This phase III trial compares the effect of adding tivozanib to standard therapy pembrolizumab versus pembrolizumab alone for the treatment of patients with high-risk renal cell carcinoma (RCC). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Tivozanib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving pembrolizumab and tivozanib together may work better than pembrolizumab alone in treating patients with RCC.

开始日期2025-03-14

申办/合作机构

Alliance for Clinical Trials in Oncology

NCT06116890

/ Recruiting临床2期

A Phase 2, Multicenter, Randomized, Double-Masked, Parallel Group Study to Assess the Efficacy and Safety of KHK4951, a Vascular Endothelial Growth Factor Receptor Inhibitor, in Patients With Neovascular Age-Related Macular Degeneration

The purpose of this study is to evaluate efficacy and safety of KHK4951 eye drops in patients with nAMD.

开始日期2024-01-31

申办/合作机构

Kyowa Kirin Co., Ltd.

NCT06116916

/ Recruiting临床2期

A Phase 2, Multicenter, Randomized, Double-Masked, Parallel-Group Study to Assess the Efficacy and Safety of KHK4951, a Vascular Endothelial Growth Factor Receptor Inhibitor, in Patients With Diabetic Macular Edema

The purpose of this study is to evaluate efficacy and safety of KHK4951 eye drops in patients with DME.

开始日期2024-01-09

申办/合作机构

Kyowa Kirin Co., Ltd.

100 项与替沃扎尼相关的临床结果

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100 项与替沃扎尼相关的转化医学

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100 项与替沃扎尼相关的专利（医药）

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400

项与替沃扎尼相关的文献（医药）

2025-10-01·Neural Regeneration Research

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish: unveiling the role of vascular endothelial growth factor signaling and microglia

Article

作者: Gence, Laura ; Rondeau, Philippe ; Diotel, Nicolas ; Fernezelian, Danielle

JOURNAL/nrgr/04.03/01300535-202510000-00025/figure1/v/2024-11-26T163120Z/r/image-tiff After brain damage, regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals, suggesting a close link between these processes. However, the mechanisms by which these processes interact are not well understood. In this work, we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury. To this end, we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms. First, using the Tg(fli1:EGFP × mpeg1.1:mCherry) zebrafish line, which enables visualization of blood vessels and microglia respectively, we analyzed regenerative angiogenesis from 1 to 21 days post-lesion. In parallel, we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry. We found that after brain damage, the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor (vegfaa and vegfbb) were increased. At the same time, neural stem cell proliferation was also increased, peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis, along with the recruitment of microglia. Then, through pharmacological manipulation by injecting an anti-angiogenic drug (Tivozanib) or Vegf at the lesion site, we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes, as well as microglial recruitment. Finally, we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis, as previously described, as well as injury-induced angiogenesis. In conclusion, we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process. In addition, we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes. This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

2025-06-01·Clinical Genitourinary Cancer

CDK4/6 Inhibition With Abemaciclib in Patients With Previously Treated Advanced Renal Cell Carcinoma

Article

作者: Xu, Wenxin ; Kaelin, William G ; McGregor, Bradley A ; Choueiri, Toni K ; McDermott, David ; Xie, Wanling ; Berg, Stephanie A ; Signoretti, Sabina ; Viswanathan, Srinivas R

BACKGROUND:

Preclincal data provide a rationale for cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors alone and in combination with HIF-2α inhibitors in treatment of clear cell renal cell carcinoma (ccRCC), with randomized phase 2 clinical trials currently open exploring the combination of palbociclib with belzutifan vs belzutifan in treatment resistant ccRCC (NCT05468697). However, single agent activity for CDK4/6 inhibitors in ccRCC has not been reported. In this multi-center phase 1b clinical trial (NCT04627064), we investigated the safety and efficacy of monotherapy with abemaciclib, an oral CDK4/6 inhibitor in patients with advanced pretreated RCC.

METHODS:

Adult patients with advanced RCC with a clear cell component and ECOG status of ≤ 2 progressing after at least 1 prior regimen including immunotherapy and a VEGFR TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. The primary objective was to evaluate the objective response rate (ORR) of abemaciclib with a secondary endpoint of safety. First imaging was performed after 8 weeks or 2 cycles. Response was assessed per RECIST 1.1 and toxicity graded per CTCAE v5.0.

RESULTS:

Eleven patients were enrolled between December 31, 2020 and October 03, 2023. Median age was 62 years (range 54-68); 73% (n = 8) had IMDC intermediate risk disease and 1 patient had translocation RCC with a clear cell component. Median number of prior therapies was 4 (range 1-9). ORR was 0% (0/11; 8 progressive disease, 1 stable disease stopping for clinical progression, 2 not evaluable with clinical progression). About 27% (n = 3) experienced grade ≥3 treatment-related adverse events (diarrhea n = 1, nausea n = 1, neutropenia n = 1).

CONCLUSION:

In patients with heavily pretreated metastatic RCC, abemaciclib monotherapy had no clinically meaningful activity without new toxicity signals. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2α inhibitors and immunotherapy.

2025-04-09·Journal of the American Chemical Society

Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug

Article

作者: Ranson, Neil A. ; Willis, Leon F. ; Brinkworth, Alice ; Xu, Yong ; Zhuravleva, Anastasia ; Radford, Sheena E. ; Foster, Richard ; Chakraborty, Pijush ; Wilkinson, Martin ; Taylor, Alexander I. P.

Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.

项与替沃扎尼相关的新闻（医药）

2025-02-18

·PRNewswire

AVEO Oncology, an LG Chem company, Presents Two Posters for Tivozanib at the 2025 ASCO GU Meeting

