Olomorasib

编者按：随着研发技术的不断进步，新一代共价药物的开发已成为业界高度关注的方向。截至目前，已有超过50种共价药物成功获批上市，并在多个疾病领域展现出显著疗效。值得关注的是，新一代共价药物正不断突破局限，向可逆性共价结合及靶向半胱氨酸以外氨基酸残基的方向快速拓展，为攻克“不可成药”靶点带来全新契机。依托端到端的CRDMO赋能平台，药明康德致力为全球合作伙伴提供覆盖共价药物发现与开发的一体化解决方案。本文将回顾2025年第三季度共价小分子领域的最新进展，并介绍药明康德在共价药物发现领域的技术与能力。 共价抑制剂在癌症领域持续进展 自KRAS G12C抑制剂sotorasib与adagrasib获批以来，共价小分子在攻克癌症领域“不可成药”靶点方面的潜力，愈发受到产业界的广泛关注。进入2025年第三季度，多款KRAS G12C共价抑制剂陆续获得美国FDA授予的突破性疗法认定（BTD），用于治疗非小细胞肺癌（NSCLC），其中包括olomorasib、RAS（ON）G12C选择性抑制剂elironrasib（RMC-6291），以及RAS（OFF）G12C选择性抑制剂D3S-001。RAS（ON）与RAS（OFF）分别指RAS分子处于活性与非活性状态。值得一提的是，先前公布的研究结果显示，在36例既往接受免疫治疗与化疗的KRAS G12C突变NSCLC患者中，elironrasib治疗组的客观缓解率（ORR）达到56%，疾病控制率（DCR）高达94%。 除KRAS G12C外，针对KRAS G12D的共价抑制剂研发也在快速推进。其中，RAS（ON）G12D选择性抑制剂zoldonrasib（RMC-9805）的临床前研究成果于今年7月发表在《科学》杂志上。目前，该疗法已进入临床阶段。根据已公布的数据，在18例可评估疗效、携带KRAS G12D突变的经治NSCLC患者中，ORR达到61%，DCR为89%。 除KRAS外，其他靶点的共价抑制剂研发也持续进展。例如，评估潜在“best-in-class”口服共价Werner解旋酶抑制剂MOMA-341的1期临床试验已完成首例患者给药。该研究旨在治疗具有高微卫星不稳定性（MSI-H）和/或DNA错配修复缺陷（dMMR）的晚期或转移性实体瘤，包括结直肠癌、胃癌和子宫内膜癌等。 其他适应症的应用拓展 除了肿瘤领域，共价抑制剂的应用也正在向免疫、代谢及炎症性疾病拓展。 今年8月，美国FDA批准赛诺菲（Sanofi）共价抑制剂Wayrilz（rilzabrutinib）上市，用于治疗既往疗效不足的持续性或慢性免疫性血小板减少症（ITP）成人患者。根据新闻稿，Wayrilz是FDA批准的首款用于ITP治疗的布鲁顿氏酪氨酸激酶（BTK）抑制剂。3期临床数据显示，第25周时，Wayrilz组23%的患者达到持久性血小板应答，而安慰剂组为0%（p<0.0001）。此外，Wayrilz组患者的血小板应答持续时间显著延长至7周，而安慰剂组仅为0.7周。同月，Wayrilz还获得欧洲药品管理局（EMA）授予孤儿药资格，用于治疗IgG4相关疾病。 在皮肤疾病领域，ITK与JAK3双靶点抑制剂ATI-2138在治疗中重度特应性皮炎（AD）的2a期试验中达到了主要及关键次要终点。研究结果显示，该药疗效与活性对照药物相当，并展现出良好的安全性。研发方计划进一步评估其在斑秃及其他作用机制相似疾病中的潜在疗效。 代谢疾病领域同样出现新的探索。用于治疗2型糖尿病（T2D）的menin靶向共价抑制剂icovamenib在公布的动物实验结果显示，与GLP-1受体激动剂（GLP-1RA）联用可更有效地控制血糖并减轻体重，同时保持瘦体重，其疗效优于GLP-1RA单药。该疗法目前正在多项2期试验中评估，用于单药或联合GLP-1RA治疗T2D患者。 商业合作进展 共价药物领域的活跃也体现在产业合作与融资上。 今年7月，诺华（Novartis）与Matchpoint Therapeutics达成最高金额约10亿美元的独家选择权与许可协议，双方将合作开发和商业化一款口服共价抑制剂，该药物靶向一类与多种炎症性疾病相关的转录因子。根据协议，Matchpoint将利用其Advanced Covalent Exploration（ACE）平台推进前期研究，直至筛选出候选化合物。 此外，Odyssey Therapeutics也在今年9月完成2.13亿美元融资，旨在通过其人工智能与共价化学平台加速开发用于治疗自身免疫疾病的新药。 ▲部分2025年第三季度共价小分子疗法相关合作交易与融资事件 总体来看，共价抑制剂正从肿瘤领域不断向免疫、炎症与代谢等多类疾病扩展，其独特的结合机制、持久效率与高选择性特征，正在为多种疾病带来新的解决方案。随着技术平台的成熟与产业合作的加深，这一领域有望在未来几年迎来更多临床与商业化突破。 药明康德助力加速共价药物开发 为帮助全球合作伙伴加速下一代共价药物的研发——从早期发现到IND申报，药明康德建立了一体化发现平台。该平台融合了三大互补技术：共价DNA编码化合物库（cDEL）、共价片段药物发现（cFBDD）以及共价高通量筛选（cHTS），为共价药物发现提供了高效的解决方案。 ▲药明康德共价药物发现能力 cDEL是一项功能强大的筛选技术，能够高效探索庞大的化学空间，大幅提升发现多样化共价分子及其结合弹头的可能性。通过将DNA标签作为“分子条形码”，该平台可在仅需极少量蛋白和化合物的条件下，实现快速且具成本效益的苗头化合物发现，在化学多样性至关重要的早期研发阶段尤为突出。 药明康德的cFBDD平台则基于一个经过严格筛选的化合物库，包含超过2600个结构多样化的片段。该平台以小而低复杂度的分子片段为核心，高效探索结合位点，并通过引入带有亲电基团的片段，快速识别可作为优化起点的共价结合物。结合高通量质谱以及X射线晶体学、核磁共振（NMR）等结构生物学方法，cFBDD能够在原子水平提供片段–蛋白相互作用的深度洞察，从而支持理性设计与系统优化。 药明康德的cHTS平台是集合了药明康德cHTS共价库和多种筛选方法的高通量筛选平台。药明康德的cHTS共价库约有6万9千个分子，涵盖50多种不同类型的共价弹头，反应活性范围多样。这些化合物能够作用于九类不同的氨基酸残基，将共价药物发现的范围从半胱氨酸扩展至丝氨酸、赖氨酸以及其他残基专属的化合物库。 在共价药物筛选平台之外，药明康德还建立了一整套早期药物发现技术平台，涵盖生物物理学、生物化学及细胞学检测，为全球合作伙伴共价药物的开发提供坚实的支持。依托端到端的一体化CRDMO赋能平台，药明康德致力于加速突破性疗法的开发，帮助合作伙伴将创新成果高效转化为造福全球患者的解决方案，以践行“让天下没有难做的药，难治的病”的愿景。 CRDMO: Q3 2025 Review of Covalent Small Molecules With advances in biopharmaceutical research and development, next-generation covalent drugs have emerged as a major focus across the industry. To date, more than 50 covalent drugs have been approved for clinical use, demonstrating substantial value across a broad range of therapeutic areas. Importantly, these next-generation therapies are advancing toward reversible covalent binding and targeting amino acid residues beyond cysteine, thereby opening new possibilities for addressing previously “undruggable” targets. Leveraging its fully integrated, end-to-end CRDMO enabling platform, WuXi AppTec provides global partners with comprehensive solutions for covalent drug discovery and development. Here, we summarize key developments in the covalent small molecules space during Q3 2025 and highlight WuXi AppTec’s capabilities and strengths in enabling innovation in covalent drug discovery. Covalent Inhibitors Continue to Make Progress in Oncology Since the approval of the KRAS G12C inhibitors sotorasib and adagrasib, the potential of covalent small molecules to tackle previously “undruggable” targets in oncology has attracted growing attention across the industry. In the third quarter of 2025, multiple KRAS G12C covalent inhibitors received Breakthrough Therapy Designation (BTD) from the U.S. FDA for the treatment of non-small cell lung cancer (NSCLC). These include olomorasib, the RAS(ON)-selective G12C inhibitor elironrasib (RMC-6291), and the RAS(OFF)-selective G12C inhibitor D3S-001. Notably, RAS(ON) and RAS(OFF) refer to the active and inactive states of the RAS molecule, respectively. In a study of 36 KRAS G12C-mutated NSCLC patients previously treated with immunotherapy and chemotherapy, elironrasib demonstrated an objective response rate (ORR) of 56% and a disease control rate (DCR) of 94%.  