Gedatolisib

ESMO 2025 showcased the breadth and urgency of breast cancer research, which remains one of the most diagnosed malignancies worldwide, and its major subtypes: HR+, HER2+ and TNBC respond differently to treatment and develop resistance through distinct mechanisms. ESMO 2025展示了乳腺癌研究的广度和紧迫性，乳腺癌仍然是全球诊断率最高的恶性肿瘤之一，其主要亚型HR+、HER2+和TNBC对治疗的反应不同，并通过不同的机制产生耐药性。Although systemic therapy has improved outcomes, long-term survival remains suboptimal, and treatment-related toxicities are still problematic. Sequencing also remains uncertain. This year at ESMO 2025, several late-breaking abstracts and presidential symposia focused on closing these gaps through targeted combinations, improved tolerability, and better biomarker driven strategies.. 尽管系统治疗改善了结果，但长期生存率仍然不理想，治疗相关的毒性问题依然存在。治疗的顺序也仍然不确定。在今年的2025年欧洲肿瘤内科学会（ESMO）会议上，几个最新的摘要和主席研讨会聚焦于通过靶向联合治疗、提高耐受性以及更好的生物标志物驱动策略来弥补这些差距。CDK4/6 dominates in the early setting CDK4/6 在早期环境中占主导地位 Adjuvant use of CDK4/6 inhibitors is redefining the management of high-risk HR+ early-stage disease. In the CDK4/6抑制剂的辅助使用正在重新定义高风险HR+早期疾病的管理。在monarchE 君主Estudy, adding abemaciclib to endocrine therapy significantly improved invasive disease-free and distant relapse-free survival, and dose reductions did not compromise 研究显示，在内分泌治疗中加入阿贝西利可显著改善无浸润性疾病生存期和无远处复发生存期，且剂量减少并不会影响疗效。benefit, 利益，while the 而NATALEE 纳塔莉trial suggests that ribociclib may reduce recurrence risk in a broader population. Beyond approved agents, new molecules aim to address resistance: Pfizer’s atirmociclib offers CDK4 selective inhibition and its KAT6 inhibitor, PF07248144, 试验表明，ribociclib可能会降低更广泛人群的复发风险。除了已批准的药物外，新分子旨在解决耐药性问题：辉瑞的atirmociclib提供CDK4选择性抑制，其KAT6抑制剂PF07248144，produced 生产a 37% response rate and a median PFS of 10.7 months; Olema’s OP3136 37%的响应率和10.7个月的中位无进展生存期；Olema公司的OP3136demonstrated 证明了preclinical synergy with CDK4/6 blockade. A wave of next-generation oral SERDs and protein degraders -camizestrant, giredestrant, imlunestrant (recently approved), palazestrant, and ARV471 - aims to achieve deeper oestrogen receptor blockade and restore endocrine sensitivity. 临床前研究显示与CDK4/6阻断剂具有协同作用。下一代口服选择性雌激素受体调节剂（SERDs）和蛋白质降解剂（如camizestrant、giredestrant、imlunestrant（最近获批）、palazestrant和ARV471）旨在实现更深层次的雌激素受体阻断并恢复内分泌敏感性。Hyper-fragmentation in the 2L+ HR+ market 2L+ HR+ 市场的过度碎片化The second line HR+ setting has splintered into targeted niches. Resistance to first-line CDK4/6 inhibition can arise from RB1 loss, CDK4 amplification, and kinase mutations, prompting exploration of alternative pathways. Several regimens are already approved for the 2L+ setting ( 二线HR+治疗已分裂为多个靶向细分领域。对一线CDK4/6抑制的耐药性可能由RB1缺失、CDK4扩增和激酶突变引起，这促使了对替代通路的探索。已有多种方案获批用于二线及后续治疗（2L+）。CAPITELLO-291 柱头-291, ，OlympiaD 奥林匹亚D, ，EMERALD 绿宝石, ，BOLERO-2 BOLERO-2, and ，以及SOLAR-1 SOLAR-1), with many more in development. For example, in the Phase 3 ），还有更多正在开发中。