Cabozantinib (s)-Malate

本文来自生命的光谱点击上方蓝字关注我们 📝 核心摘要欧洲神经肿瘤学协会（EANO）最新指南为脑膜瘤患者带来了希望，通过分子检测精准解读肿瘤“基因密码”，寻找潜在靶点，开启个性化靶向治疗新时代。文章详细解读了ESCAT分级下的各类分子靶点及其治疗潜力，为复发进展的脑膜瘤患者提供了科学的治疗路线图。脑膜瘤治疗：从“无药可用”到“精准靶向”的新希望 脑膜瘤是成年人中最常见的原发性颅内肿瘤，虽然大多数为良性，但对于那些经过手术和放疗后仍然复发或进展的患者而言，后续的治疗选择常常十分有限，甚至陷入无药可用的困境。然而，随着精准医疗的飞速发展，一扇新的大门正在为脑膜瘤患者缓缓打开。欧洲神经肿瘤学协会（EANO）最新发布的指南，系统性地阐述了如何利用分子检测来寻找潜在的治疗靶点，为脑膜瘤的靶向治疗和个体化治疗提供了清晰的路线图。 这份指南的发布，意味着脑膜瘤的治疗正在从“一刀切”的传统模式，向基于每个患者独特分子特征的“量体裁衣”式精准治疗迈进。面对复杂的治疗决策和前沿的医学信息，许多患者和家属可能会感到迷茫。为了帮助大家更好地理解复杂的治疗方案和最新的研究进展，“生命的光谱”会持续为您提供个性化的信息支持，助您拨开迷雾。读懂脑膜瘤的“基因密码”：分子检测的临床实践 分子检测是精准治疗的基石。它通过分析肿瘤组织的DNA、RNA或蛋白质，来寻找可能驱动肿瘤生长的特定基因突变、扩增或表达异常。EANO指南强调了分子检测在临床实践中的规范化操作，以确保检测结果的准确性和可靠性。检测时机：何时进行分子检测最合适？ 指南建议，对于初次诊断的脑膜瘤，分子检测的主要目的是评估复发风险，例如检测TERT启动子突变、CDKN2A/B缺失等预后不良的标志物。而以选择靶向治疗为目的的分子检测，则更适合在肿瘤复发或进展，且常规治疗手段（如再次手术、放疗）已穷尽时进行。这是因为随着肿瘤的演进，其分子特征也可能发生变化，使用最新的肿瘤组织样本进行检测，才能最准确地指导后续治疗。检测方法与报告解读 现代分子检测技术，如二代测序（NGS），能够一次性分析数百个基因，全面地描绘出肿瘤的分子图谱。一份规范的分子检测报告应详细说明检测方法、样本来源、发现的基因变异及其潜在的临床意义。理解这些报告对于制定个体化治疗方案至关重要。例如，报告中会使用欧洲肿瘤内科学会分子靶点临床可操作性量表（ESMO ESCAT）对发现的靶点进行分级，这个分级直接关系到靶向治疗的证据强度。 表1 ESMO ESCAT分级标准脑膜瘤关键分子靶点深度解析与治疗策略 EANO指南详细评估了脑膜瘤中数十种分子变异作为治疗靶点的潜力，并根据ESCAT量表进行了分级。值得注意的是，目前尚无任何靶点达到最高的I级（“可用于临床”）水平，这凸显了脑膜瘤靶向治疗研究仍处于探索阶段。然而，部分靶点已显示出令人鼓舞的前景。 图1 脑膜瘤中的分子靶点与ESCAT分级ESCAT II级靶点：最具潜力的“研究性”靶点这一级别的靶点意味着已有临床研究数据表明，针对这些靶点的治疗可能对特定患者有效，但仍需更大规模的临床试验证实。NF2基因变异： 这是脑膜瘤中最常见的分子变异，尤其在散发性病例中，高达60%的患者可检测到。NF2基因失活会间接激活mTOR和Hippo等多条信号通路。临床试验显示，mTOR抑制剂（如依维莫司）、ErbB2/EGFR抑制剂（如拉帕替尼）和FAK抑制剂等药物，在NF2变异的脑膜瘤患者中显示出延缓肿瘤生长的潜力。mTOR通路激活： 除了由NF2间接激活外，少数脑膜瘤也存在直接激活mTOR通路的基因突变（如TSC1/2突变）。mTOR抑制剂是多种癌症的标准疗法，其在脑膜瘤中的应用也备受期待。ESCAT III级靶点：“假设性”靶点，值得探索这类靶点在其他癌种中已被证实是有效的治疗靶点，或者有令人信服的临床前数据支持其在脑膜瘤中的作用，但临床数据尚不充分。PIK3CA突变： 约1-5%的脑膜瘤存在PIK3CA突变，尤其是在非NF2突变的肿瘤中。针对该靶点的PI3K抑制剂（如阿培利司）已在其他癌症中获批。目前有临床试验正在评估PI3K抑制剂联合MEK抑制剂治疗脑膜瘤的安全性和有效性。AKT1突变： 约10%的脑膜瘤存在AKT1 p.E17K这一特异性激活突变。AKT抑制剂卡帕塞替尼已在乳腺癌中获批，并在一个篮式研究中对1例AKT1突变的脑膜瘤患者显示出疗效。SMO突变： 约5%的脑膜瘤存在SMO基因突变，激活Hedgehog信号通路。SMO抑制剂（如维莫德吉）是基底细胞癌的标准疗法。在NCI-MATCH试验中，1例SMO突变的脑膜瘤患者使用维莫德吉后获得部分缓解，相关的临床试验正在进行中。SSTR2表达： 超过80%的脑膜瘤高表达生长抑素受体2（SSTR2）。这使其成为放射性配体治疗（如[¹⁷⁷Lu]Lu-DOTATATE）的理想靶点。虽然在神经内分泌瘤中已证实有效，其在脑膜瘤中的疗效尚待大型随机临床试验（如LUMEN-1研究）的验证。BAP1突变： 罕见但与恶性脑膜瘤相关。在其他BAP1相关的肿瘤中，PARP抑制剂、EZH2抑制剂等显示出潜力，但在脑膜瘤中尚无相关临床数据。 对于指南中提到的各类靶向药物，如何获取是患者最关心的问题。“生命的光谱”致力于为患者提供可靠的信息援助，对接合规渠道，打破地域和信息的壁垒，助您及时获得治疗所需的前沿药物。ESCAT IV级及以下靶点：临床证据尚不明确 这一类别包含了大量潜在靶点，如CDKN2A/B缺失（可靶向CDK4/6抑制剂）、SUFU突变、PDGFR、SMARCE1缺失等。尽管临床前研究显示了可能性，但目前缺乏支持其在脑膜瘤中常规应用的临床证据。例如，针对PD-L1的免疫检查点抑制剂（帕博利珠单抗、纳武利尤单抗）在脑膜瘤中的临床试验结果并不理想。而VEGF/VEGFR抑制剂（如贝伐珠单抗、舒尼替尼）在一些无对照研究中显示出一定的疾病控制能力，但其确切疗效仍需高级别证据证实。值得一提的是，有病例报告显示，卡博替尼（Cabozantinib）等多靶点VEGFR抑制剂可能为患者带来获益。超越单一靶点：脑膜瘤治疗的未来展望 脑膜瘤的精准治疗不仅仅局限于寻找单一的驱动基因。指南同样关注了更宏观的分子特征，这些特征虽然目前不直接指导靶向用药，但对判断预后、指导辅助治疗具有重要价值。拷贝数变异（CNV）与DNA甲基化分型： 全基因组水平的分析，如1p染色体缺失、DNA甲基化分型（良性、中间型、恶性），能够比传统的组织学分级更准确地预测肿瘤的复发风险，帮助医生决定术后是否需要辅助放疗。放疗的预测标志物： 近期研究发现，特定的基因表达谱（如34基因表达生物标志物）可能能够预测哪些患者能从术后放疗中最大获益，哪些患者可能存在放疗抵抗。这为实现放疗的“精准化”提供了新的方向，但仍需前瞻性临床试验的验证。结论：迈向脑膜瘤的个体化治疗时代 EANO的最新指南为脑膜瘤的分子检测和靶向治疗提供了宝贵的循证医学指导。尽管目前大多数靶向治疗方案仍处于研究阶段，但这清晰地指明了未来的发展方向：通过深入理解每个脑膜瘤的分子“指纹”，为每一位患者制定最合适的个体化治疗策略。对于手术和放疗后复发或进展的脑膜瘤患者来说，积极进行全面的分子检测，并根据检测结果寻求参与临床试验或探索超说明书用药的机会，可能是打破治疗僵局的关键一步。 获取最新的抗癌资讯对于治疗决策至关重要。关注“生命的光谱”公众号，我们将持续为您更新全球前沿的癌症治疗信息、药物研发动态和诊疗指南解读，与您一同在抗癌路上精准前行。 想了解更多关于脑膜瘤分子检测与靶向治疗的详细资料或加入病友群，请关注公众号《生命的光谱》。- 全文完 -内容仅供参考，不构成医疗建议