Beyond KRAS G12C, efforts to target KRAS G12D are also accelerating. The discovery of the RAS(ON) G12D-selective inhibitor zoldonrasib (RMC-9805) was published in Science in July 2025. Now in clinical development, early data showed promising efficacy—among 18 evaluable, pretreated NSCLC patients harboring KRAS G12D mutations, the ORR reached 61%, and the DCR was 89%. Progress is also being made on covalent inhibitors targeting other oncogenic drivers. For example, the first-in-human (FIH) Phase 1 study of the oral, potentially best-in-class covalent Werner helicase inhibitor MOMA-341 has dosed its first patient. The trial is evaluating MOMA-341 in advanced or metastatic solid tumors with high microsatellite instability (MSI-H) and/or DNA mismatch repair deficiency (dMMR), including colorectal, gastric, and endometrial cancers. Expanding Applications Beyond Oncology Beyond oncology, covalent inhibitors are gaining traction across immunology, metabolic, and inflammatory diseases. In August 2025, the U.S. FDA approved Sanofi’s covalent inhibitor Wayrilz (rilzabrutinib) for adult patients with persistent or chronic immune thrombocytopenia (ITP) who had an insufficient response to prior therapies. According to the company, Wayrilz is the first Bruton’s tyrosine kinase (BTK) inhibitor approved by the FDA for ITP. In the Phase 3 trial, 23% of patients in the Wayrilz arm achieved a durable platelet response at Week 25, compared with 0% in the placebo arm (p<0.0001). Moreover, the median duration of platelet response was significantly longer in the Wayrilz group (7 weeks) versus in the placebo group (0.7 weeks). In the same month, Wayrilz also received Orphan Drug Designation (ODD) from the European Medicines Agency (EMA) for the treatment of IgG4-related disease. In dermatology, the dual ITK/JAK3 inhibitor ATI-2138 met its primary and key secondary endpoints in a Phase 2a trial for moderate-to-severe atopic dermatitis (AD), showing efficacy comparable to the active control with a favorable safety profile. The developer plans to further evaluate ATI-2138 in alopecia areata and other related immune-mediated diseases. In metabolic disorders, the menin-targeted covalent inhibitor icovamenib demonstrated synergistic effects in animal studies when combined with GLP-1 receptor agonists (GLP-1RAs). The combination improved glycemic control and reduced body weight while preserving lean mass—showing superior efficacy compared with GLP-1RA monotherapy. The therapy is currently being evaluated in multiple Phase 2 clinical trials as a monotherapy and in combination with GLP-1RAs for type 2 diabetes (T2D). Strategic Collaborations and Investment Momentum The surge of innovation in covalent chemistry is also reflected in recent strategic partnerships and financing activity across the industry. In July 2025, Novartis entered into an exclusive option and license agreement worth up to approximately USD 1 billion with Matchpoint Therapeutics. The collaboration focuses on developing and commercializing an oral covalent inhibitor targeting a transcription factor associated with multiple inflammatory diseases. Under the agreement, Matchpoint will leverage its Advanced Covalent Exploration (ACE) platform to advance discovery efforts and nominate a lead candidate for further development. In September 2025, Odyssey Therapeutics raised USD 213 million in new financing to accelerate drug discovery for autoimmune diseases through its artificial intelligence and covalent chemistry platforms. Overall, covalent inhibitors are expanding beyond oncology into immunology, inflammation, and metabolic diseases. With their unique binding mechanism, durable