例如，在第 3 阶段evERA 永恒trial, giredestrant + everolimus significantly 试验中，giredestrant + everolimus 显著improved 改进的PFS versus fulvestrant + everolimus. Dual PI3K/ESR1m inhibition is also promising, as shown in PFS与氟维司群+依维莫司。双重PI3K/ESR1m抑制也显示出希望，如图所示VIKTORIA-1 维多利亚-1, where gedatolisib + fulvestrant ± palbociclib ，其中 gedatolisib + 氟维司群 ± palbociclibreduced 减少the risk of progression by ~70% and extended median PFS to 7.4–9.3 months. In 进展风险降低了约70%，并将中位无进展生存期（PFS）延长至7.4-9.3个月。在ReDiscover-2 重新发现-2, RLY2608, a mutant-selective PI3Kα inhibitor, ，RLY2608，一种突变体选择性PI3Kα抑制剂，delivered 已交付a median PFS of 10.3 months and a 38.7% response rate with fulvestrant. Epigenetic modulators (KAT6 inhibitors) and protein degraders remain additional avenues in 2L development. Another oral SERD, giredestrant reduced the risk of disease progression or death by 44% and 62% in the intention-to-treat (ITT) and ESR1-mutated populations, respectively, as shown in . 氟维司群的中位无进展生存期为10.3个月，反应率为38.7%。表观遗传调节剂（KAT6抑制剂）和蛋白质降解剂仍是二线治疗开发的其他途径。另一种口服SERD，吉列司群，在意向治疗（ITT）人群和ESR1突变人群中分别降低了44%和62%的疾病进展或死亡风险，如图所示。evERA 永恒. 。Another emerging strategy is the use of TROP2 ADCs, such as sacituzumab tirumotecan (sac-TMT), which 另一种新兴策略是使用TROP2 ADC，例如sacituzumab tirumotecan（sac-TMT），它showed 显示了a statistically significant improvement in mPFS (HR 0.35) in the China-only Phase 3 仅中国参与的三期临床试验中，mPFS（HR 0.35）有统计学意义的显著改善。OptiTROPBreast02 OptiTROP乳腺02trial comparing sac-TMT to chemotherapy in previously treated HR+/HER2- mBC. 比较 sac-TMT 与化疗在既往治疗过的 HR+/HER2- mBC 中的试验。New standard of care in triple negative breast cancer 三阴性乳腺癌护理新标准Triple negative breast cancer (TNBC) has long been an area of unmet need, but immunotherapy and antibody-drug conjugates (ADCs) are changing the paradigm. Gilead’s sacituzumab govitecan remains the standard in the 2L disease, and at 三阴性乳腺癌（TNBC）长期以来一直是一个未满足需求的领域，但免疫疗法和抗体药物偶联物（ADCs）正在改变这一现状。Gilead公司的Sacituzumab Govitecan在二线治疗中仍然是标准疗法，并且在 ESMO 2025 ESMO 2025, data from early ，早期的数据ASCENT-03 ASCENT-03(PD-L1-negative) and PRO data from‑ （PD-L1阴性）和PRO数据来自‑ ASCENT-04 上升-04(PD-L1-positive) positioned sacituzumab govitecan as a potential 1L standard as well. Furthermore, daopotamab deruxtecan (Dato‑DXd), another TROP2-directed ADC (PD-L1 阳性) 也使 sacituzumab govitecan 成为潜在的一线标准。此外，另一种靶向 TROP2 的 ADC 药物 daopotamab deruxtecan (Dato‑DXd)achieved 实现a 5-month overall survival improvement in 1L TNBC ( 一线TNBC（三阴性乳腺癌）整体生存期延长5个月（TROPION-Breast02 TROPION-乳腺02). Finally, bispecific antibodies like BNT327 and novel ADCs aim to deliver targeted cytotoxic payloads while engaging immune activation. ）。最后，像BNT327这样的双特异性抗体和新型ADC旨在传递靶向细胞毒性载荷的同时激发免疫激活。HER2-positive disease sees ADCs push forward HER2阳性疾病的ADCs向前推进The HER2+ landscape continues to be reshaped by ADCs. The HER2+ 领域继续被ADC重塑。