Raludotatug deruxtecan

Based on DESTINY-Breast05 phase 3 trial results, which showed ENHERTU reduced the risk of invasive disease recurrence or death by 53% compared to T-DM1 If approved, Daiichi Sankyo and AstraZeneca’s ENHERTU has the potential to become a new standard of care in this early breast cancer setting TOKYO & MUNICH--(BUSINESS WIRE)--The European Medicines Agency (EMA) has validated the Type II Variation marketing authorization application for ENHERTU ® (trastuzumab deruxtecan) as a monotherapy for adult patients with HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization [ISH]+) breast cancer who have residual invasive disease after neoadjuvant HER2 targeted treatment. ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/NYSE: AZN). The validation confirms the completion of the application and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The application is based on data from the DESTINY-Breast05 phase 3 trial presented at the 2025 European Society for Medical Oncology (#ESMO25) Congress and subsequently published in The New England Journal of Medicine . In the trial, ENHERTU demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (IDFS) versus trastuzumab emtansine (T-DM1) in patients with HER2 positive breast cancer with residual invasive disease following neoadjuvant therapy. “Patients who have residual invasive disease despite neoadjuvant therapy face a heightened risk of recurrence and are in need of better options following neoadjuvant treatment and surgery,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “This validation in the EU is an important step toward bringing ENHERTU to eligible patients earlier in the treatment journey to help reduce the risk of disease recurrence and progression to metastatic disease.” Additional regulatory submissions for ENHERTU also are underway in the EU, including in combination with pertuzumab for the first-line treatment of adult patients with unresectable or metastatic HER2 positive breast cancer based on data from DESTINY-Breast09 and for previously treated HER2 positive unresectable or metastatic solid tumors based on data from DESTINY-PanTumor02 , DESTINY-CRC02 and DESTINY-Lung01 . About DESTINY-Breast05 DESTINY-Breast05 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus T-DM1 in patients with HER2 positive early breast cancer with residual invasive disease in breast or axillary lymph nodes following neoadjuvant therapy and a high risk of recurrence. High risk of recurrence was defined as presentation with inoperable cancer (prior to neoadjuvant therapy) or pathologically positive axillary lymph nodes following neoadjuvant therapy. The primary endpoint of DESTINY-Breast05 is investigator-assessed IDFS, which is defined as the time from randomization until first invasive local, axillary or distant recurrence or death from any cause. The key secondary endpoint is investigator-assessed disease-free survival. Other secondary endpoints include overall survival, distant recurrence-free interval, brain metastases-free interval and safety. DESTINY-Breast05 enrolled 1,635 patients in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov . About Post Neoadjuvant Treatment for HER2 Positive Early Breast Cancer Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 1 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally. 1 In Europe, approximately 557,000 cases of breast cancer are diagnosed annually, with more than 144,000 deaths. 