efficacy, and high selectivity, they are delivering new solutions across multiple indications. As technology platforms mature and industry collaborations deepen, this field is poised to achieve additional clinical and commercial breakthroughs in the coming years. WuXi AppTec Empowers the Development of Covalent Drugs To help global partners accelerate the development of next-generation covalent drugs, from early discovery through IND-enabling studies, WuXi AppTec has established an integrated platform. By combining three complementary, state-of-the-art technologies—covalent DNA-Encoded Library (cDEL), covalent Fragment-Based Drug Discovery (cFBDD), and covalent High-Throughput Screening (cHTS)—the platform provides a highly efficient solution to advance covalent drug discovery. ▲WuXi AppTec’s capabilities in covalent drug discovery cDEL is a powerful screening technology that enables the efficient exploration of vast chemical libraries, greatly increasing the likelihood of identifying covalent binders with diverse warheads. Leveraging DNA tags as molecular barcodes, the platform allows rapid and cost-effective deconvolution of hits while requiring only minimal quantities of protein and compound. This makes it particularly valuable in the early discovery stage, where broad chemical diversity is essential. WuXi AppTec’s cFBDD platform builds on a rigorously curated library of more than 2,600 structurally diverse fragments. By focusing on small, low-complexity molecules, the platform efficiently probes binding sites and, through the incorporation of electrophilic fragments, identifies covalent hits that serve as highly effective starting points for optimization. Leveraging high-throughput mass spectrometry together with structural biology methods such as X-ray crystallography and NMR, cFBDD provides atomic-level insights into fragment–protein interactions, enabling rational design and systematic growth of covalent inhibitors. The cHTS platform from WuXi AppTec is a platform that incorporates various screening strategies. The covalent HTS library has approximately 69,000 covalent molecules featuring more than 50 distinct warhead chemotypes across a range of reactivities. Our library is purpose-built to engage with nine different amino acid residues, extending covalent drug discovery beyond cysteine to include serine-, lysine-, and other residue-focused libraries. Complementing its advanced screening capabilities, WuXi AppTec offers a comprehensive suite of early discovery technology platforms—including biophysical, biochemical, and cellular assays—to support global partners in advancing covalent drug development. Backed by an integrated, end-to-end CRDMO enabling platform, WuXi AppTec is committed to accelerating the development of transformative therapies that deliver meaningful benefits to patients worldwide—fulfilling its vision that “Every drug can be made and every disease can be treated.” 参考资料： [1] Lilly's olomorasib receives U.S. FDA's Breakthrough Therapy designation for the treatment of certain newly diagnosed metastatic KRAS G12C-mutant lung cancers. Retrieved October 7, 2025 from https://www.prnewswire.com/news-releases/lillys-olomorasib-receives-us-fdas-breakthrough-therapy-designation-for-the-treatment-of-certain-newly-diagnosed-metastatic-kras-g12c-mutant-lung-cancers-302545643.html [2] D3 Bio, Inc. Announces FDA Breakthrough Therapy Designation and Orphan Drug Designation for D3S-001 for the Treatment of Patients with KRAS G12C-Mutated Cancers. Retrieved October 7, 2025 from D3 Bio, Inc. Announces FDA Breakthrough Therapy Designation and Orphan Drug Designation for D3S-001 for the Treatment of Patients with KRAS G12C-Mutated Cancers [3] Revolution Medicines Announces Publication of a Peer-Reviewed Research Paper in Science on the Discovery and Development of Zoldonrasib, a RAS(ON) G12D-Selective Inhibitor. Retrieved October 7, 2025 from https://www.globenewswire.com/news-release/2025/07/24/3121401/0/en/Revolution-Medicines-Announces-Publication-of-a-Peer-Reviewed-Research-Paper-in-Science-on-the-Discovery-and-Development-of-Zoldonrasib-a-RAS-ON-G12D-Selective-Inhibitor.html [4] Aclaris Therapeutics