Sorafenib Tosylate

欢迎关注凯莱英药闻 今日，和誉医药宣布，公司于2024年9月16日在ESMO大会上荣获“最佳壁报奖”，授予题为“依帕戈替尼(ABSK011)在FGF19过表达的晚期肝细胞癌（aHCC）中的I期临床研究的最新安全性和有效性结果”的研究壁报。本研究壁报是肝细胞癌壁报环节唯一获奖者。 依帕戈替尼是一款高选择性小分子纤维原细胞生长因子受体4（FGFR4）抑制剂；目前，一线经免疫检查点抑制剂（ICIs）治疗进展的aHCC患者目前尚无获批的标准治疗，FGF19/FGFR4通路可能是aHCC患者的新治疗靶点。 关于I期临床最新数据 截至2024年9月5日，共入组122例患者，分别给予每日一次给药（QD）或每日两次给药（BID）频次；其中BID队列74例，包含160mg BID，220mg BID和300mg BID。5.4%的患者处于BCLC B期，89.2%患者处于BCLC C期；64.9%的患者肝功能分级（CP）得分5分，27%患者6分，6.8%患者7分；64.9%的患者经过多线治疗；85.1%的患者曾经过ICIs治疗；75.7%的患者曾经过ICIs和mTKIs治疗。 结果显示，40例经治的、FGF19过表达的肝癌患者接受了依帕戈替尼220mg BID治疗，其中38例可评估患者中，应答率达到36.8% (14/38)，疾病控制率（DCR）达到78.9%(30/38)。同时，接受过ICIs和mTKIs治疗的患者中的应答率达到44.8% (13/29)，最长DoR达到16.4个月, mDoR达到7.4个月, DCR达到79.3% (23/29)，mPFS达到 5.5个月。 在安全性上，300mg BID组发生一起剂量限制性毒性（DLT）事件。最常见的治疗相关不良反应（TRAEs，>20%）为ALT升高、腹泻、AST升高、高磷血症、胆红素升高、碱性磷酸酶升高、血小板降低、总胆汁酸升高。3-4级治疗相关不良反应(>5%)包括AST升高、ALT升高和腹泻；未发生5级不良事件。 关于依帕戈替尼 依帕戈替尼（Irpagratinib）通过与FGFR4 的激酶结合域结合抑制其催化活性，阻断下游通路激活达到抑制肿瘤生长的效果。 在肝癌细胞实验中，ABSK011 显示出比BLU554 更强的抑制细胞增殖能力；而且在可溶性及血浆蛋白结合等方面，也比BLU554有显著改善，使得ABSK011 在动物及人体中实现更高的游离药物接触，可望获得更好的靶向覆盖率及疗效。 ABSK011 抑制细胞增殖优于BLU554 ABSK011 与人/小鼠血浆蛋白的结合弱于BLU554 临床前实验中，ABSK011在多种HCC异种移植模型中显示出剂量依赖性抗肿瘤疗效，并且相较相同剂量水平的BLU554或索拉非尼具有更高疗效。 I 期数据显示，ABSK011口服后吸收迅速，系统性暴露随着剂量从 60mg 增加到240mg(每日一次)，以近似比例的方式增加。每日一次重复给药八天后， ABSK011 的浓度达到稳定状态，ABSK011 并无明显积累。ABSK011 在所有剂量下均可引起FGF19 靶向调节。 ABSK011 人体 PK数据良好 ABSK011 对FGF19调节效果突出 2024年6月，公司在2024年ESMO-GI大会上发布了依帕戈替尼联用阿替利珠单抗治疗aHCC的最新临床试验数据；其中，依帕戈替尼220mg BID联用阿替利珠队列在FGF19过表达肝细胞癌患者中显示出突出的疗效，ORR达50%。在之前接受过ICIs治疗的患者群体中，联合疗法的疗效同样显著，且安全性良好。 关于FGFR4药物 FGFR（成纤维细胞生长因子受体）是一类高度保守且高表达的跨膜酪氨酸激酶受体RTK，包括FGFR1、FGFR2、FGFR3 和FGFR4 四种受体，均由胞外区-跨膜区-胞内酪氨酸激酶区三个部分组成，在调节细胞增殖和细胞存活方面起着关键作用。选择性地结合并抑制FGFR 的泛FGFR 抑制剂可以阻断FGFR相关信号通路，从而控制肿瘤细胞增殖和死亡。据统计，FGFR畸变主要发生于胆管癌、肺癌、胃癌、乳腺癌等，每年全球约发生190万例。 FGFR 突变瘤种分布 由于FGFR4和FGFR1-3不同的结构基础，推动了FGFR4抑制剂的研发。其一，在FGFR中，FGFR4 的同源性最低，极大地改变它们对配体的特异性。其二，与FGFR1-3相比，FGFR4 在激酶结构域中含有一个独特的氨基酸，即C552 残基，这使得设计 FGFR4 特异性抑制剂成为可能。FGFR4特异性小分子抑制剂，包括 BLU-554、H3B-6527, FGF401和 INCB062079等都是通过共价结合位于激酶结构域铰链区的C552 残基以抑制 FGFR4 的激活。 研究表明，FGFR4 与其配体FGF19 形成的信号通路，在调节肝细胞胆汁酸代谢以及损伤后肝再生等方面发挥重要作用；FGF19在肝细胞癌和其他肿瘤类型中常发生扩增或过表达，约30%的肝细胞癌中发现FGF19过表达。全球超过35万例患者中出现异常的FGF19-FGFR4通路改变；由此导致全球每年约30万新增病例，中国每年约15万新增病例。 据不完全统计，目前尚无针对FGFR4开发的单靶点药物获批，在研产品涵盖反义疗法、单抗、CAR-T、ADC等。 关于和誉医药 和誉医药成立于2016 年，是一家致力于发现与开发治疗癌症及其他疾病的新型、差异化疗法，研发驱动、临床阶段的生物制药公司。其核心竞争优势在于经验丰富的管理团队，发现小分子肿瘤精准治疗及小分子肿瘤免疫治疗等疗法的内部研发团队。 截至目前，公司已拥有由16种候选药物组成的产品管线，靶点集中在FGFR、EGFR 及KRAS等。 参考资料 1、公司官网 2、海通国际、华创证券、天风证券、申港证券、华源证券 感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

Trial investigating Cabometyx® (cabozantinib) in combination with atezolizumab demonstrated a positive trend towards improvement for one of the primary endpoints of overall survival, but did not meet statistical significance Ipsen will not pursue regulatory submissions for the combination regimen in countries where we have commercialization rights (outside of the US and Japan) We remain confident in the proven profile of Cabometyx as a monotherapy and in combination with immunotherapy, across approved and potential future indications 15 September 