ALAMEDA, Calif.--(BUSINESS WIRE)--Exelixis, Inc. (Nasdaq: EXEL) today announced that its New Drug Application (NDA) for zanzalintinib, in combination with atezolizumab (Tecentriq®), has been accepted for review in the U.S. for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, and, if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy. The Food and Drug Administration (FDA) assigned a standard review with a Prescription Drug User Fee Act target action date of December 3, 2026. “We are encouraged by this meaningful progress toward addressing the needs of patients with previously treated metastatic colorectal cancer, for whom effective therapies have been limited and treatment outcomes remain poor,” said Dana T. Aftab, Ph.D., Executive Vice President, Research and Development, Exelixis. “Zanzalintinib has the potential to become an important advancement in a challenging treatment landscape, and if approved, zanzalintinib in combination with atezolizumab would provide a novel mechanism of action for patients with previously treated metastatic colorectal cancer. We are deeply grateful to the patients, caregivers and investigators contributing to the clinical research in support of this application, and we look forward to collaborating with the FDA during the review process for our first NDA for zanzalintinib.” The NDA is based on the results of the phase 3 STELLAR-303 pivotal trial, in which zanzalintinib in combination with atezolizumab demonstrated a statistically significant improvement in overall survival (OS) versus regorafenib in the intention-to-treat (ITT) population of patients with previously treated CRC. Detailed results, including OS and progression-free survival (PFS) in the ITT population and in the subset of patients without liver metastases (non-liver metastases, NLM), were presented at the 2025 European Society for Medical Oncology (ESMO) Congress and published in The Lancet. Data pertaining to the other dual primary endpoint, OS in patients without active liver metastases, were immature at the data cutoff, and the trial is proceeding to the planned final analysis for this endpoint, which is expected in mid-2026, based on current event rates. About STELLAR-303 STELLAR-303 (NCT05425940) is a global, multicenter, randomized, phase 3, open-label study that randomized patients 1:1 to either zanzalintinib in combination with atezolizumab (n=451) or regorafenib (n=450). The study includes patients with previously treated non-MSI-high metastatic CRC. The dual primary endpoints of the study are OS in the ITT population and in the NLM subgroup of patients. The ITT population consisted of all randomized patients, regardless of the presence of liver metastases. The NLM subgroup consisted of patients who did not have active liver metastases at baseline as determined by investigator assessment. Secondary endpoints include PFS, objective response rate and duration of response in the ITT population and in the NLM subgroup of patients. More information about the trial is available at ClinicalTrials.gov. About Zanzalintinib Zanzalintinib is a novel oral kinase inhibitor that inhibits the activity of the TAM kinases (TYRO3, AXL, MER), MET