Announces Positive Top-Line Results from Open-Label Phase 2a Trial of ATI-2138, a Potent and Selective Investigational Inhibitor of ITK and JAK3; Trial Achieves Primary and Key Secondary Endpoints. Retrieved October 7, 2025 from https://www.globenewswire.com/news-release/2025/07/29/3123590/37216/en/Aclaris-Therapeutics-Announces-Positive-Top-Line-Results-from-Open-Label-Phase-2a-Trial-of-ATI-2138-a-Potent-and-Selective-Investigational-Inhibitor-of-ITK-and-JAK3-Trial-Achieves-.html [5] Press Release: Sanofi’s rilzabrutinib earns orphan designation in the EU for IgG4-related disease. Retrieved October 7, 2025 from https://www.sanofi.com/en/media-room/press-releases/2025/2025-08-14-05-00-00-3133146 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Primary overall survival analysis from the Phase 3 monarchE study of Verzenio (abemaciclib) in HR+HER2-, node-positive, high-risk early breast cancer to be presented as a late-breaking oral presentation Additional presentations showcase Lilly's robust oncology pipeline with data from studies of investigational therapies targeting FRα positive ovarian cancer, KRAS G12C-mutant lung cancer, FGFR3-altered bladder cancer, and PIK3CA-mutant advanced breast cancer INDIANAPOLIS, Oct. 13, 2025 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced that new data from across its oncology portfolio and pipeline will be presented at the European Society for Medical Oncology (ESMO) Annual Meeting, taking place October 17-21 in Berlin, Germany. These presentations highlight the breadth of Lilly's portfolio across treatment modalities and tumor types. Presentation Highlights Verzenio (abemaciclib; CDK4/6 inhibitor): In a late-breaking oral presentation, Lilly will share results from the landmark seven-year analysis of monarchE, including primary overall survival analysis and updated invasive disease-free survival and distant relapse-free survival, in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, high-risk early breast cancer. Additionally, in a mini-oral presentation, Lilly will share an in-depth analysis from monarchE examining the prognostic and predictive value of the Ki-67 index, pre- and post-neoadjuvant chemotherapy. Olomorasib (investigational KRAS G12C inhibitor): In a mini oral presentation, Lilly will share results from the Phase 1/2 study on the intracranial efficacy of olomorasib, a next-generation KRAS G12C inhibitor, in patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) who have active, untreated brain metastases. LY4064809 (investigational pan-mutant-selective PI3Ka inhibitor): In a late-breaking oral presentation, Lilly will share updated results from the Phase 1/2 PIKALO-1 trial, a study of LY4064809 (STX-478), a pan-mutant-selective PI3Ka inhibitor, in PIK3CA-mutant advanced breast cancer and other solid tumors. Vepugratinib (investigational FGFR3 inhibitor): In a mini oral presentation, Lilly will share updated results from the FORAGER-1 study, a first-in-human Phase 1 study of vepugratinib (LY3866288), a potent, highly isoform-selective FGFR3 inhibitor, in FGFR3-altered urothelial cancer. LY4170156 (investigational ADC targeting FRα): In a poster presentation, Lilly will share updated safety and efficacy results from the Phase 1a/1b study of LY4170156 in patients with platinum-resistant ovarian cancer. "At ESMO 2025, we're proud to showcase new clinical data from several studies that underscore Lilly's commitment to advancing cancer care, including the primary overall survival analysis for Verzenio in the Phase 3 monarchE trial, as well as updated safety and efficacy data from our FRα ADC, PI3Kα and FGFR3 programs, all of which are poised to advance to late stage studies over the next several months," said Jacob Van Naarden, executive vice president and president of Lilly Oncology. "These data reflect the meaningful progress we have made in strengthening our oncology portfolio and our dedication to improving outcomes for people living with cancer." A full list of abstract titles and viewing details are listed below: For more information on Lilly's Oncology pipeline click here. About Verzenio (abemaciclib) Verzenio (abemaciclib) is approved to treat