Paclitaxel

TOKYO, Japan & BASKING RIDGE, NJ, USA I May 31, 2025 I Positive results from the DESTINY-Gastric04 phase 3 trial showed ENHERTU ® (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared to ramucirumab plus paclitaxel in patients with second-line HER2 positive (IHC 3+ or IHC 2+/ISH+) unresectable and/or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Results will be presented today as a late-breaking oral presentation ( LBA #4002 ) at the 2025 American Society of Clinical Oncology (#ASCO25) Annual Meeting and simultaneously published in The New England Journal of Medicine . 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/Nasdaq: AZN). In the primary endpoint analysis of OS, ENHERTU reduced the risk of death by 30% versus ramucirumab plus paclitaxel (hazard ratio [HR]: 0.70; confidence interval [CI]: 0.55-0.90; p=0.0044). Median OS was 14.7 months with ENHERTU (n=246) versus 11.4 months with ramucirumab plus paclitaxel (n=248). In the secondary endpoint analysis of progression-free survival (PFS), ENHERTU demonstrated a 26% reduction in the risk of disease progression or death versus ramucirumab plus paclitaxel (HR: 0.74; 95% CI: 0.59-0.92; p=0.0074) as assessed by investigator. Median PFS was 6.7 months with ENHERTU versus 5.6 months with ramucirumab plus paclitaxel. A confirmed objective response rate (ORR) of 44.3% (95% CI: 37.8-50.9) was seen in patients treated with ENHERTU with seven complete responses (CR) and 97 partial responses (PR) versus an ORR of 29.1% (95% CI: 23.4-35.3) with three CRs and 66 PRs in the ramucirumab plus paclitaxel arm (p=0.0006). Median duration of response (DOR) was 7.4 months (95% CI: 5.7-10.1) in the ENHERTU arm and 5.3 months (95% CI: 4.1-5.7) in the ramucirumab plus paclitaxel arm. Disease control rate (DCR) was 91.9% (95% CI: 87.7-95.1) with ENHERTU versus 75.9% (95% CI: 70.0-81.2) with ramucirumab plus paclitaxel. Improvements in OS and PFS with ENHERTU were consistent across subgroups. “Gastric cancer is particularly challenging to treat, especially in the advanced stages where the five-year survival rate remains low,” said Kohei Shitara, MD, Chief, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan and lead investigator in the DESTINY-Gastric04 trial. “The superior overall survival demonstrated in DESTINY-Gastric04 confirms that ENHERTU could become the global standard of care in the second-line metastatic setting of HER2 positive gastric cancer or gastroesophageal junction cancer.” The safety profile of ENHERTU in DESTINY-Gastric04 was consistent with previous gastric cancer clinical trials with no new safety concerns identified. The most common grade 3 or higher treatment related adverse events occurring in patients treated with ENHERTU were neutropenia (28.7%), anemia (13.9%), thrombocytopenia (8.6%), leukopenia (7.4%) and fatigue (7.0%). Interstitial lung disease (ILD) or pneumonitis occurred in 13.9% of patients treated with ENHERTU and 1.3% treated in the ramucirumab plus paclitaxel arm. In the ENHERTU arm, the majority of ILD or pneumonitis events were low grade (grade 1 [n=7; 2.9%] or grade 2 [n=26; 10.7%]) except for one grade 3 ILD event (0.4%) as determined by an independent adjudication committee. In the ramucirumab plus paclitaxel arm, there were two grade 3 (0.9%) and one grade 5 (0.4%) ILD events. “ENHERTU continues to deliver impressive results with these new data from DESTINY-Gastric04, which represent the first time a HER2 directed medicine has demonstrated a survival benefit in a randomized phase 3 trial in the second-line HER2 positive metastatic gastric cancer setting,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “Similar