Fruquintinib

点击上方蓝字 关注我们编者按：抗HER2治疗是HER2高表达（IHC 3+或IHC 2+且FISH+）晚期胃癌患者的治疗基石，近年来抗HER2联合免疫一线治疗进一步改善了患者预后，而新型HER2 ADC进一步增加了后线治疗的选择，但二线治疗仍存在抗HER2治疗空白。在2025年BOC/BOA大会的胃癌专场上，北京大学肿瘤医院彭智教授分享了近期ASCO大会的最新研究进展，并在接受《肿瘤瞭望》的采访中，进一步介绍了晚期胃癌的治疗现状，以及新型药物将如何填补治疗空白和改变临床治疗格局。01《肿瘤瞭望》：化疗、免疫、抗HER2治疗等为晚期胃癌患者构筑了一线治疗防线。但对于治疗失败的患者，二线及后线治疗仍存在哪些未被满足的临床治疗需求？彭智 教授北京大学肿瘤医院近年来，靶向治疗、免疫检查点抑制剂（ICIs）、抗体偶联药物（ADCs）等构筑了新的晚期胃癌治疗格局。新版CSCO胃癌指南按照HER2高、中、低/不表达进行分层治疗。在晚期一线治疗中，抗HER2＋免疫已成为HER2高表达的治疗标准，HER2中/低/不表达患者则选择化疗，或基于PD-L1、Claudin18.2表达选择免疫或靶向联合化疗；二线治疗中，无论HER2表达状态如何，以紫杉醇联合抗VEGFR靶向治疗或单独化疗为主，dMMR/MSI-H患者可选择免疫治疗；在三线治疗中，德曲妥珠单抗（T-DXd）、维迪西妥单抗（RC48）是HER2高表达患者的优选方案，HER2中表达患者选择RC48，而HER2低/不表达患者以单药抗VEGFR靶向治疗、免疫治疗为主[1]。由此可见，在当前的晚期胃癌治疗格局中，二线抗HER2治疗实际上仍然是空白的。表1. 2025版CSCO胃癌晚期治疗I级推荐[1]一线治疗HER2高表达HER2中/低/不表达·PD-L1 CPS≥1分：免疫＋曲妥＋化疗·PD-L1 CPS＜1分：曲妥＋化疗·根据PD-L1 CPS或TAP水平选择化疗联合免疫治疗；·Claudin18.2表达患者选择化疗联合佐妥昔单抗；·奥沙利铂/顺铂＋氟尿嘧啶类或氟尿嘧啶类＋紫杉类二线治疗HER2高表达HER2阴性dMMR/MSI-H，无论HER2状态·紫杉醇联合雷莫西尤单抗；·单药化疗·紫杉醇联合雷莫西尤单抗；·单药化疗恩沃利单抗等免疫治疗三线治疗HER2高表达HER2中表达HER2低/不表达·德曲妥珠单抗；·维迪西妥单抗·维迪西妥单抗·阿帕替尼；·纳武利尤单抗单药另一方面，在当前紫杉醇联合抗VEGFR二线治疗（不区分HER2状态）的大型III期临床试验中，尽管有一致的无进展生存期（PFS）改善，但总生存期（OS）获益有所差异；而针对HER2阳性患者，曲妥珠单抗跨线治疗的PFS和OS、客观缓解率（ORR）均无获益[2-5]。因此，亟需为晚期胃癌患者寻找新的二线治疗方案，满足患者更多的治疗需求，尤其需要进一步填补二线抗HER2治疗的空白。表2.已报道晚期胃癌二线治疗III期研究（非头对头比较，请谨慎解读）[2-5]_RAINBOW研究（N=665）Rainbow-Asia研究（N=440）FRUTIGA研究（N=703）T-ACT研究（N=91）治疗方案雷莫西尤单抗±紫杉醇（不区分HER2状态）呋喹替尼±紫杉醇（不区分HER2状态）曲妥珠单抗±紫杉醇（HER2+）中位OS（月）9.6 vs 7.4，HR 0.80，P=0.0178.71 vs 7.92，HR 0.963，P=0.74269.6 vs 8.4，HR 0.96，P=0.606410.2 vs 10.0，HR 1.23中位PFS（月）4.4 vs 2.9，HR 0.635 ，P＜0.00014.14 vs 3.15，HR 0.714 5.6 vs 2.7，HR 0.57，P＜0.00013.7 vs 3.2，HR 0.91；P=0.3ORR28% vs 16%，P=0.000126.5% vs 21.9%42.5% vs 22.4%，P＜0.000132% vs 33%，P=1.0002《肿瘤瞭望》：您在本次BOC/BOA大会上，介绍了近期ASCO大会报道的新型HER2 ADC二线治疗的DESTINY-Gastric-04（DG-04）研究。您如何评价该研究结果及其可能对临床实践产生的影响？彭智 教授北京大学肿瘤医院T-DXd是新一代靶向HER2的抗体偶联药物（ADC），具有高药物抗体比、旁观者效应、循环稳定等药物机制优势，使其显示出高效低毒的药物特征，在众多实体瘤领域取得了突破性进展。在晚期胃癌领域，既往报道的DG-01、06研究已改变临床实践，T-DXd成为HER2高表达晚期胃癌患者的≥3线治疗标准[1]；而在欧美国家开展的II期DG-02研究[6]显示T-DXd在HER2高表达晚期胃癌二线治疗中具有巨大的应用潜力，大家对T-DXd能否进一步改变二线治疗格局充满期待。DG-04是一项全球多中心、III期随机对照临床试验[7]，纳入了494例接受过曲妥珠单抗治疗进展的晚期HER2阳性（IHC 3+或IHC 2+/ISH+）胃及胃食管结合部腺癌患者，随机（1:1）接受T-DXd或雷莫西尤单抗＋紫杉醇（RAM＋PTX）治疗。中国研究者和患者也为该研究贡献了重要的数据，有将近20%的入组患者来自中国或其他地区（两组各49例）。此次ASCO大会报道的中期分析数据显示达到了主要终点，T-DXd组患者的中位OS达到了14.7个月，相较于RAM＋PTX组延长3.3个月（14.7 vs 11.4个月），死亡风险显著降低30%（HR 0.70，95%CI：0.55-0.90，P=0.0044）。