people with certain HR+, HER2- breast cancers in the adjuvant and advanced or metastatic settings. Verzenio is an oral tablet taken twice daily and available in strengths of 50 mg, 100 mg, 150 mg, and 200 mg. Discovered and developed by Lilly researchers, Verzenio was first approved in 2017 and is currently authorized for use in more than 90 counties around the world. For full details on indicated uses of Verzenio in HR+, HER2- breast cancer, please see full Prescribing Information, available at . INDICATIONS FOR VERZENIO VERZENIO is a kinase inhibitor indicated: in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib) Severe diarrhea associated with dehydration and infection occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, diarrhea occurred in 81 to 90% of patients who received Verzenio. Grade 3 diarrhea occurred in 8 to 20% of patients receiving Verzenio. Most patients experienced diarrhea during the first month of Verzenio treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19 to 26% of patients with diarrhea required a Verzenio dose interruption and 13 to 23% required a dose reduction. Instruct patients to start antidiarrheal therapy, such as loperamide, at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose. Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, neutropenia occurred in 37 to 46% of patients receiving Verzenio. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19 to 32% of patients receiving Verzenio. Across trials, the median time to first episode of Grade ≥3 neutropenia ranged from 29 to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 to 16 days. Febrile neutropenia has been reported in <1% of patients exposed to Verzenio across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider. Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. In Verzenio-treated patients in EBC (monarchE), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In Verzenio-treated patients in MBC (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported. Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue Verzenio in all patients with Grade 3 or 4 ILD or pneumonitis. Grade ≥ 3 increases in alanine aminotransferase (ALT) (2 to 6%) and aspartate aminotransferase (AST) (2 to 3%) were reported in patients receiving Verzenio. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days. Monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or 4 hepatic transaminase elevation. Venous thromboembolic events (VTE) were reported in 2 to 5% of patients across three clinical trials in 3559 patients treated with Verzenio (monarchE, MONARCH 2, MONARCH 3). VTE included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to VTE have been reported in patients treated with Verzenio. Verzenio has not been studied in patients with early breast cancer who had a history of VTE. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for EBC patients with any grade VTE and for MBC patients with a Grade 3 or 4 VTE. Verzenio can cause fetal harm when administered to a pregnant woman, based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for 3 weeks after the last dose. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. The most common adverse reactions (all grades, ≥ 10%) observed in monarchE for Verzenio plus tamoxifen or an aromatase inhibitor vs tamoxifen or an aromatase inhibitor, with a difference between arms of ≥ 2%, were diarrhea (84% vs 9%), infections (51% vs 39%), neutropenia (46% vs 6%), fatigue (41% vs 18%), leukopenia (38% vs 7%), nausea (30% vs 9%), anemia (24% vs 4%), headache (20% vs 15%), vomiting (18% vs 4.6%), stomatitis (14% vs 5%), lymphopenia (14% vs 3%), thrombocytopenia (13% vs 2%), decreased appetite (12% vs 2.4%), ALT increased (12% vs 6%), AST increased (12% vs 5%), dizziness (11% vs 7%), rash (11% vs 4.5%), and alopecia (11% vs 2.7 %). The most frequently reported ≥ 5% Grade 3 or 4 adverse reaction that occurred in the Verzenio arm vs the tamoxifen or an aromatase inhibitor arm of monarchE were neutropenia (19.6% vs 1%), leukopenia (11% vs <1%), diarrhea (8% vs 0.2%), and lymphopenia (5% vs <1%). Lab abnormalities (all grades; Grade 3 or 4) for monarchE in ≥ 10% for Verzenio plus