1 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast cancer. 2 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer. 2 Approximately one in five cases of breast cancer is considered HER2 positive. 3 For patients with HER2 positive early breast cancer, achieving pathologic complete response (pCR) with neoadjuvant treatment is the earliest indicator of improved long-term survival. 4 However, approximately half of patients who receive neoadjuvant treatment do not experience pCR, putting them at increased risk of disease recurrence. 5,6,7,8,9 Despite receiving additional treatment for residual disease in the post-neoadjuvant setting, some patients still experience invasive disease or death and current treatment options have shown limited impact on central nervous system recurrence. 10 Once patients are diagnosed with metastatic disease, the five-year survival rate drops from nearly 90% to approximately 30%. 11 Post-neoadjuvant therapy represents a key opportunity to minimize the risk of recurrence and prevent progression to metastatic disease for patients with residual disease. New treatment options are needed in the early breast cancer setting to help reduce the likelihood of disease progression and improve long-term outcomes for more patients. 12,13 About ENHERTU ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. ENHERTU (5.4 mg/kg) in combination with pertuzumab is approved in the U.S. as a first-line treatment for adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test, based on the results from the DESTINY-Breast09 trial. ENHERTU (5.4 mg/kg) is approved in more than 90 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU (5.4 mg/kg) is approved in more than 90 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. ENHERTU (5.4 mg/kg) is approved in more than 60 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial. ENHERTU (5.4 mg/kg) is approved in more than 70 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 ( ERBB2 ) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4 mg/kg) is approved in more than 80 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 , DESTINY-Gastric02 and/or DESTINY-Gastric04 trials. ENHERTU (5.4 mg/kg) is approved in more than 10 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02 , DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. About the ENHERTU Clinical Development Program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU as a monotherapy or in combination or sequentially with other cancer medicines across multiple HER2 targetable cancers. About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and DATROWAY ® in July 2020 , except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and DATROWAY. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of eight ADCs in clinical development crafted from ADC technology discovered in-house by Daiichi Sankyo. The DXd ADC Technology platform of Daiichi Sankyo consists of seven ADCs in clinical development where each ADC is comprised of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADCs include ENHERTU and DATROWAY, which are being jointly developed and commercialized globally with AstraZeneca, and ifinatamab deruxtecan (I-DXd), raludotatug deruxtecan (R-DXd) and patritumab deruxtecan (HER3-DXd), which are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939 and DS3790 are being developed by Daiichi Sankyo. An additional ADC being developed by Daiichi Sankyo is DS3610, which consists of an antibody attached to a novel payload that acts as an agonist of STING. Ifinatamab deruxtecan, raludotatug deruxtecan, patritumab deruxtecan, DS-3939, DS3610 and DS3790 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit . ________________________________ References 1 World Health Organization. Breast Fact Sheet . Accessed February 2026. 2 Cheng X, et al. Genes . 2024;15(7):903. 3 Tarantino P, et al. Ann Oncol . 2023;34(8):645-659. 4 Spring LM, et al. Clin Cancer Res . 2020;26(12):2838-2848. 5 Schneeweiss A, et al. Ann Oncol . 2013;24(9):2278-2284. 6 Swain SM, et al. Ann Oncol . 2018;29(3):646-653. 7 Huober J, et al. J Clin Oncol . 2022;40(25):2946-2956. 8 Masuda N, et al. Breast Cancer Res Treat . 2020;180(1):135-146. 9 Gao HF, et al. Presented at ASCO Annual Meeting 2025. 10 Geyer CE, et al. N Engl J Med . 2025;392(3):249-257. 11 National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer. Accessed February 2026. 12 von Minckwitz G, et al. N Engl J Med . 2019;380(7):617-628. 13 Zaborowski AM and Wong SM. BJS . 2023;110(7):765-772. Contacts Media Contacts: Global: Jennifer Brennan Daiichi Sankyo, Inc. jennifer.brennan@daiichisankyo.com +1 908 900 3183 (mobile) EU: Simone Jendsch-Dowé Daiichi Sankyo Europe GmbH simone.jendsch-dowe@daiichisankyo.com +49 (89) 78080 (office) Japan: Daiichi Sankyo Co., Ltd. DS-PR_jp@daiichisankyo.com Investor Relations Contact: DaiichiSankyoIR_jp@daiichisankyo.com

点击蓝字 关注我们 妇科癌症涵盖卵巢癌、子宫内膜癌、宫颈癌以及外阴与阴道恶性肿瘤，是全球范围内重要的公共卫生挑战。本文重点梳理Nabil Ismaili在《Biomedicines》期刊发表的一篇综述，介绍2025年卵巢癌研究方面的最新进展，以期为同行提供参考。 2025年卵巢癌研究交付了妇科肿瘤学年度最具范式转变意义的进展：突破免疫疗法壁垒，并且新机制药物不断取得突破。 铂耐药复发性卵巢癌的里程碑 在ESMO 2025全体会议上报告的ENGOT-ov65/KEYNOTE-B96试验具有里程碑意义[1]。这项全球性、双盲、III期试验评估了帕博利珠单抗联合每周紫杉醇（研究者酌情可选加贝伐珠单抗）对比安慰剂联合每周紫杉醇（±贝伐珠单抗）在既往接受过1-2线治疗、铂耐药复发性卵巢癌患者中的疗效。双重主要终点是PD-L1 CPS≥1患者（约占643例ITT人群的75%）的无进展生存（PFS）和总生存（OS）。在第二次预设的中期分析（数据截止日期：2025年3月5日；中位随访26.6个月），该试验达到了两个终点。在PD-L1 CPS≥1人群中，帕博利珠单抗显著改善了PFS（中位8.3 vs. 7.2个月；HR=0.72；p=0.0014），并且显著改善了OS（中位18.2 vs. 14.0个月；HR=0.76；p=0.0053），这是卵巢癌中首个基于免疫检查点抑制剂方案产生统计学显著性的OS改善。生存获益同样可在ITT人群中观察到（中位OS 17.7 vs. 14个月；HR=0.81；p=0.0114）。安全性特征与各药物已知特征一致。该试验确立了帕博利珠单抗+每周紫杉醇作为铂耐药复发性卵巢癌的新治疗标准。 新治疗机制的药物展现强大活性 发表在《柳叶刀》上的ROSELLA/ENGOT-ov68试验采用一种新的生物学策略。这项III期试验比较了白蛋白结合型紫杉醇联合relacorilant（一种选择性糖皮质激素受体调节剂）与单用白蛋白结合型紫杉醇在铂耐药复发性卵巢癌患者中的疗效[2]。该联合方案显著改善了主要终点BICR评估的PFS（中位5.7 vs. 3.8个月；HR=0.70；p<0.0001），并在中期分析中显示出显著的OS获益（中位15.97 vs. 11.5个月；HR=0.69；p=0.012）[3]。这验证了糖皮质激素受体调节是克服化疗耐药的可行治疗策略。 抗体偶联药物（ADC）继续显示出非凡前景。II期REJOICE-Ovarian01试验评估了raludotatug deruxtecan（一种靶向钙粘蛋白-6的ADC）在铂耐药复发性卵巢癌患者中的疗效。2025 ESMO报告的剂量优化部分的初步分析显示，在107例重度经治患者（中位既往4线治疗）中，确认的客观缓解率（ORR）为50.5%，完全缓解率为7.5%，中位PFS为7.8个月。值得注意的是，在不同水平的CDH6表达中均观察到活性，表明CDH6是卵巢癌中极具前景的靶点。该药物用于进一步研发的剂量为5.6 mg/kg[4]。 一些早期试验也报告了其他新药。INCB123667（一种选择性CDK2抑制剂）的I期研究在晚期铂耐药和难治性卵巢癌患者中显示出初步疗效信号和可控的安全性特征，突显CDK2可能是克服耐药的另一个潜在靶点[5]。此外，Lee等人报告了一项帕博利珠单抗和乐伐替尼在复发性透明细胞卵巢癌中的II期试验结果，在这种以预后差和对化疗耐药而闻名的组织学亚型中，该方案的治疗活性值得进一步研究[6]。 完善一线和维持治疗 针对高风险III/IV期上皮性卵巢癌的III期ICON8B试验的长期随访提供了关于化疗强度的重要数据[7]。