– Cumulative data of three Phase 3 studies demonstrate greater exposure of tivozanib is associated with increased clinical benefit – – Patient Reported Outcomes were numerically better for patients receiving tivozanib in a second line setting versus third line – BOSTON, Feb. 18, 2025 /PRNewswire/ -- AVEO Oncology, an LG Chem company ("AVEO"), is a biopharmaceutical company that is trying to provide differentiated solutions to improve cancer patients lives, presented two posters during the 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting highlighting continued data for tivozanib, a next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) designed to block the VEGF pathway by selectively inhibiting all three VEGF receptors. "Following the TiNivo-2 study results presentation at ESMO 2024 and publication in The Lancet, we were excited to share this data with the oncology community at ASCO GU 2025," said Michael Bailey, president and Chief Executive Officer. "These data build on the robust clinical evidence for tivozanib generated over different studies that have consistently demonstrated clinical benefit and tolerability in the advanced RCC population." Poster title: " Integrated efficacy and safety exposure response (ER) analysis of tivozanib (TIVO) for the treatment of renal cell cancer (RCC)." – (Abstract: 461; Poster: D29) AVEO presented data from an exploratory analysis evaluating the efficacy and safety exposure response relationship of tivozanib from three Phase 3 trials that have been conducted with TIVO: TIVO-1, TIVO-3, and TiNivo-2. The objective of the analysis was to better understand the relationship between tivozanib exposure with progression free survival (PFS), tumor size (TS), and hypertension (HTN) using pharmacokinetic (PK) and exposure response (ER) modeling in metastatic renal cell carcinoma (RCC). The analysis demonstrated a strong correlation between higher exposure of tivozanib and improvements in PFS while the exposure level of both the standard dose of 1.34 mg dose and low dose 0.89 mg of tivozanib was associated with a similar incidence of hypertension. Poster Title: "Patient-reported outcomes (PROs) for tivozanib (TIVO) + nivolumab (NIVO) vs TIVO monotherapy in patients with renal cell carcinoma (RCC) following an immune checkpoint inhibitor (ICI): results of the phase 3 TiNivo-2 study." – (Abstract: 459; Poster: D27) AVEO presented a poster with data from an exploratory analysis evaluating patient reported outcomes (PROs) from the TiNivo-2 study. TiNivo-2 is a randomized, Phase 3 trial designed to assess the efficacy and safety of a PD-1 inhibitor combination following disease progression on or after prior PD-1/PD-L1 therapy. While the study did not meet its primary endpoint of demonstrating a benefit of adding nivolumab to tivozanib versus tivozanib alone after prior immune checkpoint inhibitor (ICI) exposure, clinically meaningful outcomes were observed with tivozanib monotherapy (1.34 mg) as a second-line (2L) and third-line (3L) treatment following ICI therapy. The analysis used the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease-Related Symptoms (FKSI-DRS) and European Organization for Research and Treatment of Cancer (EORTC) QLQ C30 questionnaires, administered at baseline, day 1 of each cycle, and at the end of treatment, to collect patient outcomes. The analysis indicated that tivozanib maintained the FKSI-DRS and EORTC QLQ-C30 mean scores over time in both treatment arms. Importantly, in the tivozanib monotherapy arm, the proportion of patients who had improvement in FKSI-DRS and EORTC QLQ-C30 scores was numerically better in patients receiving 2L versus 3L treatment, while the portion of patients with a deterioration was smaller in the 2L than in the 3L. INDICATIONS FOTIVDA is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hypertension was reported in 45% of patients (22% ≥ Grade 3). Hypertensive crises were reported in 0.8% of patients. Do not initiate FOTIVDA in patients with uncontrolled hypertension. Monitor for hypertension and treat as needed. Reduce the FOTIVDA dose for persistent hypertension not controlled by anti-hypertensive medications. Discontinue FOTIVDA for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis. Cardiac failures were reported in 1.6% of patients (1% ≥ Grade 3); 0.6% of events were fatal. Monitor for signs or symptoms of cardiac failure during treatment with FOTIVDA. Manage with dose interruption, dose reduction, or discontinuation. Cardiac ischemia were reported in 3.2% of patients; 0.4% of events were fatal. Arterial thromboembolic events were reported in 2.0% of patients, including death due to ischemic stroke (0.1%). Closely monitor patients at risk for, or who have a history of these events. Discontinue FOTIVDA in patients who develop severe arterial thromboembolic events, such as myocardial infarction and stroke. Venous Thrombotic Events (VTE) were reported in 2.4% of patients, including 0.3% fatal events. Closely monitor patients who are at increased risk for these events. Discontinue in patients who develop serious VTEs. Hemorrhagic Events were reported in 11% of patients; 0.2% of events were fatal. Use FOTIVDA with caution in patients who are at risk for or who have a history of bleeding. Proteinuria was reported in 8% of patients (2% = Grade 3). Monitor during treatment with FOTIVDA. For moderate to severe proteinuria, reduce the dose or interrupt treatment. Discontinue in patients who develop nephrotic syndrome. Gastrointestinal (GI) Perforation including fatal cases, has been reported in patients receiving FOTIVDA. Monitor for symptoms of GI perforation or fistula formation periodically throughout treatment with FOTIVDA. Permanently discontinue FOTIVDA in patients who develop severe or life-threatening GI perforation. Thyroid Dysfunction events were reported in 11% of patients (0.3% ≥ Grade 3). Monitor thyroid function before and during treatment with FOTIVDA. Wound Healing Complications: Withhold FOTIVDA for at least 24 days prior to elective surgery and do not administer for at least 2 weeks after major surgery and until adequate wound healing is observed. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) can occur with FOTIVDA. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue if signs or symptoms of RPLS occur. Embryo-fetal Toxicity: FOTIVDA can cause fetal harm. Advise patients of the potential risk to a fetus, to avoid becoming pregnant and to use contraception during treatment and for one month after the last dose of FOTIVDA. Advise males with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of FOTIVDA. Allergic Reaction to Tartrazine: FOTIVDA 0.89 mg capsule contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients. ADVERSE REACTIONS Common adverse reactions include fatigue/asthenia, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis. Serious adverse reactions include bleeding (3.5%), venous thromboembolism (3.5%), arterial thromboembolism (2.9%), acute kidney injury (2.3%), and hepatobiliary disorders (2.3%). DRUG INTERACTIONS Avoid coadministration with strong CYP3A4 inducers. USE IN SPECIFIC POPULATIONS Advise women not to breastfeed during treatment and for at least 1 month after the last dose. The recommended dosage for patients with end-stage renal disease has not been established. Reduce the FOTIVDA dose for patients with moderate hepatic impairment. The recommended dosage in patients with severe hepatic impairment has not been established. To report SUSPECTED ADVERSE REACTIONS, contact AVEO Pharmaceuticals, Inc. at 1-833-FOTIVDA (1-833-368-4832) or FDA at 1-800-FDA-1088 or . Please see full Prescribing Information for FOTIVDA® (tivozanib). About FOTIVDA® (tivozanib) FOTIVDA® (tivozanib) is an oral, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). It is a potent, selective inhibitor of VEGFRs 1, 2, and 3 with a long half-life designed to improve efficacy and tolerability. AVEO received U.S. Food and Drug Administration (FDA) approval for FOTIVDA on March 10, 2021, for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies, based on data from the TIVO-3 trial comparing FOTIVDA to sorafenib. FOTIVDA was approved in August 2017 in the European Union and other countries in the territory of its partner Recordati UK Ltd. for the treatment of adult patients with advanced RCC. FOTIVDA was discovered by Kyowa Kirin. About AVEO Pharmaceuticals, Inc. AVEO is an oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for patients with cancer. AVEO currently markets FOTIVDA® (tivozanib) in the U.S. for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. AVEO continues to develop FOTIVDA in immuno-oncology and other novel targeted combinations in RCC and other indications, and has other investigational programs in clinical development. AVEO became a wholly owned subsidiary of LG Chem Life Sciences USA, Inc. on January 19, 2023. AVEO continues to operate under the AVEO Oncology, an LG Chem company, name. About LG Chem, Ltd. and LG Chem Life Sciences LG Chem, Ltd. (LG Chem) is a leading global chemical company with a diversified business portfolio in the key areas of petrochemicals, advanced materials, and life sciences. The company manufactures a wide range of products from high-value added petrochemicals to renewable plastics, specializing in cutting- edge electronic and battery materials, as well as drugs and vaccines to deliver differentiated solutions for its customers. LG Chem Life Sciences develops, manufactures, and globally commercializes pharmaceutical products, with a focus on Oncology, Immunology, and Metabolic diseases. Our mission is to transform people's lives through inspiring science and leading innovation. For more information, please visit . Contacts Media: John F. Kouten JFK Communications, Inc. [email protected] (908) 227-4714 SOURCE AVEO, an LG Chem company WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床结果上市批准临床3期ASCO会议免疫疗法

