Vepdegestrant

– Data support initiation of a combination cohort in the ongoing Phase 1 clinical trial to evaluate ARV-393 plus glofitamab as a chemotherapy-free combination approach in diffuse large B-cell lymphoma (DLBCL); initiation expected in 2026 – NEW HAVEN, Conn., Dec. 06, 2025 (GLOBE NEWSWIRE) -- Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, today announced preclinical data for ARV-393, a PROTAC BCL6 degrader, in combination with glofitamab, a CD20×CD3 bispecific antibody, presented in a poster at the 67th American Society of Hematology (ASH®) Annual Meeting and Exposition, held December 6–9, 2025, in Orlando, Florida. In a humanized high-grade B-cell lymphoma (HGBCL) cell line–derived xenograft (CDX) model, the combination of ARV-393 and glofitamab resulted in significantly enhanced tumor growth inhibition (TGI) and increased rates of tumor regression compared with either agent alone. These preclinical data suggest mechanistic synergies between BCL6 degradation with ARV-393 and T-cell engagement. “Despite advances in treatment options, many patients with diffuse large B-cell lymphoma continue to face limited options once standard therapies fail. By pursuing a chemotherapy-free combination approach, we aim to address this significant unmet need and potentially offer patients a more targeted, better-tolerated therapeutic alternative,” said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer, Arvinas. “The initiation of our Phase 1 combination clinical trial, planned for 2026, represents an important step toward defining the potential of ARV-393 in the treatment of this aggressive form of lymphoma.” Key highlights from the poster presentation include: In a humanized HGBCL CDX model ARV-393 (3 mg/kg) combined with glofitamab (0.15 mg/kg) achieved 81% TGI with concomitant dosing and 91% TGI with sequential dosing (ARV-393 followed by glofitamab), versus 38% for single-agent ARV-393 and 36% for glofitamab alone.At a higher ARV-393 dose (6 mg/kg) combined with glofitamab (0.15 mg/kg), an increase in tumor regressions was observed with concomitant (10/10 mice) and sequential dosing (7/8 mice) vs single-agent ARV-393 (5/11 mice) or glofitamab (0/11 mice).RNA sequencing and biomarker analyses revealed that ARV-393 upregulated CD20 expression and genes that promote interferon signaling and antigen presentation, while downregulating proliferation-associated gene sets. These collective effects likely contributed to the observed synergistic antitumor activity. “We believe these results underscore the potential for ARV-393 and provide a strong mechanistic rationale for exploring ARV-393 in combination with glofitamab as a chemotherapy-free treatment strategy for patients with diffuse large B-cell lymphoma,” said Angela