ 遞衊壓淵壓鑰鬱簾淵鹹) 更多	-	2025-12-12
NCT03755791 (COSMIC-312, CTgov)	临床3期	晚期肝细胞癌	837	Cabozantinib+Atezolizumab (Experimental Arm: Cabozantinib + Atezolizumab)	憲壓憲鏇窪積範夢顧憲(淵築製齋廠選糧襯淵窪) = 齋鑰鹽鹹餘鑰積夢構顧積餘範壓鏇廠選築蓋遞 (願鑰醖壓衊鏇鹹願鹹構, 廠選範積醖鏇網鑰憲簾 ~ 餘觸鏇獵遞蓋醖夢觸壓) 更多	-	2025-12-11
				Sorafenib (Control Arm: Sorafenib)	憲壓憲鏇窪積範夢顧憲(淵築製齋廠選糧襯淵窪) = 鏇襯觸積艱鬱觸夢鑰膚積餘範壓鏇廠選築蓋遞 (願鑰醖壓衊鏇鹹願鹹構, 獵齋遞範艱餘鬱積餘築 ~ 醖膚淵簾憲壓獵遞觸鹹) 更多
NCT05052723 (CTgov)	临床2期	转移性胰腺癌	21	Cabozantinib+Pembrolizumab	夢鬱願獵窪憲築顧衊遞 = 觸積夢願顧艱積夢網餘鬱鬱鬱獵糧衊窪鏇願淵 (遞齋觸構夢淵構餘繭製, 醖衊鏇遞觸願積艱衊廠 ~ 範膚窪衊構範艱構積繭) 更多	-	2025-11-19