2025-01-30

·ioncology

年度盘点丨行则将至，未来可期！盛锡楠教授分享2024年度晚期肾癌治疗重要进展

- 年度盘点 - 2024年度晚期肾癌治疗重要进展盛锡楠教授编者按：道阻且长，行则将至；行而不辍，未来可期。近年来，肾癌领域的部分免疫治疗遭遇“滑铁卢”，没有达到主要终点；但随着更多靶向、免疫等治疗药物的研究进展，晚期肾癌治疗取得了长足进步。尤其多项靶免联合治疗的大型Ⅲ期研究相继取得成功，标志着晚期肾癌一线治疗进入了靶免联合治疗时代。2024年晚期肾癌取得了多项突破，我们特邀北京大学肿瘤医院盛锡楠教授分享重要研究进展，或许可为未来的肾癌治疗和研究提供更多参考借鉴。 01 透明细胞肾细胞癌一线治疗自2018年底公布第一项免疫联合用于晚期肾透明细胞癌的随机对照Ⅲ期临床研究以来，目前已经有多项随机对照Ⅲ期临床研究显示免疫联合治疗可以改善晚期肾癌的一线治疗预后。2023年ESMO大会公布了特瑞普利单抗联合阿昔替尼的RENOTORCH研究结果，显示联合治疗组的中位PFS达到18.0个月（舒尼替尼单药组为9.8个月），降低疾病进展或死亡风险35%。2024年4月国家药品监督管理局（NMPA）批准特瑞普利单抗联合阿昔替尼用于中高危不可切除或转移性肾细胞癌的一线治疗，同时也纳入2024版中国临床肿瘤学会（CSCO）肾癌诊疗指南一线治疗的Ⅰ级推荐，标志着国内晚期肾癌正式步入靶向联合免疫治疗的时代。随着一线免疫联合方案的增加，未来需要通过预测标志物等筛选优势获益人群，为患者提供个体化治疗策略。 PD-L1单抗联合靶向治疗进展自PD-1与PD-L1单抗为代表的免疫检查点抑制剂被引入晚期肾透明细胞癌的治疗后，已先后开展了多项随机对照3期临床研究，但大部分为以PD-1单抗为基础的联合方案，而以PD-L1单抗为基础的联合方案仅有IMmotion151研究和JAVELIN RENAL 100研究两项。IMmotion151研究未能证实阿替利珠单抗联合贝伐单抗显著优于舒尼替尼靶向治疗。虽然JAVELIN RENAL100研究显示，阿昔替尼联合阿维鲁单抗显著改善一线治疗的无进展生存（PFS）时间，并由此获批美国FDA晚期肾癌一线治疗适应证。但2024 ASCO年会所公布的最终生存分析结果显示[1]，经过68个月的中位随访时间后，联合治疗在PD-L1阳性患者中的中位总生存（mOS）为43.2个月（对照组为36.2个月，HR=0.86）；在意向性治疗（ITT）人群中的mOS为44.8个月（对照组为38.9个月，HR=0.88）。尽管联合治疗可以延长总生存期近7个月，但是仍没有达到统计学显著性界值，为靶向联合PD-L1单抗的应用埋下了阴霾。 △ PD-L1阳性人群和总人群中的OS分析 2024年ESMO大会，公布了由北京大学肿瘤医院和中国医学科学院肿瘤医院牵头的ETER-100研究中期分析结果[2]，这项试验是国内第2项晚期肾透明细胞癌的Ⅲ期临床研究，也是全球第3项靶向联合PD-L1单抗免疫治疗的大型研究，比较了安罗替尼联合PD-L1单抗贝莫苏拜单抗（TQB2450）对比舒尼替尼作为晚期肾细胞癌（RCC）患者一线治疗的效果。主要终点是PFS。今年ESMO大会公布的结果显示[2]，在平均随访19.52个月后，靶免联合组显著延长了PFS（风险比HR 0.53；P<0.0001；中位PFS 18.96个月 vs 9.76个月），并提高了ORR（71.59% vs 25.10%；P<0.0001）。目前总生存数据尚不成熟，初步来看是有利于靶向联合免疫治疗组。研究在安全性方面和之前的研究数据基本类似。当前的研究结果显示，免疫疗法联合TKI对于晚期肾癌患者的总生存期具有显著的延长作用，这一发现重新点燃了PD-L1单抗联合靶向治疗晚期肾癌的希望。 △ 两个治疗组的PFS分析不同IMDC危险分层人群的获益分析目前晚期肾癌的一线免疫联合治疗数据均支持IMDC中高危患者免疫联合治疗较既往单独靶向治疗可获得显著获益，这一结论也在近年来多项3期临床研究的随访数据以及专为中高危人群设计的RENOTORCH研究中得到验证。 2024年ASCO-GU公布的CheckMate 9ER研究55个月随访结果表明[3]，对于未经治疗的aRCC患者，纳武利尤单抗联合卡博替尼方案的PFS（16.4个月vs. 8.4个月，HR 0.58）、OS（46.5个月vs. 36.0个月，HR 0.77）和ORR（55.7% vs. 27.7%）均优于舒尼替尼。基于IMDC分层，在低危人群中，联合治疗组的mOS未取得显著获益（HR=1.10）；在中/高危人群中，联合治疗组的mPFS（15.4个月 vs 7.1个月，HR=0.56）和mOS显著获益（43.9个月 vs 29.3个月，HR=0.73）；联合治疗组的ORR达52.6%，显著优于舒尼替尼组。不同转移部位疗效评估，肝、骨、肺转移的肾细胞癌患者，PFS、OS、ORR均能从联合治疗组中显著获益。因此，国内外指南仍推荐免疫联合治疗作为中高危晚期肾透明细胞癌患者的一线治疗，而对于低危人群，靶向药物仍然可以作为治疗选择之一。 △ CheckMate 9ER研究IMDC低危人群的PFS、OS、ORR分析但并非所有低危患者都不能从免疫联合治疗中获益。2024年ASCO-GU大会公布了CheckMate-214研究的8年随访数据[4]，显示纳武利尤单抗+伊匹木单抗继续显示出较舒尼替尼具有统计学意义和临床意义的长期生存和持久的缓解获益。在ITT人群中，双免联合组的中位OS更长（52.7个月vs. 37.8个月；HR 0.72，95%CI 0.62，0.83）；在IMDC低危患者中，虽然双免治疗组初始获益并不明显，但经过长期随访，双免治疗组的OS获益凸显（77.9个月 vs 66.7个月），并且双免联合具有更加持久（DOR：61.5 vs 33.2月）和深度（CR率：16% vs 8%）的缓解。尽管随访时间延长，但联合治疗组并未出现新的安全性信号。因此，NCCN指南、ESMO指南等国外指南均将双免疫治疗纳入IMDC低危人群的推荐治疗。 △ CheckMate 214研究中IMDC低危人群的OS和DOR分析 2024 ASCO年会公布了一项IMDC真实世界研究[5]，该研究从传统意义的低危患者中筛选出极低危患者，其标准定位为从初诊至接受全身治疗的时间≥3年、无脑肝或骨转移、卡氏评分90或100的患者。数据分析显示，IMDC极低危人群接受双免疫、靶向联合免疫以及单独靶向治疗的ORR分别为23.5%、58.1%和55%，2年OS率分别为71.3%、87.2%和92.1%；而低危患者的ORR分别为35%、51.4%和37.9%，2年OS率分别为86.4%、84.1%和81.1%。这表明极低危患者仍然能从单独抗血管靶向药物治疗中获益，而非极低危患者似乎从联合免疫治疗中更能获益。该结果仍然需要进一步的前瞻性试验和更长时间的随访来验证，但对于生物学行为较差的患者，即使是低危患者，仍然可以考虑积极的免疫联合治疗。 △ IMDC真实世界研究的OS分析因此，对于晚期肾透明细胞癌的一线治疗，随着可选择方案的增加，不仅仅需要考虑危险分层，还需要结合转移部位等疾病特征。当然，如果有更好的预测标记物，将会有更好的优化治疗选择。筛选获益预测因素由于目前缺乏预测性生物标志物，因此需要进一步明确最有可能从靶免联合治疗中受益的患者。2024年在ESMO大会公布的CheckMate 9ER研究的生物标志物分析结果表明[6]，蛋白质岩藻糖基化和唾液酸化机制或许可潜在驱动aRCC患者纳武利尤单抗联合卡博替尼和舒尼替尼耐药。参与补体级联反应和脂质代谢的血清糖蛋白可预测纳武利尤单抗联合卡博替尼和舒尼替尼治疗aRCC的缓解情况。 2024年欧洲泌尿外科年会（EAU）公布了NORA真实世界研究中纳武利尤单抗联合伊匹木单抗一线治疗晚期肾细胞癌患者OS的预后因素[7]。结果提示，中位随访11.9个月，13.3%的患者OS<3个月，86.7%的患者OS≥3个月，其中OS<3个月组较OS≥3个月组的患者基线有更多的不良因素：IMDC评分更差（高危28.6% vs 25.3%）、ECOG PS评分更高（≥2分，25.7% vs 4.8%）、Karnofsky PS更低（≥70分，62.9% vs 82.5%）、既往肾切除率更低（54.3% vs 64.6%）、转移负荷更高，基线平均转移器官数更多（2.1 vs 1.8）。随着未来更长时间随访与更多研究的探索，未来可能会出现更多有关OS预后因素的相关数据。 02 透明细胞肾细胞癌一线治疗失败后的选择晚期肾透明细胞癌的治疗已经进入免疫联合时代，一线治疗失败后虽然有众多未用过的方案可供选择，如继续靶向或靶向联合免疫，但目前尚无高等级循证医学证据支持相应选择。因此，一线治疗后如何选择成为临床待解的难题，也是未来临床研究的热点。序贯靶向方案针对免疫联合治疗失败后的二线选择，2023 ASCO年会公布了一项卡博替尼联合阿替利珠单抗对比卡博替尼单药的随机对照3期CONTACT-03研究，结果证实联合免疫未能优于卡博替尼单药治疗。 TiNivo-2研究是一项全球多中心、随机、开放标签的3期研究[8]，分析了纳武利尤单抗联合替沃扎尼或替沃扎尼单药治疗经1~2种治疗（包括免疫治疗）后出现进展患者的疗效。主要终点是PFS；关键次要终点是OS，其他次要终点包括PFS、ORR、DoR和安全性/耐受性。研究共纳入343名患者，随机接受替沃扎尼联合纳武利尤单抗（n=171）或替沃扎尼（n=172）。研究结果表明，联合治疗组和单药组的PFS分别为5.7个月和7.4个月，OS分别为17.7个月和22.1个月。两组ORR接近，分别为33%和34%。结果提示，对于晚期肾细胞癌患者，不推荐再次尝试ICI治疗。此外，研究数据明确指出，在免疫治疗后，替沃扎尼单药治疗展现出了一定的疗效，为这一阶段的患者提供了潜在的治疗选择。因此，对于晚期肾透明细胞癌一线接受免疫联合后的治疗，继续免疫联合靶向药物不能获益，而选择单独靶向治疗已经成为共识。 △ TiNivo-2研究ITT人群PFS分析新型靶向药物近年来，缺氧诱导因子（HIF）-2α成为了肾癌靶向治疗的关注焦点。贝组替凡是一种小分子药物，能够结合并稳定HIF的α亚基，从而阻止其进入细胞核并激活下游基因的表达。这种作用机制使得贝组替凡能够抑制VHL相关肿瘤的血管生成和细胞增殖，进而达到控制肿瘤生长的目的。这一发现为VHL相关肿瘤的治疗提供了新的思路和方法，也为贝组替凡的研发奠定了坚实的基础。2024年11月，NMPA批准贝组替凡上市，用于治疗VHL相关肾细胞癌等肿瘤，为患者提供了新的治疗选择。贝组替凡单药对比依维莫司的LITESPARK-005研究共入组746名患者（贝组替凡374名，依维莫司372名）。既往数据证实，贝组替凡可显著改善免疫检查点抑制剂和抗血管生成药物治疗后进展的晚期ccRCC患者的无进展生存期（HR 0.75，P＜0.001）和客观缓解率（21.9% vs. 3.5%，P＜0.00001），而依维莫司则未达到该水平。2024年ESMO大会更新PFS获益，并公布了OS结果[9]。与依维莫司相比，贝组替凡持续具有PFS获益（5.6个月vs. 5.6个月；HR 0.75；95% CI 0.63~0.88）；贝组替凡的12个月和24个月估计PFS率更优（12个月：33.7% vs 17.6%；24个月：17.5% vs 4.1%）。贝祖替凡治疗组的中位OS为21.4个月，依维莫司组为18.2个月（HR 0.92；95% CI 0.77~1.10；P=0.18）。12个月时估计OS率分别为67.9% vs. 65.8%，24个月时估计OS率分别为45.2% vs. 41.2%。结果表明，与接受依维莫司治疗相比，接受贝组替凡治疗的晚期ccRCC患者可获得更好的PFS和ORR结局。 △ 贝组替凡和依维莫司治疗组的PFS和OS分析其他的HIF-2α抑制剂如2024 ASCO年会公布的DFF332[10]，在中位既往治疗线数为2的40例晚期肾癌患者中获得了5%的ORR和52.5%的疾病控制率（DCR）。2024 ESMO年会公布的NKT2152[11]，作为中位既往三线治疗的100例晚期肾癌患者的后线治疗，获得了20%的ORR和7.4个月的PFS期，剂量递增组的中位PFS期为9.2个月。相较上述HIF-2α抑制剂的单药疗效数据，HIF-2α抑制剂联合治疗方案更值得关注，并在初期研究中获得了更好的疗效。由北京大学肿瘤医院与全国多中心研究团队开展的LITESPARK-010是一项I期、2队列、开放标签研究的队列1的研究结果，这项研究旨在分析使用贝组替凡联合仑伐替尼（联合或不联合帕博利珠单抗）治疗中国晚期ccRCC患者的疗效和安全性。2024年ASCO大会报告的初步数据显示[12]，贝组替凡联合仑伐替尼对于既往接受过治疗的中国ccRCC患者而言，抗肿瘤活性良好。贝组替凡120 mg联合仑伐替尼20 mg的安全性与各自药物的安全性概况一致。这一结果表明，对于多线治疗失败的患者，这种联合治疗方案具有较好的初步疗效。 △ LITESPARK-010研究的PFS和OS分析 03 非透明细胞肾细胞癌治疗非透明细胞肾细胞癌因其显著不同的分子特征和临床行为，仍需要个体化及创新性的治疗策略提高治疗效果，改善远期生存。靶免治疗 2024年ASCO-GU大会公布的KEYNOTE-B61研究[13]表明，仑伐替尼联合帕博利珠单抗用于晚期nccRCC一线治疗具有良好的疗效。延长随访结果显示，ORR为50.6%，DCR为82.3%，中位DOR为19.5个月，中位PFS为17.9个月，中位OS尚未达到，安全性可控。亚组分析结果表明，这一联合方案在不同组织类型的nccRCC中均显示出不错的ORR，为患者提供了新的治疗选择。此外，仑伐替尼与帕博利珠单抗的联合治疗方案在改善患者生存质量和延长生存期方面也表现出明显优势。这为nccRCC患者提供了一种新的治疗策略，但仍需进一步研究以确定其在不同患者群体中的最佳应用。 △ KEYNOTE-B61研究的ORR、DOR、PFS和OS分析 2024年ASCO大会公布了一项开放标签的、单臂、国内多中心、II期试验[14]，评估信迪利单抗联合阿昔替尼在富马酸水合酶缺乏型肾细胞癌中的疗效和安全性。研究的主要终点为ORR和PFS。在38名可进行疗效评估的患者中，研究者观察到了显著的疗效。结果显示，ORR达60.5%，疾病控制率达86.8%，中位PFS为19.83个月。这种联合方案疗效良好，未来可通过评估FH基因突变，预测靶免联合治疗的疗效，从而实现更精准的个体化治疗。 △ 信迪利单抗联合阿昔替尼治疗组的ORR和PFS分析双免治疗 2024 ESMO年会公布了晚期非透明细胞癌双免疫治疗的随机对照2期SUNNIFORECAST研究结果[15]，显示纳武利尤单抗联合伊匹木单抗方案相对于常规治疗方案，PFS（5.52个月 vs 5.65个月）和OS（42.4个月 vs 33.9个月）均未观察到统计学差异，PD-L1表达阳性（CPS>1%）亚组获益更为显著。 △ SUNNIFORECAST研究的PFS和PS分析在另一项特异性双抗的研究中[16]，22例非透明细胞肾细胞癌患者接受一线PM8002/BNT327治疗，中位随访9.0个月，ORR为36.4%。不同亚型中，乳头状癌ORR最高，DCR为90.9%，中位PFS为15.1个月。此外，研究中对于双抗药物的3级以上不良反应发生率更低（41.5%，KEYNOTE-426研究为75.8%），表现出了很好的发展前景。 △ PM8002/BNT327治疗nccRCC的ORR、DCR和PFS分析随着靶免治疗及双免治疗的不断发展，晚期肾癌患者的生存取得了显著进展。未来，随着预测标志物的探索，有望进行个体化治疗，进一步改善患者生存。参考文献上下滑动查看更多内容 [1]. 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The Lancet, 2024, 404(10460): 1309-1320. [9]. Rini, B. I., et al. LBA74 Final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC). Annals of Oncology 35 (2024): S1262-S1263. [10]. Sumanta Kumar Pal, et al. Preliminary safety, pharmacokinetics and clinical activity of DFF332, an oral HIF2α inhibitor, as monotherapy in a phase 1 dose escalation study in patients with advanced clear cell renal cell carcinoma. ASCO 2024. 4513. [11]. Jonasch E, McGregor B A, Msaouel P, et al. 1690O NKT2152, a novel oral HIF-2α inhibitor, in participants (pts) with previously treated advanced clear cell renal carcinoma (accRCC): Preliminary results of a phase I/II study[J]. Annals of oncology, 2024, 35(Supplement 2): S1011-S1012. [12]. Sheng X, Guo H, Yao X, et al. Belzutifan plus lenvatinib (len) for Chinese patients (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Preliminary results of cohort 1 of the phase 1 LITESPARK-010 study[J]. ASCO 2024. 4537 [13]. Martin H Voss, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): Extended follow-up of the phase 2 KEYNOTE-B61 study. 2024 ASCO GU 2. [14]. Hao Zeng, Xingming Zhang, Jiayu Liang, et al, Sintilimab plus axitinib for advanced fumarate hydratase-deficient renal cell carcinoma: A multi-center, open-label, single-arm, phase II study (SAFH) [J]. JCO 42, 4523-4523(2024).DOI:10.1200/JCO.2024.42.16_suppl.4523. [15]. L. Bergmann et al, LBA75 - Prospective randomised phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer: Results of the SUNNIFORECAST trial. Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623 [16]. Xinan Sheng, et al, 1692P - A phase Ib/IIa trial to evaluate the safety and efficacy of PM8002/ BNT327, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced renal cell. Annals of Oncology (2024) 35 (suppl_2): S1012-S1030. 10.1016/annonc/annonc1609 盛锡楠教授主任医师，教授，博士生导师北京大学肿瘤医院泌尿肿瘤内科副主任中国抗癌协会泌尿生殖肿瘤整合康复专业委员会副主任委员中国抗癌协会泌尿系统肿瘤专业委员会常委中国临床肿瘤学会(CSCO)理事中国临床肿瘤学会肾癌专家委员会常委兼秘书长中国临床肿瘤学会尿路上皮癌专家委员会常委国家肿瘤质控中心膀胱癌质控专家委员会委员北京肿瘤防治研究会泌尿肿瘤分委会候任主任委员北京抗癌协会泌尿生殖肿瘤专委会青委会主任委员北京医学会肿瘤分会常委（来源：《肿瘤瞭望-泌尿时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