Cacace, Ph.D., Chief Scientific Officer, Arvinas. “These preclinical results support our belief in the clinical potential and combinability of ARV-393 and the possibility to provide real benefit to patients in need.” ARV-393 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin lymphoma and Arvinas plans to share clinical data from this trial at a medical congress in 2026. Additionally, Arvinas plans to add a glofitamab combination cohort in patients with DLBCL in the ongoing Phase 1 clinical trial of ARV-393 in 2026. About ARV-393 ARV-393 is an investigational, orally bioavailable PROTAC designed to specifically target and degrade B-cell lymphoma 6 protein (BCL6), a transcriptional repressor and major driver of B-cell lymphomas. During B-cell development, tightly controlled BCL6 protein expression regulates >600 genes to facilitate rapid B-cell proliferation and tolerance of somatic hypermutation and gene recombination for antibody generation. Deregulated BCL6 expression is common in B-cell lymphoma and promotes cancer cell survival, proliferation, and genomic instability. PROTAC-mediated degradation has the potential to address the historically undruggable nature of BCL6. About Arvinas Arvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROTAC (PROteolysis TArgeting Chimera) protein degrader platform, Arvinas is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including ARV-102, targeting LRRK2 for neurodegenerative disorders; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; ARV-806, targeting KRAS G12D for mutated cancers, including pancreatic and colorectal cancers; and vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding: Arvinas’ beliefs regarding the clinical potential and combinability of ARV-393 and possibility to benefit patients; Arvinas’ plans to add a glofitamab combination cohort in patients with diffuse large B-cell lymphoma (“DLBCL”) to Arvinas’ ongoing Phase 1 clinical trial of ARV-393, and the timing thereof; Arvinas’ plans to share clinical data from the Phase 1 clinical trial of ARV-393 in patients with relapsed/refractory non-Hodgkin lymphoma, and the timing thereof; whether a chemotherapy-free combination approach will address significant unmet need for patients with DLBCL and potentially offer patients a more targeted, better-tolerated therapeutic alternative; and the ARV-393 preclinical data showing the potential for ARV-393, and providing a strong mechanistic rationale for exploring ARV-393 in combination with glofitamab as a chemotherapy-free treatment strategy for patients with DLBCL. All statements, other than statements of historical fact, contained in this press release, including statements regarding Arvinas’ strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “target,” “goal,” “potential,” “will,” “would,” “could,” “should,” “look