2024 - Ipsen (Euronext: IPN; ADR: IPSEY) announced today detailed final overall survival (OS) data from the Phase III CONTACT-02 trial investigating the combination of Cabometyx® (cabozantinib) and atezolizumab in metastatic castration-resistant prostate cancer (mCRPC). The trial investigated the combination regimen versus a second novel hormonal therapy (NHT) in men previously treated with one NHT and measurable soft-tissue disease. At a median follow-up of 24.0 months, these data demonstrated a numerical but not statistically significant improvement in OS for the combination versus a second NHT (hazard ratio: 0.89; 95% confidence interval: 0.72-1.10; P=0.296). As previously announced, the trial met the other primary endpoint of progression-free survival (PFS), demonstrating a statistically significant benefit in PFS.1 Safety for the combination appeared to be consistent with the known safety profiles of the individual medicines, and no new safety signals were identified. Based on the results of the final OS analysis and anticipated challenging regulatory environment in the countries in which Ipsen has commercialization rights (outside the US and Japan), Ipsen will not pursue regulatory submissions for this combination regimen in mCRPC. We remain confident, in the proven profile of Cabometyx as a monotherapy and in combination with immunotherapy across approved indications, as well as its ongoing future potential. Ipsen wishes to thank the patients, their families and healthcare teams for their participation in this clinical trial. Cabometyx (cabozantinib) is a small molecule that inhibits multiple receptor tyrosine kinases, including VEGFRs, MET, RET and the TAM family (TYRO3, MER, AXL).2 These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis (the growth of new blood vessels that tumors need to grow), drug resistance, modulation of immune activities and maintenance of the tumor microenvironment.2,3,4,5 Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of Cabometyx outside of the U.S. and Japan. Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited (Takeda) for the commercialization and further clinical development of Cabometyx for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize Cabometyx in the U.S. In over 65 countries outside of the United States and Japan, including in the European Union, Cabometyx is currently indicated as a:3 Monotherapy for advanced renal cell carcinoma (aRCC). as first-line treatment of adults with intermediate- or poor-risk disease. in adults following prior VEGFR-targeted therapy. A combination with nivolumab for the first-line treatment of aRCC in adults. Monotherapy for the treatment of adults living with locally advanced or metastatic differentiated thyroid carcinoma, refractory or not eligible to radioactive iodine who have progressed during or after prior systemic therapy. Monotherapy for the treatment of hepatocellular carcinoma in adults who have previously been treated with sorafenib. The detailed recommendations for the use of