DESTINY-Breast09 DESTINY-乳腺癌09trial showed that trastuzumab deruxtecan (T‑DXd) significantly improved progression-free survival compared with the historic THP regimen in the 1L setting with ~70% of patients remaining progression-free at two years. This leadership extends to earlier disease stages with data presented at ESMO 2025: . 试验显示，与历史上的THP方案相比，trastuzumab deruxtecan（T-DXd）在一线治疗中显著改善了无进展生存期，约70%的患者在两年内保持无进展。这一领先地位延伸至更早的疾病阶段，相关数据已在ESMO 2025上公布。DESTINY-Breast11 命运-乳腺11demonstrated 证明a pCR rate of 67.3% in the neoadjuvant setting and the 新辅助治疗环境下的病理完全缓解（pCR）率为67.3%，并且DESTINY-Breast05 DESTINY-乳腺癌05showed a 53% 显示了53%reduction 减少in the risk of invasive disease recurrence or death in the adjuvant setting. Finally, for HR+/HER2+ metastatic disease, maintenance palbociclib + anti-HER2 therapy + endocrine therapy in the 在辅助治疗环境中，有侵袭性疾病复发或死亡的风险。最后，对于HR+/HER2+转移性疾病，维持palbociclib +抗HER2治疗+内分泌治疗在PATINA 包浆trial extended median PFS to 44.3 months vs 29.1 months, while patient-reported outcomes (PRO) 试验将中位无进展生存期（PFS）延长至44.3个月，而对照组为29.1个月，同时患者报告的结果（PRO）data 数据at ESMO 2025 reaffirm a favourable risk-benefit ratio. 在2025年欧洲肿瘤内科学会（ESMO）上重申了良好的风险收益比。What else is in store? 还有什么别的安排？As the therapeutic toolbox expands, oncologists face increasing complexity in determining how and when to deploy each modality. Serial biomarker testing via tissue biopsy, liquid biopsy, or circulating tumour DNA will likely become integral to detecting resistance mutations and guiding treatment transitions.. 随着治疗工具箱的扩展，肿瘤科医生在确定如何以及何时部署每种治疗方式时面临越来越多的复杂性。通过组织活检、液体活检或循环肿瘤DNA进行的连续生物标志物检测，可能会成为检测耐药突变和指导治疗转换的重要组成部分。Key questions persist: what is the optimal sequencing of CDK4/6 inhibitors, SERDs, PI3K/AKT/mTOR inhibitors, and ADCs? Can early use of CDK4-selective agents or KAT6 inhibitors delay resistance? And how can efficacy be balanced with cost and quality of life? 关键问题仍然存在：CDK4/6抑制剂、SERDs、PI3K/AKT/mTOR抑制剂和ADC的最佳使用顺序是什么？早期使用CDK4选择性药物或KAT6抑制剂能否延缓耐药性？如何在疗效与成本和生活质量之间取得平衡？Investigators are exploring whether next-generation SERDs and complete oestrogen receptor antagonists could eventually replace aromatase inhibitors or tamoxifen in the adjuvant setting, though this will be challenging, given the long-term safety, efficacy, and affordability of existing endocrine therapies.. 调查人员正在探索下一代SERDs和完全雌激素受体拮抗剂是否最终可以替代辅助治疗中的芳香酶抑制剂或他莫昔芬，尽管考虑到现有内分泌疗法的长期安全性、有效性和可负担性，这将是一个挑战。New agents, such as mutant-selective PI3K inhibitors, are designed to reduce adverse events like hyperglycaemia; however, high drug costs may limit real-world adoption unless substantial survival benefits are demonstrated. Ensuring equitable access to these complex regimens across healthcare systems remains essential.. 新型药物，如突变选择性PI3K抑制剂，旨在减少高血糖等不良反应；然而，除非能证明其显著的生存益处，高昂的药物费用可能限制其在现实中的应用。确保在各医疗系统中公平获取这些复杂治疗方案仍然至关重要。ESMO 2025 highlighted both extraordinary progress and the continued need for innovation to further improve outcomes across all breast cancer subtypes. ESMO 2025 强调了在所有乳腺癌亚型中取得的非凡进展，同时也指出了为进一步改善结果而继续创新的必要性。