中位随访72个月，与标准三周一次紫杉醇/卡铂/贝伐珠单抗相比，剂量密集的每周紫杉醇联合三周一次卡铂/贝伐珠单抗显著改善了OS（中位OS 49.8 vs. 39.6个月；HR=0.79；p=0.01）。这强化了剂量密集型化疗在含贝伐珠单抗方案中对于特定高风险患者的作用。 在维持治疗方面，FIRST/ENGOT-OV44试验评估了dostarlimab（抗PD-1）联合尼拉帕利（PARP抑制剂）作为晚期卵巢癌的一线维持治疗方案[8]。根据ASCO 2025报告，该试验显示，与尼拉帕利单药相比，联合治疗显著改善了PFS，尤其是在同源重组缺陷（HRD）阳性肿瘤中，表明在前期维持治疗中，免疫疗法与PARP抑制剂联合具有协同效应。 FZOCUS-1试验研究了氟唑帕利联合或不联合阿帕替尼（一种VEGFR2抑制剂）作为一线维持治疗。发表在《临床肿瘤学杂志》上的研究显示，与安慰剂组相比，氟唑帕利联合阿帕替尼显著延长了PFS，提供了一种新的维持治疗策略。这种方案在那些因BRCA基因状态或既往使用过贝伐珠单抗而可能限制PARP抑制剂使用的患者群体中，尤其具有意义[9]。 关于创新的给药方法，OVATION-2试验提供了腹腔内IMNN-001（一种TLR8激动剂）联合新辅助化疗的更新生存分析，结果显示出激活晚期卵巢癌局部免疫微环境可产生良好效果。更新分析显示，IMNN-001联合新辅助化疗的中位PFS为14.9个月，而新辅助化疗单药为11.9个月；中位OS分别为46.0个月和33.0个月[10]。 综上，ENGOT-ov65/KEYNOTE-B96显示免疫疗法在铂耐药患者中产生明确的生存获益，可以说是2025年妇科肿瘤学最具范式转变意义的发现，因为卵巢癌被认为是“免疫学冷肿瘤”，多项免疫检查点抑制剂单药或联合化疗的试验均告失败。ROSELLA试验验证了一个全新的靶点——糖皮质激素受体。Raludotatug deruxtecan的显著活性表明CDH6是一个极具前景的ADC靶点。ICON8B的长期OS获益强化了剂量密集型化疗在靶向治疗时代仍然具有重要意义，特别是对于高风险患者。FIRST试验关于dostarlimab-尼拉帕利维持治疗的阳性结果创造了一种新的、可能具有协同作用的前线治疗选择，尤其是在HRD阳性疾病中。在透明细胞癌中探索帕博利珠单抗-乐伐替尼等组合，有助于解决这种疾病未满足的临床需求。 参考文献 （上下滑动可查看） 1. Colombo, N. et al. Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase III ENGOT-ov65/KEYNOTE-B96 study. Ann. Oncol. 2025, 36, LBA3. 2. Olawaiye, A. et al. ROSELLA: A Phase 3 Study of Relacorilant in Combination with Nab-Paclitaxel versus Nab-Paclitaxel Monotherapy in Patients with Platinum-Resistant Ovarian Cancer. J. Clin. Oncol. 2025, 43, LBA5507.  3. Olawaiye, A.B. et al. Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): An open-label, randomised, controlled, phase 3 trial. Lancet 2025, 405, 2205–2216.  4. Ray-Coquard, I.L. et al. LBA42 Raludotatug Deruxtecan (R-DXd) in Patients with Platinum-Resistant Ovarian Cancer: Primary Analysis of the Phase II Dose-Optimization Part of REJOICE-Ovarian01. Ann. Oncol. 2025, 36, S1585–S1586. 5. Damian, S. et al. Safety and Preliminary Efficacy from a Phase 1 Study of INCB123667, a Selective CDK2 Inhibitor, in Patients with Advanced Platinum-Resistant and Refractory Ovarian Cancer. J. Clin. Oncol. 2025, 43, 5514.  6. Lee, E.K. et al. A Phase II Trial of Pembrolizumab and Lenvatinib in Recurrent or Persistent Clear Cell Ovarian Carcinoma. J. Clin. Oncol. 2025, 43, 5515.  7. Clamp, A. et al. ICON8B: GCIG Phase III Randomised Trial Comparing First-Line Weekly Dose-Dense Chemotherapy + Bevacizumab to Three-Weekly Chemotherapy + Bevacizumab in High-Risk Stage III–IV Epithelial Ovarian Cancer: Final Overall Survival Analysis. Ann. Oncol. 2025, 36, 1064O.  8. Hardy-Bessard, A.-C. et al. FIRST/ENGOT-OV44: A Phase 3 Clinical Trial of Dostarlimab and Niraparib in First-Line Advanced Ovarian Cancer. J. Clin. Oncol. 2025, 43, LBA5506.  9. Wu, L. et al. Fuzuloparib with or without apatinib as maintenance therapy in newly diagnosed, advanced ovarian cancer (FZOCUS-1): A multicenter, randomized, double-blind, placebo-controlled phase 3 trial. CA Cancer J. Clin. 2026, 76, e70042.  10. Thaker, P.H. et al. A Phase I/II Study of the Safety and Efficacy of Intraperitoneal IMNN-001 in Combination with Neoadjuvant Chemotherapy of Paclitaxel and Carboplatin in Patients Newly Diagnosed with Advanced Epithelial Ovarian Cancer: Updated Survival Analysis from OVATION-2 Trial. J. Clin. Oncol. 2025, 43, 5516. （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息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，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。