tamoxifen or an aromatase inhibitor with a difference between arms of ≥ 2% were increased serum creatinine (99% vs 91%; .5% vs <.1%), decreased white blood cells (89% vs 28%; 19.1% vs 1.1%), decreased neutrophil count (84% vs 23%; 18.7% vs 1.9%), anemia (68% vs 17%; 1% vs .1%), decreased lymphocyte count (59% vs 24%; 13.2 % vs 2.5%), decreased platelet count (37% vs 10%; .9% vs .2%), increased ALT (37% vs 24%; 2.6% vs 1.2%), increased AST (31% vs 18%; 1.6% vs .9%), and hypokalemia (11% vs 3.8%; 1.3% vs 0.2%). The most common adverse reactions (all grades, ≥ 10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole vs anastrozole or letrozole, with a difference between arms of ≥ 2%, were diarrhea (81% vs 30%), fatigue (40% vs 32%), neutropenia (41% vs 2%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3.1%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%). The most frequently reported ≥ 5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 1%), diarrhea (9% vs 1.2%), leukopenia (7% vs <1%)), increased ALT (6% vs 2%), and anemia (6% vs 1%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥ 10% for Verzenio plus anastrozole or letrozole with a difference between arms of ≥ 2% were increased serum creatinine (98% vs 84%; 2.2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs 0.6%), anemia (82% vs 28%; 1.6% vs 0%), decreased neutrophil count (80% vs 21%; 21.9% vs 2.6%), decreased lymphocyte count (53% vs 26%; 7.6% vs 1.9%), decreased platelet count (36% vs 12%; 1.9% vs 0.6%), increased ALT (48% vs 25%; 6.6% vs 1.9%), and increased AST (37% vs 23%; 3.8% vs 0.6%). The most common adverse reactions (all grades, ≥ 10%) observed in MONARCH 2 for Verzenio plus fulvestrant vs fulvestrant, with a difference between arms of ≥ 2%, were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 2.7%), thrombocytopenia (16% vs 3%), alopecia (16% vs 1.8%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4.5%), pyrexia (11% vs 6%), and weight decreased (10% vs 2.2%). The most frequently reported ≥ 5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (25% vs 1%), diarrhea (13% vs 0.4%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (5.7% vs 3.5%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥ 10% for Verzenio plus fulvestrant with a difference between arms of ≥ 2% were increased serum creatinine (98% vs 74%; 1.2% vs 0%), decreased white blood cells (90% vs 33%; 23.7% vs .9%), decreased neutrophil count (87% vs 30%; 32.5% vs 4.2%), anemia (84% vs 34%; 2.6% vs .5%), decreased lymphocyte count (63% vs 32%; 12.2% vs 1.8%), decreased platelet count (53% vs 15%; 2.1% vs 0%), increased ALT (41% vs 32%; 4.6% vs 1.4%), and increased AST (37% vs 25%; 3.9% vs 4.2%). The most common adverse reactions (all grades, ≥ 10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), constipation (17%), leukopenia (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%). The most frequently reported ≥ 5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were diarrhea (20%), neutropenia (24%), fatigue (13%), and leukopenia (5%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (99%; .8%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 26.6%), anemia (69%; 0%), decreased lymphocyte count (42%; 13.8%), decreased platelet count (41%; 2.3%), increased ALT (31%; 3.1%), and increased AST (30%; 3.8%). Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. With severe hepatic impairment (Child-Pugh C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min). Please see full Prescribing Information and Patient Information for Verzenio. AL HCP ISI 12OCT2021 About Olomorasib Olomorasib (LY3537982) is an investigational, oral, potent, and highly selective next-generation inhibitor of the KRAS G12C protein. KRAS is the most common oncogene across all tumor types, and KRAS G12C mutations occur in 13% of patients with non-small cell lung cancer (NSCLC), and 1-3% of patients with other solid tumors.1 Olomorasib was specifically designed to target KRAS G12C mutations and has pharmacokinetic properties which potentially allow for high predicted target occupancy and high potency when used as monotherapy or in combination.2 Olomorasib is currently being