CSCO会议ASCO会议临床3期临床结果

2025-01-13

·ioncology

年度盘点丨锁爱莉教授：2024胃癌靶向治疗的进展与思考

点击蓝字关注我们年度盘点微专辑扫描二维码可查看更多内容编者按近年来，随着研究的深入，胃癌分子机制的探究逐渐由组织学分型过渡到分子分型，不同生物标志物对晚期胃癌的一线及后续治疗格局产生深远的影响。值此岁末之际，《肿瘤瞭望消化时讯》荣幸地邀请了西安交通大学第一附属医院的锁爱莉教授对2024年度晚期胃癌靶向治疗领域的热点与最新进展进行回顾与总结，回顾往昔，放眼未来，为晚期胃癌治疗的发展建言献策。锁爱莉教授西安交通大学第一附属医院肿瘤内科副主任主任医师，教授，博士生导师美国Emory大学访问学者中国抗癌协会食管肿瘤整合康复专委会常委中国抗癌协会肿瘤胃病学专委会常委中国抗癌协会整合肿瘤肾脏病专委会委员陕西省抗癌协会化疗专委会青委主任委员陕西省抗癌协会老年肿瘤外科专委会副主任委员陕西省抗癌协会安宁疗护专委会副主任委员主持国科金面上项目2项，一作/通讯作者SCI论文20余篇，IF>10的10余篇，授权国家发明专利3项晚期胃癌一线治疗随着研究的深入，胃癌分子机制的探究逐渐由组织学分型 (Lauren分型和WHO分型)过渡到分子分型 (TCGA和ACRG分型) 。癌症基因组图谱(TCGA)基于分子差异，提出将GC分为4组亚型：EB病毒阳性(EBV)、微卫星不稳定(MSI)、基因组稳定(GS)和染色体不稳定(CIN)。CIN亚型的分子特征包括TP53突变、RTK突变（EGFR、ERBB2、ERBB3、FGFR、JAK2、MET）、KRAS/NRAS、VEGFA等。胃癌分子特征为靶向治疗提供潜在靶点，目前HER2靶点已建立标准治疗，新型药物正在探索；而针对CLDN18.2、FGFR等的靶向治疗正在探索进军HER2阴性领域。 HER2——首个用于指导mG/GEJ患者临床决策的生物标志物不同研究中胃癌患者HER2过表达/扩增率存在差异，处于13%～22%不等的水平，既往两项大型多中心研究数据显示，中国胃癌患者的HER2阳性率为12%~13%。ToGA研究中，曲妥珠单抗+化疗开启了胃癌一线抗HER2治疗时代。随后，HER2靶向治疗开始了崎岖的探索之路，经历了拉帕替尼+化疗的3期TRIO-013/LOGIC 研究、帕妥珠单抗+曲妥珠单抗+化疗的3期 JACOB 等一系列失败研究。随着免疫治疗时代的到来，KEYNOTE-811 研究中的帕博利珠单抗+曲妥珠单抗+化疗重塑了晚期胃癌HER2阳性一线治疗。KEYNOTE-811 最终分析表明：ITT （OS：20 vs.16.8个月）和 PD-L1 CPS≥1 人群显著获益（OS：20.1 vs.15.7个月），结果支持该方案作为不可切除/转移性 HER2+ G/GEJ 合并 PD-L1 CPS≥1 患者的一线标准治疗。 Zanidatamab (ZW25) 是一种人源化、双特异性抗体，正在开发用于治疗 HER2-表达的癌症，包括HER2阳性GC/GEJC。ZW25+替雷利珠单抗+CAPOX 一线治疗的Ⅰb/Ⅱ期研究初步结果表明其良好的疗效和安全性。截至2022年11月22日，中位研究随访期18.2个月(范围：2.1～30.9)后，共有13例患者(39.4%)仍在接受治疗，DOR为22.8个月，中位PFS 16.7个月。 DESTINY-Gastric03 (DG-03)是一项Ⅰb/2期研究，意在探索T-Dxd单药或连用化疗/免疫治疗HER2+晚期/转移性食管、胃或胃食管交界处腺癌患者的安全性、耐受性、药代动力学、免疫原性以及初步抗肿瘤活性。DESTINY-Gastric03 研究第 2 部分（剂量扩展）评估了 T-DXd 单药或与氟嘧啶和/或帕博利珠单抗联合用于 HER2+（IHC 3+ 或 IHC 2+/ISH+）GC/GEJA 的一线治疗。DG-03研究结果表明，一线 T-DXd与氟尿嘧啶和/或帕博利珠单抗联合治疗疗效良好。 CLDN18.2——已被确证的胃癌新兴靶点 Claudin是一个由27种不同蛋白质组成的家族，是紧密连接的主要结构组分，可存在于全身各部位。Claudin18.2 (CLDN18.2）是Claudin18的一种亚型，在各种类型癌症中广泛表达，包括胃癌、食管癌、胰腺癌、肺癌和卵巢癌。2023~2024 ASCO GI/ASCO/ESMO公布了多种CLDN18.2靶向疗法的初步结果。2024年，日本、英国、欧盟、韩国、美国FDA 先后批准VYLOY (zolbetuximab) 与化疗联用一线治疗HER2阴性、CLDN18.2阳性的局部晚期不可切除或转移性G/GEJ腺癌。 2018年，安斯泰来开展zolbetuximab两项Ⅲ期临床研究——SPOTLIGHT和 GLOW，两项研究中，4507 例患者有有效的 CLDN18.2 IHC 结果1730 (38.4%) 显示 CLDN18.2 高表达；在 3705 例 HER2 阴性且具有有效 CLDN18.2 IHC 结果的患者中，1568 例 (42.3%) 显示 CLDN18.2 高表达。研究表明，Zolbetuximab联合化疗可显著降低疾病进展和死亡风险，恶心和呕吐是Zolbetuximab组最常见的TEAEs，最常见于第1个周期，且在随后的治疗周期中减少。基于这两项结果，Zolbetuximab成为全球首个且目前唯一获批的CLDN18.2靶向药物。最新ESMO胃癌在线指南也新增 CLDN18.2 作为HER2阴性患者一线治疗分层，推荐 zolbetuximab 联合化疗。此外，Zolbetuximab联合mFOLFOX6和纳武利尤单抗治疗CLDN18.2+、HER2- mG/GEJ患者的Ⅱ期试验正在开展，其他CLDN18.2靶向药在晚期GC/GEJC 一线治疗中的探索目前主要为单抗类（图1）。图1.CLDN18.2 靶向治疗在研药物 FGFR2b——一种新兴生物标志物以识别mG/GEJ亚组人群 FGFR2是跨膜酪氨酸激酶受体的成纤维细胞生长因子受体(FGFR)家族的成员，调节细胞存活、分化和增殖；FGFR2的基因组畸变包括扩增、点突变和致癌融合，已在各种类型的癌症(包括胃癌)中被发现。大型队列研究纳入493例GC患者，发现FGFR2过表达率为21.9%～32.1%。 Bemarituzumab是一种人源化IgG1单克隆抗体，可选择性与 FGFR2b 结合，抑制FGFR2b信号通路并介导ADCC。全球、随机、双盲、安慰剂对照Ⅱ期试验FIGHT研究评估了Bemarituzumab + mFOLFOX6 一线治疗 FGFR2b+G/GEJ腺癌的疗效和安全性。ITT人群显示：Bemarituzumab组mOS延长了5.7个月（19.2个月 vs. 13.5个月，HR 0.77）；FGFR2b+（IHC 2+/3+, ≥10%）的患者显示出更好的生存获益：mPFS HR 0.43；mOS HR 0.52。FGFR2b ≥ 10% 人群ORR达56.5%，且安全性可控。角膜 TEAEs 是 bemarituzumab-mFOLFOX6 组停止治疗的主要原因。≥2 级角膜事件的中位发病时间比任何级别的角膜事件的发病时间长（23.7 周 vs. 16.9 周），这表明在未来的研究中可能有机会通过预防措施及早识别和积极管理 AEs。