值得注意的是，RAM＋PTX组有25.8%的患者后续接受了HER2 ADC治疗，其中21.0%的患者接受了T-DXd后续治疗。在删除后续治疗影响后，T-DXd组相较于RAM＋PTX组的死亡风险降低幅度扩大至36%（HR 0.64，95%CI：0.44-0.93）。图1. DG-04研究主要终点OS结果（上）及其亚组分析（下）在次要终点方面也显示了T-DXd的全面获益：T-DXd组患者的中位PFS显著延长，疾病进展或死亡风险显著降低26%（6.7 vs 5.6个月，HR 0.74，95%CI：0.59-0.92，P=0.0074）；ORR显著提高15.2%（44.3% vs 29.1%，P=0.0006）；疾病控制率（DCR）提高16%（91.9% vs 75.9%）中位持续缓解时间（DoR）延长2.1个月（7.4 vs 5.3个月）。此外，T-DXd的安全性良好，不良事件可管可控，其≥3级的治疗期间不良事件（TEAEs）（68.0% vs 73.8%）、严重TEAEs（41.0% vs 43.3%）发生率均低于RAM＋PTX组；且耐受良好，导致停药、剂量中断、减剂量的TEAEs发生率均低于RAM＋PTX组。T-DXd的不良事件谱与既往报道一致，主要表现为中性粒细胞减少、贫血、白细胞减少等血液毒性，总体上低于或相近于RAM＋PTX组（图2）。图2. DG-04研究安全性汇总（上）及不良事件谱（下）从上述研究结果可见，T-DXd用于晚期胃癌二线治疗，相较于当前标准方案具有显著的生存获益改善和疗效提升，且表现了出色的治疗安全性和耐受性。如前所述，当前胃癌晚期二线治疗并没有抗HER2治疗方案，而是使用抗VEGFR联合化疗。DG-04研究的成功，无疑将填补这一治疗空白。03《肿瘤瞭望》：展望未来，您认为新型HER2 ADC还有哪些重要的研究方向，有望如何进一步改变临床实践？彭智 教授北京大学肿瘤医院新型HER2 ADC正在改变晚期胃癌的治疗格局，未来有望进一步向前拓展。在晚期胃癌一线治疗领域，我们知道基于KEYNOTE-811研究[8]，“靶免化”（帕博利珠单抗＋曲妥珠单抗＋FP或CAPOX）联合方案已被临床广泛应用。基于HER2 ADC的联合治疗能否进一步革新晚期一线治疗标准？目前，T-DXd±帕博利珠单抗＋氟尿嘧啶或卡培他滨的DG-05研究[9]以及HER2双特异性抗体Zanidatamab±替雷利珠单抗＋化疗的HERIZON-GEA-01研究[10]等晚期胃癌一线治疗的III期临床试验正在开展中，国内外也有其他HER2 ADC向晚期一线治疗发起冲刺，期待未来能够进一步取得阳性结果并改变临床实践。△III期DG-05研究设计此外，ADC、靶向和免疫治疗药物的研发也在不断升级中，尤其双靶点的单克隆抗体显示了巨大的应用潜力。ARTEMIDE-Gastric01研究[11]将探索T-DXd联合氟尿嘧啶以及PD-1/TIGIT双特异性抗体Rilvegostomig方案，用于HER2高表达及PD-L1 CPS≥1的晚期胃癌一线治疗的疗效和安全性，有望提供新的胃癌精准治疗方案。除了HER2以外，胃癌治疗靶点变得越来越丰富，包括Claudin18.2、MET、EGFR或FGFR2等均有新的研究进展，例如FGFR2b抑制剂贝玛妥珠单抗联合mFOLFOX6用于晚期胃癌一线治疗的III期FORTITUDE-101研究已经于近期宣布达到主要研究终点[12]。随着可治疗靶点的增加，不同靶点共表达的患者应该如何选择精准治疗策略？也是未来值得进一步探索的问题。参考文献上下滑动查看更多内容[1]中国临床肿瘤学会（CSCO）指南工作委员会.CSCO胃癌诊疗指南.人民卫生出版社.2025年4月.[2]Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. doi:10.1016/S1470-2045(14)70420-6[3]Xu RH, Zhang Y, Pan H, et al. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021;6(12):1015-1024. doi:10.1016/S2468-1253(21)00313-7Wang F, Shen L, Guo W, et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med. 2024;30(8):2189-2198. doi:10.1038/s41591-024-02989-6[4]Wang F, Shen L, Guo W, et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med. 2024;30(8):2189-2198. doi:10.1038/s41591-024-02989-6[5]Makiyama A, Sukawa Y, Kashiwada T, et al. Randomized, Phase II Study of Trastuzumab Beyond Progression in Patients With HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: WJOG7112G (T-ACT Study). J Clin Oncol. 2020;38(17):1919-1927. doi:10.1200/JCO.19.03077[6]Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023 Jun 14:S1470-2045(23)00215-2.