About the authors 关于作者Hymlaire Lamisere, PhD, is a senior business analyst at Lifescience Dynamics with a Doctorate in Immunology and over three years of consulting experience in the biopharmaceutical industry. He has supported clients across oncology, cardiometabolic, and rare diseases, with expertise in competitive intelligence, market research, and strategic advisory. Hymlaire Lamisere，博士，是Lifescience Dynamics的资深业务分析师，拥有免疫学博士学位，并在生物制药行业有超过三年的咨询经验。他为肿瘤学、心脑代谢和罕见病领域的客户提供支持，专长于竞争情报、市场研究和战略咨询。His work spans pipeline strategy, conference intelligence, and cross-functional insight generation to inform commercialisation and medical strategy. 他的工作涵盖管道战略、会议情报以及跨职能洞察生成，以指导商业化和医学战略。Will Torres is a consultant at Lifescience Dynamics. He has over six years of life sciences consulting experience, working across a broad range of therapy areas, including oncology, rare disease, and infectious disease. Torres has managed projects across a broad range of practice areas such as competitive intelligence, market research, and strategic advisory.. 威尔·托雷斯是生命科学动态公司的顾问。他拥有超过六年的生命科学咨询经验，涉足广泛的治疗领域，包括肿瘤学、罕见病和传染病。托雷斯管理过涉及多个实践领域的项目，如竞争情报、市场研究和战略咨询。Kasia Koczula is an engagement manager at Lifescience Dynamics, bringing over eight years of consulting experience in the life sciences sector. She holds a PhD in Haematological Oncology and has worked across a broad range of therapy areas, including oncology, cardiovascular diseases, and rare diseases. 卡西亚·科祖拉是生命科学动态公司的参与经理，拥有八年以上生命科学领域的咨询经验。她持有血液肿瘤学博士学位，并在包括肿瘤学、心血管疾病和罕见疾病在内的广泛治疗领域工作过。Koczula specialises in competitive intelligence, market research, and strategic advisory services, supporting clients with evidence-based insights to drive informed decision-making.. 科丘拉专注于竞争情报、市场研究和战略咨询服务，为客户提供基于证据的洞察，以推动明智的决策制定。

Celcuity公司日前公布其进行中3期VIKTORIA-1临床试验的最新积极结果。该试验评估其在研广谱PI3K/mTORC1/2抑制剂gedatolisib组合在接受过CDK4/6抑制剂及芳香化酶抑制剂治疗后疾病进展的激素受体阳性（HR+）、HER2-晚期乳腺癌患者中的疗效与安全性。根据此积极结果，Celcuity已启动该疗法的新药申请（NDA）滚动递交。 针对PIK3CA野生型（WT）亚群分析的结果显示，与活性对照药物相比，gedatolisib、palbociclib、fulvestrant三联方案使疾病进展或死亡风险降低76%，中位无进展生存期（PFS）达到9.3个月，而对照组仅为2.0个月，延长了7.3个月（HR=0.24，95% CI：0.17-0.35，p<0.0001）；客观缓解率为31.5%，中位缓解持续时间（DOR）为17.5个月。 同时，gedatolisib联合fulvestrant的双联方案亦展现显著疗效，使疾病进展或死亡风险降低67%，中位无进展生存期为7.4个月，相较于活性对照药物的2.0个月延长5.4个月（HR=0.33，95% CI：0.24-0.48，p<0.0001）。双联组的客观缓解率为28.3%，中位DOR为12.0个月，而对照组因仅有一例客观缓解，未能确定DOR。根据新闻稿，gedatolisib为在接受过CDK4/6抑制剂治疗后出现疾病进展的HR+/HER2-/PIK3CA WT晚期乳腺癌患者中，在3期研究中取得积极结果的首个PI3K/AKT/mTOR通路抑制剂。 参考资料： [1] Celcuity Provides Update on Status of the PIK3CA Mutated Cohort of Phase 3 VIKTORIA-1 Trial and Releases Additional Data Analysis From Phase 1b Clinical Trial. Retrieved October 18, 2025 from https://ir.celcuity.com/press-releases/ 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，传递医学新知