forward,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Arvinas may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on such forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Arvinas makes as a result of various risks and uncertainties, including but not limited to: whether Arvinas will be able to successfully conduct and complete development for its product candidates, including ARV-393; other risks associated with drug development, including unexpected costs or delays; that positive data from preclinical or early clinical studies of Arvinas’ product candidates, including ARV-393, are not necessarily predictive of the results of later clinical studies and any future clinical trials of Arvinas’ product candidates; Arvinas’ ability to protect its intellectual property portfolio; Arvinas’ reliance on third parties; whether Arvinas will be able to raise capital when needed; whether Arvinas’ cash and cash equivalents will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other important factors discussed in the “Risk Factors” section of Arvinas’ Annual Report on Form 10-K for the year ended December 31, 2024 and subsequent other reports on file with the U.S. Securities and Exchange Commission. The forward-looking statements contained in this press release reflect Arvinas’ current views with respect to future events, and Arvinas assumes no obligation to update any forward-looking statements, except as required by applicable law. These forward-looking statements should not be relied upon as representing Arvinas’ views as of any date subsequent to the date of this release. Contacts Investors:Jeff Boyle+1 (347) 247-5089Jeff.Boyle@arvinas.com Media:Kirsten Owens+1 (203) 584-0307Kirsten.owens@arvinas.com

编者按 在晚期激素受体阳性（HR+）乳腺癌的治疗中，一线治疗通常为抗雌激素药物与CDK4/6抑制剂双剑合璧。然而，在接受此类治疗的过程中，患者最终会发展出对这些抗雌激素药物的耐药性。随着对HR+肿瘤进展及耐药机制的理解加深，基于精准治疗的新一代内分泌疗法正不断涌现，其中不乏针对基因突变所致的信号传导通路异常的研究。今年发表在《Nature Reviews Clinical Oncology》的一篇文章，综述了晚期HR+乳腺癌治疗模式的演变，为进一步探索药物排兵布阵的策略提供了重要参考。 抗雌激素治疗之新型药物的崛起历程 抗雌激素治疗是早期和晚期HR+乳腺癌治疗的基础。内源性雌激素在绝经前女性中，主要由卵巢分泌，而在绝经后或进行了卵巢功能抑制的绝经前女性中，雌激素主要由外周脂肪等组织中的雄激素通过芳香化酶的作用转化而来。表达雌激素受体（ER）的乳腺癌细胞依赖雌激素的调控增殖和存活（图1）。有效的抗雌激素疗法主要通过减少体内循环的雌激素水平或直接靶向ER，来阻止ER信号传导，从而减缓乳腺癌的发展。 图1 晚期HR+治疗中可用的信号传导通路。 a.雌激素与野生型ER结合后，ER二聚化并转移到细胞核内，调控基因转录。ESR1基因突变后可以让ER在没有雌激素的情况下持续激活。新型药物旨在对野生型和/或突变型的ER进行抑制和/或降解。b.抗体-药物偶联物（ADC）可针对细胞表面蛋白信号通路进行靶向治疗。细胞基质中存在RAS-MAPK和PI3K-AKT信号通路，针对后者已有PI3K、AKT和mTOR抑制剂应用于临床。c.在细胞周期调控方面，CDK4/6、CDK2都起到了重要作用，新一代CDK2/4及CDK2/4/6抑制剂正在研发中。 目前，已经获批并广泛应用于临床的内分泌治疗（ET）药物主要有：选择性雌激素受体调节剂（SERM）他莫昔芬；芳香化酶抑制剂（AI）来曲唑、阿那曲唑和依西美坦；以及选择性雌激素受体降解剂（SERD）氟维司群。 然而，在HR+转移性乳腺癌（mBC）的治疗中，长期使用抗雌激素治疗不可避免地会发生耐药，可分为ER依赖性和非ER依赖性耐药。前者肿瘤仍然依赖于ER信号传导，如ESR1突变；后者则可能激活了其他信号通路，如PI3K-AKT通路，而绕过了ER的作用。mBC的一线治疗通常建议ET联合CDK4/6抑制剂（CDK4/6i）2，了解其耐药的分子机制及基因调控的变化，将为mBC个性化方案的制定提供重要指导，以尽可能延长肿瘤控制时间，进而改善患者的晚期预后。 基于对ER依赖性耐药的理解（图1a），Elacestrant作为对ESR1突变有较好疗效的口服SERD已被应用于临床。此外，更多新一代口服SERD药物以及SERM药物已经进入后期临床研究。其中，Lasofoxifene是一种新型口服SERM，在ESR1突变模型中表现突出且不会增加子宫内膜增厚及子宫内膜癌的风险。除了经典的SERM与SERD，也有新型作用机制的药物研发。Vepdegestrant是一种口服双功能蛋白降解剂，与ER结合后，可介导与E3泛素连接酶复合物的相互作用，促进蛋白酶体对ER进行高效降阶。另外，Palazestrant不仅能够完全拮抗ER，阻断其信号传导，还可以降阶ER，既是完全ER拮抗剂（CERAN），同时也是SERD药物。 这些新型药物在早期HR+乳腺癌中的研究成果势必会影响晚期治疗格局。在新辅助和辅助治疗阶段使用更强的抗雌激素治疗进展后，晚期治疗格局的应对之策还需进一步探讨。 晚期治疗策略之新型药物的强强联合 在明确了细胞周期蛋白D与CDK4/6形成复合体可激活DNA复制（图1c）之后，CDK4/6i应运而生，与传统抗雌激素治疗的联合应用展现出了强大的抗肿瘤效果。ET+CDK4/6i已被纳入晚期HR+乳腺癌首选的一线治疗策略。而对PI3K-AKT-PTEN-mTOR信号通路的理解（图1b），让ET联合依维莫司成为目前CDK4/6i耐药后的重要选择。此外，若患者伴有BRCA1/2基因突变，PARP抑制剂单药治疗也显示出了相较于化疗的优势。 PI3K-AKT-PTEN信号通路下的精准治疗 新一代测序技术（NGS）的出现，使得依据基因组生物标志物为晚期乳腺癌患者量身定制治疗方案成为可能。这些技术可以分析肿瘤组织或血液样本。通过检测循环肿瘤DNA（ctDNA）中的突变，临床医生可以用无创的方式，连续监测在高度选择性药物治疗的压力下肿瘤的耐药性突变。 一系列转化研究利用NGS识别了新的药物靶点，推动了PI3K-AKT-PTEN信号通路上的三种新型抑制剂获得FDA批准进入临床应用，包括一种AKT抑制剂和两种PI3K抑制剂。通过明确晚期HR+乳腺癌患者PIK3CA、AKT1或PTEN的突变情况，可为其提供精准的靶向治疗，进一步延缓肿瘤进展时间。 新一代CDK抑制剂的临床初探 除了PI3K-AKT-PTEN信号通路的新型药物研发，下一代CDK抑制剂也开展了临床研究。RGT-419B是一种CDK2/4抑制剂，目前在人体I期试验中显示出了良好的耐受性和抗肿瘤活性。CDK2抑制剂BLU-222、Tagtociclib，以及CDK4抑制剂PF-07220060在晚期乳腺癌中的疗效和安全性仍在探索阶段。 ET联合CDK4/6i的组合探索 在HR+晚期的治疗中，ET联合CDK4/6i无疑是最重要的治疗策略之一，其协同抗肿瘤的作用已被MONARCH、MONALEESA和PALOMA系列的多个大型三期随机对照临床所验证，让阿贝西利、瑞波西利和哌柏西利顺利获批进入临床应用。在此背景下，众多新型抗雌激素治疗物开展了与经典CDK4/6i的联合应用研究。 CDK4/6i经治之后再挑战 自CDK4/6i在HR+/HER2-晚期乳腺癌的一线治疗中广泛应用以来，探讨其进展之后的治疗策略从未停止。除了以上提到的种种新型治疗选择，研究证实，在CDK4/6i经治之后再挑战也成为了一种选择。 PARP1选择性抑制剂 此外，新型PARP1选择性抑制剂Saruparib也在其临床研究中取得了不错的结果，同样为伴有BRCA1、BRCA2、PALB2或RAD51C/D突变的晚期HR+患者提供了更多的选择。 全新治疗维度之 ADC 引领变革 新一代的抗体药物偶联物（ADC）已强势加入 HR+/HER2-晚期乳腺癌的治疗选择。自靶向 HER2 的德曲妥珠单抗面世以来，甚至基于其研究结果提出了 HER2 低表达的全新概念。靶向 TROP2 的戈沙托珠单抗继三阴性乳腺癌之后，也取得了 ER+/HER2-晚期乳腺癌的适应症。其他已经 进入临床研究后期的靶向 TROP2 和 HER3 的新型药物，也会为 ADC 的治疗注入新鲜血液。 晚期格局排兵布阵之未被满足的需求 经过对目前治疗格局的梳理及对后起之秀的展望，可见新型治疗方案如雨后春笋般涌现出来。然而，在这激烈的角逐背后，必然隐藏着对于未来治疗格局影响。可以明确的是，精准治疗是未来为患者制定个性化治疗方案的有力抓手。尤其是ctDNA技术的突破，让这一切变得更加简单可靠。通过无创监测，即可准确地、及时地判断抗雌激素治疗联合CDK4/6i治疗之后的基因突变情况（图2），从而选择适合的靶向药物，提高治疗效率。 图 2.抗雌激素治疗联合 CDK4/6i 方案的耐药机制 在精准治疗的基础之上，HR+/HER2-晚期乳腺癌进展之后的治疗格局看似明朗，但靶向治疗该联合哪些新型抗雌激素治疗药物？是选择单药治疗还是联合治疗？ADC的治疗时机到底如何选择？在什么情况下哪些治疗的线数可以提前？这些都给临床决策带了新的问题。 总结 随着新一代抗雌激素药物、针对信号通路的靶向药物及ADC类药物不断地从临床研究走向临床应用，学术界可借助NGS快速发展的力量，持续关注药物相关的基因组和分子机制的研究，对耐药的深刻理解，有望推动新型疗法的开发及临床应用。同时，在ctDNA的辅助之下，有望为患者进一步优化对治疗选择的预测，尽可能的为患者带来最大获益。 参考文献： [1] Lloyd, Maxwell R et al. “Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer.” Nature reviews. Clinical oncology vol. 21,10 (2024): 743-761. [2] 《NCCN Guidelines® Breast cancer (Version 6.2024)》. 审核编号：CN-153471 过期日期：2026-05-20 本材料由阿斯利康提供，仅供医疗卫生专业人士参考 编辑：Linna 审校：Max 排版：Mythero 执行：Ocean 本平台旨在为医疗卫生专业人士传递更多医学信息。本平台发布的内容，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。如该等信息被用于了解医学信息以外的目的，本平台不承担相关责任。本平台对发布的内容，并不代表同意其描述和观点。若涉及版权问题，烦请权利人与我们联系，我们将尽快处理。