[7]Shitara K, Gumus M, Pietrantonio F, et al. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study.2025 ASCO.LBA4002.[8]Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402(10418):2197-2208. doi:10.1016/S0140-6736(23)02033-0[9]Kohei Shitara, et al.An open-label, randomized, multicenter, phase 3 study of trastuzumab deruxtecan (T-DXd) + chemotherapy (chemo) ± pembrolizumab (pembro) versus chemo + trastuzumab ± pembro in first-line metastatic HER2+ gastric or gastroesophageal junction (GEJ) cancer: DESTINY-Gastric05.ASCO 2025;TPS4207[10]Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Future Oncol. 2022 Sep;18(29):3255-3266.[11]ruihua Xu, et al.ARTEMIDE-Gastric01: A phase 3 randomized study of rilvegostomig with fluoropyrimidine and trastuzumab deruxtecan (T-DXd) as first-line (1L) treatment for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer (GC/GEJC).ASCO 2025;TPS4204[12]https://investors.amgen.com/news-releases/news-release-details/amgen-announces-positive-topline-phase-3-results-bemarituzumab彭智 教授博士，博士生导师北京大学肿瘤医院主任医师北京大学博雅青年学者国家级青年人才项目获得者中国抗癌协会胃癌专委会委员中国抗癌协会肿瘤转移专委会委员中国抗癌协会肿瘤精准治疗委员会委员CSCO胃癌专家委员会委员兼秘书CSCO肿瘤营养治疗专家委员会委员中国免疫学会临床免疫分会委员北京癌症防治学会消化道精准治疗专委会副主任委员北京癌症防治学会胃癌防治专委会秘书长《中华医学杂志》《肿瘤综合治疗电子杂志》编委获得中华医学会一等奖、中国抗癌协会青年科学家奖、中国抗癌协会一等奖等（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。

The new survey results echo similar findings from a recent Takeda-sponsored survey of U.S. adults with metastatic colorectal cancer, which found that about two-thirds wished they had more power in the treatment process. A new survey from Takeda due to be presented at the ESMO Gastrointestinal Cancers Congress in Spain this week highlights major gaps in the treatment experiences of people with metastatic colorectal cancer.The survey, commissioned by Takeda—which sells colorectal cancer drug Fruzaqla—and conducted by The Harris Poll, included more than 800 adult colon cancer patients across Europe and Canada.The vast majority of patients surveyed were either actively undergoing treatment or deciding on a treatment plan. To improve the entire treatment experience, many in the group said they’d like to better understand their diagnosis and treatment options.Also negatively impacting the treatment experience is the survey’s finding that nearly two-thirds of the patients