to our strategy in other tumor types, we continue to pursue the development of ENHERTU in earlier stages of gastric cancer and have recently initiated phase 3 trials evaluating ENHERTU as part of a combination regimen as a first-line treatment in patients HER2 positive metastatic disease.” “Patients with HER2 positive metastatic gastric cancer who experience progression after first-line treatment have historically faced poor outcomes,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “These results showed that ENHERTU reduced the risk of death by nearly one-third in patients with previously treated HER2 positive metastatic gastric cancer, reinforcing the benefit of ENHERTU in this setting.” ENHERTU is currently approved in more than 70 countries in the second-line or third-line metastatic setting of HER2 positive gastric cancer based on DESTINY-Gastric01 , a randomized phase 2 trial, and DESTINY-Gastric02 and DESTINY-Gastric06 , two single-arm phase 2 trials. Daiichi Sankyo and AstraZeneca are currently evaluating ENHERTU in the first-line metastatic setting through the DESTINY-Gastric05 and ARETEMIDE-Gastric01 phase 3 trials. The majority of patients in the DESTINY-Gastric04 trial had received no prior treatment with an immune checkpoint inhibitor (84.1% in the ENHERTU arm and 84.7% in the ramucirumab plus paclitaxel arm) and had two or more metastatic sites (70.3% in the ENHERTU arm and 69.8% in the ramucirumab plus paclitaxel arm). Median duration of follow-up was 16.8 months in the ENHERTU arm and 14.4 months in the ramucirumab plus paclitaxel arm. Median treatment duration was 5.4 months (range: 0.7-30.3) with ENHERTU and 4.6 months (range: 0.9-34.9) with ramucirumab plus paclitaxel. Of the patients that discontinued treatment from the ramucirumab plus paclitaxel arm, 52 (21.0%) proceeded to receive ENHERTU and 12 (4.8%) disitamab vedotin post-trial. As of the data cut-off of October 24, 2024, 18.9% of patients receiving ENHERTU and 18.5% receiving ramucirumab plus paclitaxel remained on study treatment. Summary of DESTINY-Gastric04 Primary Analysis Results About DESTINY-Gastric04 DESTINY-Gastric04 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (6.4 mg/kg) versus ramucirumab and paclitaxel in patients with HER2 positive (IHC 3+ or IHC 2+/ISH+) unresectable and/or metastatic gastric or GEJ adenocarcinoma with disease progression on or after a trastuzumab-containing regimen. The primary endpoint is OS. Secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate and safety. In March 2025, an Independent Data Monitoring Committee recommended unblinding DESTINY-Gastric04 based on the superior efficacy of ENHERTU seen at a planned interim analysis. DESTINY-Gastric04 enrolled 494 patients in Asia, Europe and South America. For more information about the trial, visit ClinicalTrials.gov . About HER2 Positive Gastric Cancer Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth leading cause of cancer-related death. 1 Approximately one million cases of gastric cancer were diagnosed in 2022. 1 Gastric cancer is associated with a poor prognosis, particularly in advanced stages of the disease where the five-year survival rate is 5% to 10%. 2 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including gastric cancer. 3 Approximately one in five gastric cancers are considered HER2 positive. 3,4 Prior to the results of the DESTINY-Gastric04 trial of ENHERTU, no other HER2 directed medicine has demonstrated a survival benefit in the second-line metastatic setting in a randomized clinical trial. 