Cabometyx are described in the Summary of Product Characteristics (EU SmPC). Prostate cancer is the second most common cancer in men and the fourth most common cancer overall globally.6 In 2020, there were more than 1.4 million new cases of prostate cancer and about 375,300 deaths worldwide.6 Prostate cancer is considered mCRPC when it has spread beyond the prostate and does not respond to androgen-suppression therapies, a common treatment for prostate cancer.7 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years.8 CONTACT-02 is a global, multicenter, randomized, Phase III, open-label study that enrolled 575 patients who were randomized 1:1 to the experimental arm of Cabometyx in combination with atezolizumab and the control arm of a second NHT (either abiraterone and prednisone or enzalutamide). The study included patients with mCRPC who have measurable extra-pelvic soft tissue metastasis and who have progressed on one prior NHT. The two primary endpoints of the trial are progression-free survival (PFS) and OS. The PFS analysis was conducted in the first 400 randomized patients (PFS in the intent-to-treat [ITT] population) and assessed by a blinded independent radiology committee (BIRC) per RECIST 1.1. The OS analysis was conducted in the ITT population (n=507). The secondary endpoint is objective response rate (ORR) per BIRC. The trial is sponsored by Exelixis and co-funded by Ipsen, Roche and Takeda. Takeda is conducting the trial in Japan. More information about CONTACT-02 is available at ClinicalTrials.gov. We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience. Our pipeline is fueled by external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 80 countries. Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com. References 1 Agarwal et al. Cabozantinib Plus Atezolizumab vs Second Novel Hormonal Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC): Primary Analyses From the Phase 3 CONTACT-02 Study. As presented at the ASCO GU congress 2024, San Francisco, USA 2 El-Khoueiry A. et al., Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treatment Reviews. 2021 Jul;98:102221. DOI: 10.1016/j.ctrv.2021.102221. 3 European Medicines Agency. Cabometyx® (cabozantinib) EU Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Last accessed: September 2024 4 Yakes M. et al., Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308. DOI: 10.1158/1535-7163.MCT-11-0264 5 Hsu et al., AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer 2021 DOI: 10.1159/000520501 6 Prostate cancer statistics. World Cancer Research Fund International. Available at: https://www.wcrf.org/cancer-trends/prostate-cancer-statistics/. Accessed August 2024 7 Prostate Cancer: Types of Treatment. Cancer.Net. Available at: https://www.cancer.net/cancer-types/prostate-cancer/types-treatment. Accessed September 2024 8 Moreira, D. M., et al. Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2017; 15: 60–66.e2 The content above comes from the network. if any infringement, please contact us to modify.