reported feeling unheard or dismissed by their healthcare providers (HCPs) at least some of the time. As a possible solution, about half of the respondents said they’d like to have more non-medical conversations with their HCPs—about their quality of life and how to manage daily experiences, for example—and many said they’d also prefer to have access to a wider range of healthcare services.Beyond HCP interactions, the surveyed patients named several other factors that play a major role in their treatment decisions: potential side effects, impact on physical health or quality of life and fear of becoming a burden on loved ones.They cited about a dozen groups and resources that provide guidance in making those decisions. Friends and family ranked highest among the European respondents, while the Canadian patients pointed to their oncologists; other prominent influences include caregivers, social media, fellow colon cancer patients and internet searches.Only about a quarter of all respondents said patient organization resources helped provide guidance in making treatment decisions; the survey’s authors noted that this indicates that such organizations “seem to remain underutilized.” The new survey results echo similar findings from a recent Takeda-sponsored survey of U.S. adults with metastatic colorectal cancer, which found that about two-thirds wished they had more power in the treatment process and that only a small percentage of patients relied on patient groups for decision-making support—though about 20% said they were looking for more support from advocacy groups.The expansion of the survey to Canada and Europe “underscores our commitment to addressing patient needs worldwide,” Annarita Egidi, head of Takeda’s Europe and Canada oncology business unit, said in a statement sent to Fierce Pharma Marketing.“The survey findings emphasize the importance of holistic care, as many patients seek more comprehensive conversations that address their overall quality of life,” she continued. “The data also revealed the crucial role of support networks, such as family, friends and patient organizations, in influencing treatment choices. While a significant number of patients reported feeling unheard at times, we see this as an opportunity to enhance communication and ensure that every patient feels valued and understood.”