5 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) is approved in more than 80 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (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 80 countries 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 30 countries 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 has 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 60 countries 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 70 countries 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-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (5.4 mg/kg) is approved in Brazil, Israel, Russia, Saudi Arabia, Taiwan, U.K. and the U.S. 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 anti-cancer therapies 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 seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and DATROWAY, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide . 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 www.daiichisankyo.com . SOURCE: Daiichi Sankyo

点击上方蓝字 关注我们编者按：2025年5月26日，中国医科大学附属第一医院徐莹莹教授、辽宁省肿瘤医院张强教授、陆军军医大学第二附属医院朱波教授联合团队在Nature旗下的Signal Transduction and Targeted Therapy（STTT）发表2期TREND研究成果。该研究首次证实替雷利珠单抗联合无铂、低剂量的白蛋白紫杉醇序贯表柔比星/环磷酰胺（NabP-EC）方案用于三阴性乳腺癌（TNBC）新辅助治疗，具有良好的疗效反应和可控的安全性，为规避铂类毒性同时保持疗效提供全新策略。与此同时，该研究还进行了多组学的生物标志物探索性分析，可为TNBC新辅助免疫治疗的精准筛选提供参考。三阴性乳腺癌（TNBC）因缺乏治疗靶点，复发转移风险高，预后较差。尽管既往的KEYNOTE-522和IMpassion-031研究显示，新辅助免疫检查点抑制剂（ICI）可相较于化疗提高病理完全缓解（pCR）率，并延长生存，但配伍化疗方案的优化及获益人群的筛选仍亟待探索。铂类是目前配伍新辅助免疫治疗的主流化疗药物，但其严重的骨髓抑制作用可能因破坏机体固有免疫而影响免疫治疗疗效。探索平衡疗效与安全性的化疗配伍方案，并精准预测免疫治疗响应、锁定免疫治疗敏感人群，成为破局的关键。这项前瞻性、单臂、单中心、2期临床试验TREND，纳入患者为淋巴结阳性或至少T2的未治疗TNBC，所有患者均接受了替雷利珠单抗（PD-1抑制剂）新辅助免疫治疗，联合无铂、低剂量新辅助化疗方案治疗，即白蛋白-紫杉醇序贯表柔比星/环磷酰胺（NabP-EC方案）。主要终点为病理完全缓解（pCR），次要终点包括客观缓解率（ORR）和安全性。研究还对治疗前、后的肿瘤样本进行批量RNA测序、单细胞RNA测序、T细胞受体测序、全外显子测序及质谱流式细胞术分析。疗效分析在44例可评估疗效的患者中，30例（68.18%）达到了pCR，其中14例（31.82%）达到了完全缓解（CR），ORR为93.18%，显示出显著的疗效。此外，研究还观察到，高PD-L1表达水平与更好的病理反应相关，PD-L1 CPS≥20组pCR率达89.47%（见下图b）。安全性分析在安全性方面，90.57%（48/53）的患者经历了至少一次治疗相关不良事件（TRAEs），其中11.32%（6/53）为≥3级不良事件，包括肝损伤和中性粒细胞缺乏。最常见的免疫相关不良反应是甲减和甲亢。新辅助治疗前的基因表达谱pCR（病理完全缓解）和非pCR患者新辅助治疗前的基因表达存在差异。非pCR患者中的脂质代谢相关基因（如FABP3和ACOX2）表达增加，而pCR患者中的GABRP、NECTIN4和CADM4基因表达升高。此外，pCR患者中的免疫相关通路呈富集状态。研究人员进一步通过分析新辅助免疫治疗前（C0期）的样本，识别了pCR和非pCR患者之间的三个差异表达基因（DEGs），并构建了一个预测模型。该模型能够显著区分pCR和非pCR患者，并预测新辅助免疫联合化疗的疗效（AUC 0.876；验证队列中的AUC为0.861）。肿瘤微环境（TME）动态变化在pCR患者中，治疗前后基因表达发生了显著变化，有1160个基因上调和1007个基因下调。相比之下，非pCR患者的变化较小，只有112个基因上调和131个基因下调。研究还发现Ki-67基因表达可预测疗效，一周期治疗后Ki-67基因表达的减少超过30%与更高的pCR率相关，95%的患者达到了pCR，这一比例显著高于Ki-67减少不足30%的患者（53.33%）。此外，在pCR患者中，免疫相关通路在治疗早期（第一周期后）即显著激活，而在非pCR患者中，这些通路激活较晚。研究人员通过聚类分析，发现与pCR相关的聚类在治疗后显示出T细胞激活、淋巴细胞增殖和相关免疫功能的激活特征。pCR和非pCR患者CD8 T淋巴细胞的转录和克隆多样性研究发现，非pCR患者中CD8 T淋巴细胞和巨噬细胞的富集增加，而pCR患者中成纤维细胞富集。其中，高表达CDKN1A的CD8 T淋巴细胞（CDKN1A+ CD8 T淋巴细胞）在pCR患者的原发病灶和淋巴结中富集，可能在ICIs治疗反应中发挥关键作用。因此，研究人员构建了CDKN1A+ CD8 T淋巴细胞评分的治疗指数，并分析了该评分与新辅助免疫治疗反应的关系。结果显示，pCR组中CDKN1A+ CD8 T淋巴细胞的富集，表明新辅助tislelizumab可能通过提高这些细胞的数量来增强免疫反应。此外，研究评估了转移性淋巴结和原发肿瘤中CD8 T淋巴细胞的克隆关系差异。在pCR患者中，淋巴结中TCR多样性增加，克隆性降低，这可能有助于免疫治疗的反应。总之，这项2期TREND研究显示，替雷利珠单抗联合白蛋白结合型紫杉醇及蒽环类为基础的新辅助免疫联合无铂、低剂量化疗方案在早期TNBC患者中具有良好的疗效和可控的安全性。这一发现为早期TNBC的新辅助治疗提供了新的选择。此外，该研究还揭示了可能的生物标志物和免疫细胞亚群，通过PD-L1 CPS、Ki-67动态变化及CDKN1A+ CD8 T淋巴细胞实现精准分层，为未来的个体化治疗提供了线索。▌参考文献：[1] Zhang Q, Wang M, Li Y, Zhang H, Wang Y, Chen X, Yao L, Cui M, Dong H, Li X, Liu J, Zhu B, Xu Y. Efficacy, safety and exploratory analysis of neoadjuvant tislelizumab (a PD-1 inhibitor) plus nab-paclitaxel followed by epirubicin/cyclophosphamide for triple-negative breast cancer: a phase 2 TREND trial. Signal Transduct Target Ther. 2025 May 26;10(1):169. doi: 10.1038/s41392-025-02254-3. PMID: 40414961.[2] Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549[3] Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X（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。↙点击阅读原文，查看文献全文