中山大学肿瘤防治中心徐瑞华教授牵头开展的一项随机、多中心、双盲、安慰剂对照的 3 期FORTITUDE-101研究旨在评估比较 bemarituzumab 联合化疗与安慰剂联合化疗在≥10%的肿瘤细胞FGFR2b 表达阳性的晚期胃或 GEJ腺癌且既往未接受过针对不可切除或转移性疾病治疗的受试者中的有效性和安全性。期待相关数据的公布，为晚期胃癌一线治疗提供新的治疗武器。 DKK1——具备治疗潜力的Wnt/β-catenin双向调控靶点 DKK1在多种肿瘤中高度表达，它通过激活Akt信号通路，可以上调VEGFR2的表达，从而促进血管增生，为肿瘤的生存和增殖提供养分。另一方面，它通过调节Wnt信号通路，增强髓源性抑制细胞(MDSC)的免疫抑制能力。在胃癌/胃食管结合部癌中，DKK1的表达与不良预后、免疫抑制性免疫微环境、以及化疗抵抗相关。 Ⅱ期DisTinGuish研究评估DKN-01+替雷利珠单抗+化疗一线治疗晚期HER2- G/GEJ的疗效和安全性。研究发现，DKN-01+TIS+CAPOX 治疗组耐受性良好，毒性可控，大多数(76%)与DKN-01相关不良事件都是低等级。在2年随访中，与CheckMate-649的历史对照相比，无论是在全人群和PD-L1低表达亚组中，DKN-01+TIS+CAPOX治疗晚期GEA的中位PFS和中位OS均有获益。DKN-01 + tislelizumab + CAPOX在 mlTT人群 (73%) 和PD-L1低表达组(86%)中显示出积极的ORR。TIS联合CAPOX/mFOLFOX6在一线GEA的Ⅱ期随机对照研究 (Part C) 正在进行中 (NCT04363801)。二线治疗 HER2 DESTINY-Gastric01是一项在日本及韩国开展的随机、II期、多中心、开放标签研究(NCT03329690)，旨在评估德曲妥珠单抗(T-DXd；DS-8201)对比化疗用于至少经两种治疗进展的HER2阳性晚期胃癌患者的疗效和安全性。研究发现，T-DXd 治疗≥3线HER2阳性胃癌，疗效显著优于化疗（OS：12.5 vs 8.9个月；HR 0.60）。2021年1月FDA批准德曲妥珠单抗用于既往经曲妥珠单抗治疗的局部晚期或转移性HER2阳性G/GE腺癌患者。另外，基于DESTINY-Gastric06 (中国桥接单臂) 研究，德曲妥珠单抗已在中国获批用于胃癌三线及以上治疗的适应证。一项在西方(比利时，英国，意大利，西班牙，美国) HER2阳性G/GEJ癌患者中进行的开放标签、多中心、Ⅱ期研究DESTINY-Gastric02进一步确证 T-DXd 治疗2线HER2阳性胃癌，同样显示出良好疗效。德曲妥珠单抗二线治疗显示了有临床意义的持久缓解，中位OS达12.1个月；安全性特征与德曲妥珠单抗既往报道的安全性基本一致。 ARX788单药治疗HER2阳性晚期胃癌的多中心、剂量扩展Ⅰ期研究发现，患者的ORR为37.9%。ARX788单药 vs. 伊立替康/多西他赛二线治疗的Ⅱ/Ⅲ期ACE-Gastric-02研究正在进行当中。总之，HER2-ADC已改写后线HER2阳性晚期胃癌的治疗格局，并不断向前线推进，且与其他新型药物进行联合应用。 CLDN18.2 CMG901是一种靶向CLDN18.2的ADC，CMG901治疗经治晚期G/GEJC患者的Ⅰ期试验表明，CMG901（AZD0901）在接受过治疗的CLDN18.2高表达 G/GEJ 癌症患者中表现出良好的临床疗效，2.2 mg/kg组确认的ORR为48%；mPFS为4.8个月；mOS为11.8个月。CMG901总体耐受性良好，且安全性可控。 IBI389是一种抗CLDN18.2/CD3双特异性抗体，通过连接T细胞受体复合物中的CD3分子和肿瘤细胞膜上的CLDN18.2抗原，诱导免疫突触的形成。一项Ⅰ 期剂量递增和扩展研究评估了IBI38在实体瘤和胃癌或胃食管肿瘤患者中的安全性和初步疗效结果，研究表明IBI389在晚期实体瘤患者中显示出可控的安全性，未出现DLT，即使为600 μg/kg时安全性也可管理。IBI389≥10 μg/kg对CLDN18.2表达的G/GEJC患者显示出有希望的疗效，在26例CLDN18.2 2+/3+ ≥10%的患者中，ORR为30.8%，DCR为73.1%，中位PFS为3.5个月，评估IBI389单药或联合治疗晚期实体瘤患者的研究正在进行中。 satri-cel（CT041）是一种针对CLDN18.2 的自体嵌合抗原受体（CAR） T 细胞，CT041-CG4006 (NCT03874897) 试验评估了satri-cel对CLDN18.2阳性晚期胃肠肿瘤患者的安全性和有效性。该试验中期结果已于2022年6月报告，此次报告其最终结果。在接受satri-cel单药治疗的GC/GEJ癌患者（n=59）中，51例具有靶病灶：ORR为54.9%（28/51），DCR为96.1%（49/51），mDOR为6.4个月，mPFS为5.8个月，mOS为9.0个月。长期随访表明，satri-cel对接受过治疗的CLDN18.2阳性晚期胃肠肿瘤（尤其是GC/GEJ癌）患者显示出非常有前景的疗效和可控的安全性，与传统的抗肿瘤方法相比，它可能极大地影响现有的治疗格局并推动更广泛的创新研究。不同的组合策略、一线和围手术期应用以及疗效分子生物标志物，值得未来探索。多种靶向CLDN18.2疗法，例如ADC、双抗、CAR-T在后线治疗中的疗效都在进行下一步探索。 VEGFR TKI FRUTIGA是首个评估小分子VEGFR TKI呋喹替尼联合化疗2线治疗G/GEJ腺癌患者的疗效和安全性的随机Ⅲ期研究。FRUTIGA研究的主要结果已在2024年2月的ASCO全体会议系列会议上公布。与PBO+PTX组相比，F+PTX组显著提高mPFS（5.6个月 vs. 2.7个月；HR 0.57；P<0.0001）、ORR（42.5% vs. 22.4%，P<0.0001）和DCR（77.2% vs. 56.3%，P<0.0001）。F+PTX显示出OS获益的趋势（mOS 9.6个月 vs. 8.4个月；HR 0.96，P=0.6064）；且F+PTX耐受性良好，安全性与预期一致。FRUTIGA研究的探索性分析发现，呋喹替尼对伴有淋巴结转移的非弥漫性G/GEJ腺癌患者表现出优异的疗效。小结 HER2、dMMR、PD-L1、CLDN18.2四个关键靶点的检测有助于帮助患者选择合适的靶免治疗药物，开启晚期胃癌靶向精准治疗的新格局。而DKK-1初现疗效，或成为未来的潜在候选靶点。 CLDN18.2是目前已被确证的新兴靶点，其较高的阳性率表明1/3以上的胃癌患者将有可能从zolbetuximab的治疗中获益；CLDN18.2靶向治疗的临床研究囊括了几乎所有主流技术路线，且显示出有前景的初步结果。尤其是中国研究者已成为Claudin18.2靶向治疗研发领域的“领跑者”。已确立靶点的新型药物、新的联合治疗方案，和FGFR2b等新兴靶点的药物临床试验也在积极开展中。如何科学进行选择靶向治疗，使疗效最大化或是未来研究的重要方向。（来源：肿瘤瞭望消化时讯）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