and VEGF receptors. These kinases play important roles in oncogenic processes, including tumor cell proliferation, metastasis, angiogenesis, drug resistance and evasion of antitumor immunity. With zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including colorectal cancer, kidney cancer and neuroendocrine tumors. Zanzalintinib is an investigational agent that is not approved for any use and is the subject of ongoing clinical trials. About CRC CRC is the third most common cancer and a leading cause of cancer-related deaths in the U.S.1 Approximately 159,000 new cases will be diagnosed in the U.S. in 2026, with around 55,000 expected deaths from the disease.1 CRC is most frequently diagnosed among people aged 65-74 and is more common in men and in people of non-Hispanic American Indian/Alaska Native descent.2 Nearly a quarter of CRC cases are diagnosed at the metastatic stage, at which point the five-year survival rate is around just 15%.1,2 The liver is the most common site for CRC metastasis. Liver metastases significantly impact survival, with a median five-year survival rate of less than 14% when treated with palliative chemotherapy.3 About Exelixis Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules and biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our pipeline of franchise molecules, including our novel oral kinase inhibitor zanzalintinib, and to extend the impact of our flagship commercial product, CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit www.exelixis.com, follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the therapeutic potential of zanzalintinib, in combination with atezolizumab, as a treatment for patients with previously treated mCRC; the regulatory review process, including the PDUFA target action date assigned by the FDA, and Exelixis’ plans to collaborate with the FDA while the application is reviewed; and Exelixis’ scientific pursuit to create transformational treatments that give patients more hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere, including the risk that the FDA may not approve the combination of zanzalintinib with atezolizumab as a treatment for patients with previously treated mCRC in a timely fashion, if at all; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating zanzalintinib and/or atezolizumab; Exelixis’ ability to protect its intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting the ability of Exelixis to obtain regulatory approval for zanzalintinib in new indications detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law. Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis. TECENTRIQ is a registered U.S. trademark of Genentech, a member of the Roche Group. ____________________ 1 Cancer Facts & Figures 2026. ACS website. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2026/2026-cancer-facts-and-figures.pdf. Accessed February 2026. 2 Cancer Stat Facts: Colorectal Cancer. SEER website. Available at: https://seer.cancer.gov/statfacts/html/colorect.html. Accessed February 2026. 3 Ros J, Salva F, Dopazo C, et al. Liver transplantation in metastatic colorectal cancer: are we ready for it? Br J Cancer. May 2023;128(10):1797-1806.