studied in combination with pembrolizumab with or without chemotherapy for first-line treatment of KRAS G12C-mutant advanced NSCLC, and other advanced solid tumors, including: NCT06119581 and NCT06890598. About LY4064809 LY4064809 (STX-478) is an investigational, oral, next-generation inhibitor phosphoinositide 3-kinase alpha (PI3Kα) inhibitor designed to selectively target tumors with PIK3CA mutations while sparing wild-type PI3Kα. Activating mutations in the PIK3CA gene (which encodes PI3Kα enzyme) are oncogenic drivers present in approximately 40% of hormone receptor positive (HR+)/HER2-negative breast cancers and occur at lower frequencies in many other cancers.3,4 LY4064809 is currently being studied in patients with HR+ breast cancer and other solid tumors with PIK3CA mutations, NCT05768139.5 About Vepugratinib (LY3866288/LOXO-435) Vepugratinib is an investigational, oral, isoform-selective fibroblast growth factor receptor 3 (FGFR3) inhibitor that has shown antitumor activity across FGFR3-mutant in vivo preclinical models, with preserved potency against FGFR3 gatekeeper resistance mutants.6 Inhibition of oncogenic FGFR3 shows clinical benefit in advanced urothelial cancer; however, currently approved FGFR-targeted therapies that are not selective for FGFR3 demonstrate dose-limiting off target toxicities, and susceptibility to resistance mutations. Vepugratinib is designed to selectively target FGFR3 alterations with the goal of avoiding dose-limiting hyperphosphatemia and other clinical adverse events that drive chronic intolerance to pan-FGFR inhibitors.6 Vepugratinib is currently being studied in an open-label, multicenter, Phase 1a/b study in patients with FGFR3-altered advanced urothelial carcinoma and other solid tumors, NCT05614739. About LY4170156 LY4170156 is an investigational, next-generation ADC targeting folate receptor alpha (FRα). Folate receptor alpha (FRα) is a cell-surface glycoprotein encoded by the gene FOLR1 that binds to the essential nutrients folic acid and reduced folates, bringing them into cells to facilitate cell division and growth.7 FRα is overexpressed in many solid tumors such as ovarian, non-small cell lung, and colorectal cancers.7 LY4170156 was designed to target FRα across expression levels with improved therapeutic index. LY4170156 is composed of a Fcγ silent, humanized monoclonal antibody, a proprietary polysarcosine hydrophobicity masking agent (PSARlink®) with a cleavable linker, and a topoisomerase 1 inhibitor exatecan payload. LY4170156 is currently being studied in patients with ovarian cancer as well as other FRα-expressing solid tumors, NCT06400472. About Inluriyo (imlunestrant) Inluriyo (imlunestrant) (pronounced en-loo-ree-yoh) is an oral estrogen receptor antagonist that delivers continuous ER inhibition, including in ESR1-mutant cancers. The estrogen receptor (ER) is the key therapeutic target for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. Inluriyo is a U.S. FDA approved oral prescription medicine, 200 mg tablets taken as a once-daily dose of 400 mg taken on an empty stomach, at least 2 hours before food or 1 hour after food. Inluriyo is also currently being studied in combination with abemaciclib for advanced breast cancer and as an adjuvant treatment in early breast cancer, including: NCT04975308, NCT05514054 and NCT04188548. INDICATION FOR INLURIYO (imlunestrant) INLURIYO is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. IMPORTANT SAFETY INFORMATION FOR INLURIYO Warnings and Precautions — Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Inluriyo can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of imlunestrant to pregnant rats during the period of organogenesis led to embryo-fetal mortality and structural abnormalities at maternal exposures that were below the human exposure at the recommended dose based on area under the curve (AUC). Avoid the use of imlunestrant in pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Inluriyo and for 1 week after the last dose. Serious and Fatal Adverse Reactions Serious adverse reactions occurred in 10% of patients who received Inluriyo. Serious adverse reactions in >1% of patients included