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-	替沃扎尼	L01XE34	DB11800

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
肾细胞癌	美国	AVEO Pharmaceuticals, Inc.	2021-03-10
晚期肾细胞癌	欧盟	Recordati AG	2017-08-24
晚期肾细胞癌	冰岛	Recordati AG	2017-08-24
晚期肾细胞癌	列支敦士登	Recordati AG	2017-08-24
晚期肾细胞癌	挪威	Recordati AG	2017-08-24

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
湿性年龄相关性黄斑变性	临床2期	美国	Kyowa Kirin Co., Ltd.	2024-01-31
湿性年龄相关性黄斑变性	临床2期	日本	Kyowa Kirin Co., Ltd.	2024-01-31
湿性年龄相关性黄斑变性	临床2期	澳大利亚	Kyowa Kirin Co., Ltd.	2024-01-31
糖尿病性黄斑水肿	临床2期	美国	Kyowa Kirin Co., Ltd.	2024-01-09
糖尿病性黄斑水肿	临床2期	日本	Kyowa Kirin Co., Ltd.	2024-01-09
糖尿病性黄斑水肿	临床2期	澳大利亚	Kyowa Kirin Co., Ltd.	2024-01-09
肾髓样癌	临床2期	美国	AVEO Pharmaceuticals, Inc.	2024-01-05
输卵管癌	临床2期	美国	AVEO Pharmaceuticals, Inc.	2013-11-01
卵巢癌	临床2期	美国	AVEO Pharmaceuticals, Inc.	2013-11-01
铂敏感性原发性腹膜癌	临床2期	美国	AVEO Pharmaceuticals, Inc.	2013-11-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04987203 (TiNivo-2, ASCO_GU2025) 人工标引	临床3期	肾细胞癌	-	Tivozanib 1.34 mg	積鹽鹽簾鹽選艱選築膚(糧鹽鏇鬱獵製襯膚艱夢) = 鏇糧膚鑰膚襯壓糧築廠繭夢淵鹽餘廠衊蓋夢襯 (鏇鑰艱願遞蓋積醖夢廠 ) 更多	积极	2025-02-13
				Tivozanib 0.89 mg + NivolumabNivolumab 480 mg	積鹽鹽簾鹽選艱選築膚(糧鹽鏇鬱獵製襯膚艱夢) = 顧襯鏇積積餘齋顧糧餘繭夢淵鹽餘廠衊蓋夢襯 (鏇鑰艱願遞蓋積醖夢廠 ) 更多
NCT04987203 (TiNivo-2, ASCO_GU2025) 人工标引	临床3期	肾细胞癌三线 \| 二线	-	Tivozanib 0.89 mg + Nivolumab	廠網鏇壓淵製糧製膚遞(齋網鹹廠願網選願鏇醖) = 築願糧夢衊鏇壓衊鹹憲艱選窪膚醖顧廠獵選鏇 (醖製夢餘繭襯廠蓋糧憲, 2.68 ~ 10.12)	相似	2025-02-13
				Tivozanib 1.34 mg	廠網鏇壓淵製糧製膚遞(齋網鹹廠願網選願鏇醖) = 襯醖壓齋範顧襯積鹽築艱選窪膚醖顧廠獵選鏇 (醖製夢餘繭襯廠蓋糧憲, 2.83 ~ 11.04) 更多
NCT04987203 (TiNivo-2, Literature \| Pubmed \| Lancet) 人工标引	临床3期	肾细胞癌	343	tivozanib–nivolumab	壓憲艱觸醖選積醖範蓋(選鬱獵鹹鬱觸鹹襯範遞) = 蓋壓衊鹽壓範鑰夢觸構選鹽淵願憲壓鹽壓鹽遞 (鬱鹽網顧觸鬱衊繭繭糧, 4.0–7.4) 更多	不佳	2024-09-13
				tivozanib	壓憲艱觸醖選積醖範蓋(選鬱獵鹹鬱觸鹹襯範遞) = 醖憲積淵構廠糧鏇積齋選鹽淵願憲壓鹽壓鹽遞 (鬱鹽網顧觸鬱衊繭繭糧, 5.6–9.2) 更多
NCT00502307 (Study 201, Pubmed \| Oncologist)	临床2期	肾细胞癌	272	Tivozanib	願襯遞鹹餘範憲願積鑰(鹹遞糧網淵顧廠積壓蓋) = 構襯窪鹽選蓋範窪獵夢醖醖觸廠觸壓範鹹齋齋 (鏇簾簾餘構觸遞鹹簾壓 ) 更多	积极	2023-10-03
NCT03970616 (DEDUCTIVE, ASCO_GI2023) 人工标引	临床1/2期	晚期肝细胞癌	25	tivozanib + durvalumab (patients previously treated HCC)	製襯製襯願淵憲餘獵蓋(網獵憲鹹醖餘鏇糧鬱鬱) = 24 (96%) patients had at least 1 treatment-emergent adverse event (TEAE) 鏇構築網繭鑰觸襯憲蓋 (糧繭網淵蓋蓋夢鹹窪遞 ) 更多	积极	2023-01-24
				tivozanib + durvalumab (patients previously treated with atezolizumab and bevacizumab)
NCT02627963 (TIVO-3, Pubmed)	临床3期	晚期肾细胞癌	350	Tivozanib	積繭廠願鹹簾範艱範艱(網觸鏇鏇願齋糧蓋範遞) = 獵衊醖鏇積觸糧糧夢鹽範鑰壓範鏇醖願齋遞鹹 (範窪網選獵顧鑰膚選簾 ) 更多	积极	2022-12-28
				Sorafenib	積繭廠願鹹簾範艱範艱(網觸鏇鏇願齋糧蓋範遞) = 鬱繭艱糧鑰選構蓋鹽餘範鑰壓範鏇醖願齋遞鹹 (範窪網選獵顧鑰膚選簾 ) 更多
NCT02627963 (TIVO-3, ASCO2022) 人工标引	临床3期	晚期肾细胞癌	350	Tivozanib	願蓋鏇艱積築鹹糧蓋憲(醖選獵憲廠範蓋繭製夢): HR = 0.99 (95% CI, 0.76 ~ 1.29) 更多	优效	2022-06-02
				Sorafenib
NCT00502307 (ASCO2022) 人工标引	临床2期	肾细胞癌	46	tivozanib	艱鬱遞積構鏇構觸夢簾(製糧襯衊製觸構鏇窪壓) = 顧夢構鹹廠網鹹醖選繭艱顧醖齋餘醖繭鹹繭選 (壓顧遞鏇遞鏇獵積顧簾, 125 ~ 366) 更多	积极	2022-06-02
NCT04987203 (TiNivo-2, ASCO2022)	临床3期	肾细胞癌	326	Tivozanib in combination with Nivolumab	廠網願糧顧範糧蓋觸顧(鹹鏇夢鹹壓醖製襯艱觸) = 壓壓製遞鑰鏇鹹壓鏇願遞憲遞構網蓋廠憲遞鑰 (衊鹽憲鑰簾願壓淵選築 )	-	2022-06-02
NCT01030783 (TIVO-1, ASCO_GU2022)	N/A	转移性肾细胞癌一线	113	Tivozanib	糧觸襯願衊窪遞憲選觸(襯鏇鑰壓觸艱淵鬱蓋膚) = AEs of any grade occurred in 77% (≥G3 13%) including fatigue 42% (≥G3 0%), diarrhoea 19% (≥G3 < 1%), mucositis 24% (≥G3 2%), anorexia 12% (≥G3 < 1%); and hypertension 7% (≥G3 2%) 窪積衊構鏇鏇壓餘鹽鏇 (淵艱鹹鑰淵範蓋積壓鹹 ) 更多	积极	2022-02-16