pleural effusion (1.2%). Fatal adverse reactions occurred in 1.8% of patients who received Inluriyo, including cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock, and upper gastrointestinal hemorrhage (each 0.3%). Most Common Adverse Reactions The most common adverse reactions (incidence ≥10%), including laboratory abnormalities, in patients who received Inluriyo were: hemoglobin decreased (30%), musculoskeletal pain (30%), calcium decreased (26%), neutrophils decreased (26%), AST increased (25%), fatigue (23%), diarrhea (22%), ALT increased (21%), triglycerides increased (21%), nausea (17%), platelets decreased (16%), constipation (10%), cholesterol increased (10%), and abdominal pain (10%). Drug Interactions Imlunestrant is a CYP3A substrate. Avoid concomitant use of Inluriyo with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce the dosage of Inluriyo. Avoid concomitant use of Inluriyo with strong CYP3A inducers. If concomitant use cannot be avoided, increase the dosage of Inluriyo. Imlunestrant inhibits both P-gp and BCRP. Avoid concomitant use unless otherwise recommended in the Prescribing Information for P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions. Use in Specific Populations — Lactation Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with Inluriyo and for 1 week after the last dose. Use in Specific Populations — Hepatic Impairment Reduce the dose of Inluriyo for patients with moderate ( Child-Pugh B) or severe ( Child-Pugh C) hepatic impairment. No dosage adjustment is recommended for patients with mild hepatic impairment ( Child-Pugh A). Inluriyo (imlunestrant) is available as 200 mg tablets. Please click to access Prescribing Information for Inluriyo. IN HCP ISI M APP About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram, and LinkedIn. P-LLY Trademarks and Trade Names All trademarks or trade names referred to in this press release are the property of the company, or, to the extent trademarks or trade names belonging to other companies are references in this press release, the property of their respective owners. Solely for convenience, the trademarks and trade names in this press release are referred to without the ® and ™ symbols, but such references should not be construed as any indicator that the company or, to the extent applicable, their respective owners will not assert, to the fullest extent under applicable law, the company's or their rights thereto. We do not intend the use or display of other companies' trademarks and trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Verzenio (abemaciclib) as a potential treatment for people with certain types of early breast cancer, Inluriyo (imlunestrant) as a treatment for people with certain types of breast cancer, olomorasib as a potential treatment for certain KRAS G12C-mutant advanced solid tumors, preclinical data for an antibody-drug conjugate targeting folate receptor alpha and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that any of these therapies will prove to be a safe and effective treatment or receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. Ji, Wang C, Fakih M. Targeting KRASG12C-mutated advanced colorectal cancer: Research and clinical developments. OncoTargets and Therapy. 2022;Volume 15:747-756. doi:10.2147/ott.s340392 Peng S-B, Si C, Zhang Y, et al. Abstract 1259: Preclinical characterization of Ly3537982, a novel, highly selective and potent KRAS-G12C inhibitor. Cancer Research. 2021;81(13_Supplement):1259-1259. doi:10.1158/1538-7445.am2021-1259 Dirican E, et al. Tumor Biol. 2016;37(6):7033-7045. Martinez-Saez O, et al. Breast Cancer Res. 2020;22(1):45. First-in-Human Study of STX-478, a Mutant-Selective PI3Kα Inhibitor as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors. Clinicaltrials.gov Identifier: NCT05768139. Updated March 25, 2025. Accessed March 31, 2025. Kalli, Kimberly R et al. "Folate receptor alpha as a tumor target in epithelial ovarian cancer." Gynecologic oncology vol. 108,3 (2008): 619-26. doi:10.1016/j.ygyno.2007.11.020. Viricel W, et al. Cancer Res. 2023;83(suppl 7):1544. SOURCE Eli Lilly and Company WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED