AbstractThe combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment.

摘要三氟尿苷/盐酸替吡拉西（FTD/TPI）联合雷莫昔单抗治疗晚期胃癌（AGC）具有临床活性。我们评估了这种组合与FTD/TPI单药治疗AGC患者的疗效和安全性。我们回顾性分析了接受FTD/TPI加ramucirumab或FTD/TPI单药治疗作为三线或更晚期治疗的AGC患者的数据。

This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081).

这项研究包括36名接受FTD/TPI加ramucirumab治疗的患者和70名接受FTD/TPI单药治疗的患者。FTD/TPI加ramucirumab组的客观缓解率（ORR）和疾病控制率（DCR）分别为25.8%和58.1%，FTD/TPI组分别为5.0%和38.3%（ORR，P=0.007；DCR，P=0.081）。

The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030).

FTD/TPI加ramucirumab组的中位无进展生存期（PFS）显着延长（中位PFS，2.9比1.8个月；风险比[HR]：0.52；P=0.001）。还观察到数字生存获益（中位总生存期，7.9个月比5.0个月；HR:0.68，P=0.089）。在多变量分析中，FTD/TPI加ramucirumab组的PFS显着长于FTD/TPI单药治疗组（HR:0.61，P=0.030）。

The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC.

FTD/TPI加ramucirumab组发热性中性粒细胞减少症的发生率高于FTD/TPI组（13.8%比2.9%）；然而，没有发现新的安全信号。与FTD/TPI单一疗法相比，FTD/TPI加ramucirumab在严重预处理的AGC患者中具有可接受的毒性，具有临床益处。

Further investigation via randomized trials is warranted to confirm these findings..

有必要通过随机试验进行进一步调查，以证实这些发现。。

IntroductionGastric cancer is the fifth most common type of cancer and is the fourth-leading cause of cancer-related death1. Its incidence and mortality rates are notably high in East Asia. While systemic chemotherapy has prolonged survival of patients with advanced gastric cancer (AGC), median overall survival (OS) remains suboptimal2.

引言胃癌是第五大最常见的癌症类型，是癌症相关死亡的第四大原因1。它的发病率和死亡率在东亚特别高。虽然全身化疗延长了晚期胃癌（AGC）患者的生存期，但中位总生存期（OS）仍然不理想2。

Several chemotherapeutic agents such as trifluridine/tipiracil hydrochloride (FTD/TPI), irinotecan, nivolumab, and trastuzumab deruxtecan are beneficial as third- or later-line treatment for AGC3. Notably, in a large Japanese cohort study of 10,581 patients with AGC receiving palliative systemic chemotherapy, only 2390 patients (22.6%) underwent third-line chemotherapy4.

几种化学治疗剂如三氟尿苷/盐酸替吡拉西（FTD/TPI），伊立替康，nivolumab和曲妥珠单抗-德鲁替康作为AGC3的三线或更高线治疗是有益的。值得注意的是，在一项针对10581名接受姑息性全身化疗的AGC患者的大型日本队列研究中，只有2390名患者（22.6%）接受了三线化疗4。

This finding highlights the need for further developing treatment strategies in later lines of therapy.FTD/TPI is an oral medication comprising a nucleoside antitumor component, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. The TAGS trial of FTD/TPI demonstrated improvement in OS over placebo for heavily pretreated patients with AGC5.

这一发现强调了在以后的治疗方案中进一步开发治疗策略的必要性。FTD/TPI是一种口服药物，包含核苷抗肿瘤成分三氟尿苷和胸苷磷酸化酶抑制剂替吡拉西。FTD/TPI的TAGS试验表明，对于经过严重预处理的AGC5患者，OS优于安慰剂。

Preclinical data showed that the combination of FTD/TPI and bevacizumab, a specific angiogenesis inhibitor against vascular endothelial growth factor (VEGF)-A, enhanced antitumor effects compared with FTD/TPI alone6,7. Ramucirumab, an anti-VEGF-receptor 2 monoclonal antibody, is an established standard of care for AGC, as evidenced by the results of the REGARD and RAINBOW trials8,9.

临床前数据显示，与单独的FTD/TPI相比，FTD/TPI和贝伐单抗（一种针对血管内皮生长因子（VEGF）-a的特异性血管生成抑制剂）的组合增强了抗肿瘤作用6,7。Ramucirumab是一种抗VEGF受体2单克隆抗体，是AGC的既定护理标准，REGARD和RAINBOW试验的结果证明了这一点8,9。

Several single-arm phase II trials of FTD/TPI combined with ramucirumab exhibited promising antitumor activity and feasible safety profile in pretreated patients with AGC10,11.Nivolumab, an immune checkpoint inhibitor targeting programmed cell death-1 (PD-1), has been approved for the primary treatment of AGC and is widely used in clinical pr.

FTD/TPI联合ramucirumab的几项单臂II期临床试验在AGC10,11预处理患者中表现出有希望的抗肿瘤活性和可行的安全性。Nivolumab是一种靶向程序性细胞死亡-1（PD-1）的免疫检查点抑制剂，已被批准用于AGC的主要治疗，并广泛用于临床pr。

Data availability

数据可用性

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

本研究中使用和/或分析的数据集可根据合理要求从通讯作者处获得。

AbbreviationsAGC:

缩写AGC：

Advanced gastric cancer

进展期胃癌

CI:

CI公司：

Confidence interval

置信区间

DCR:

DCR:

Disease control rate

疾病控制率

ECOG PS:

ECOG PS：

Eastern Cooperative Oncology Group Performance Status

东部肿瘤协作组的绩效状况

FTD/TPI:

FTD/TPI：

Trifluridine/tipiracil hydrochloride

三氟啶/盐酸替吡拉西

HR:

人力资源部：

Hazard ratio

危险比

IFI:

IFI：

Anti-PD-1 inhibitor-free interval

抗PD-1无抑制剂间隔

LM:

LM公司：

Liver metastasis

肝转移

ORR:

ORR：

Objective response rate

客观回应率

OS:

操作系统：

Overall survival

总体生存率

PD-1:

PD-1：

Programmed cell death-1

程序性细胞死亡-1

PFS:

PFS：

Progression-free survival

无进展生存期

RECIST:

背诵者：

Response Evaluation Criteria in Solid Tumors

实体瘤的反应评估标准

VEGF:

VEGF：

Vascular endothelial growth factor

血管内皮生长因子

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Download referencesAcknowledgementsThe authors thank Editage (https://www.editage.jp) for English language editing. We also thank all the patients who participated in this study and their families.Author informationAuthor notesThese authors contributed equally: Yukiya Narita and Takatsugu Ogata.Authors and AffiliationsDepartment of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, JapanYukiya Narita, Takatsugu Ogata, Yasunobu Ishizuka, Tomoki Sakakida, Munehiro Wakabayashi, Hiroyuki Kodama, Kazunori Honda, Toshiki Masuishi, Hiroya Taniguchi, Shigenori Kadowaki, Masashi Ando & Kei MuroDepartment of Endoscopy, Aichi Cancer Center Hospital, Nagoya, JapanMasahiro TajikaAuthorsYukiya NaritaView author publicationsYou can also search for this author in.

下载参考文献致谢作者感谢编辑(https://www.editage.jp)用于英语编辑。我们还要感谢所有参与这项研究的患者及其家人。作者信息作者注意到这些作者做出了同样的贡献：成田由纪和绪方孝。作者和附属机构爱知癌症中心医院临床肿瘤学系，爱知名古屋市千草区1-1 Kanokoden，464-8681，日本成田县，绪方孝县，石冢靖县，坂田县友木市，木内弘市，小玉广行，本田和弘，Masuishi Toshiki，Taniguchi，Shigenori Kadowaki，Masashi Ando&Kei MuroDepartment of内窥镜检查，爱知癌症中心医院，名古屋，田正弘NaritaView作者出版物您也可以在中搜索此作者。

PubMed Google ScholarTakatsugu OgataView author publicationsYou can also search for this author in

PubMed Google ScholarTakatsugu OgataView作者出版物您也可以在

PubMed Google ScholarYasunobu IshizukaView author publicationsYou can also search for this author in

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PubMed Google ScholarTomoki SakakidaView author publicationsYou can also search for this author in

PubMed Google ScholarTomoki SakakidaView作者出版物您也可以在

PubMed Google ScholarMunehiro WakabayashiView author publicationsYou can also search for this author in

PubMed Google Scholarmanuehiro WakabayashiView作者出版物您也可以在

PubMed Google ScholarHiroyuki KodamaView author publicationsYou can also search for this author in

PubMed谷歌学者Hiroyuki KodamaView作者出版物您也可以在

PubMed Google ScholarKazunori HondaView author publicationsYou can also search for this author in

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PubMed Google ScholarToshiki MasuishiView author publicationsYou can also search for this author in

PubMed Google ScholarToshiki MasuishiView作者出版物您也可以在

PubMed Google ScholarHiroya TaniguchiView author publicationsYou can also search for this author in

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PubMed Google ScholarShigenori KadowakiView author publicationsYou can also search for this author in

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PubMed Google ScholarMasashi AndoView author publicationsYou can also search for this author in

PubMed Google ScholarMasashi AndoView作者出版物您也可以在

PubMed Google ScholarMasahiro TajikaView author publicationsYou can also search for this author in

PubMed Google ScholarMasahiro TajikaView作者出版物您也可以在

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PubMed Google ScholarKei MuroView作者出版物您也可以在

PubMed Google ScholarContributionsAll authors contributed to the study conception or design. YN and TO were involved in data acquisition. YN wrote the original draft of the manuscript. All the authors reviewed and approved the final version of the manuscript before submission.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献所有作者都为研究概念或设计做出了贡献。YN和TO参与了数据采集。YN写了手稿的初稿。所有作者在提交之前都审查并批准了稿件的最终版本。对应作者对应。

Yukiya Narita.Ethics declarations

成田由纪。道德宣言

Competing interests

相互竞争的利益

The authors declare the following financial interests/personal relationships which may be considered potential competing interests: Y Narita: research funding to my institution from Chugai, MSD, Amgen, ONO Pharmaceutical, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, and Pfizer; honoraria for lectures, presentations, and speaker bureaus from Yakult Honsha, Taiho, Eli Lilly, Daiichi Sankyo, Ono Pharma, and Bristol-Meyers Squibb and; participation on the Advisory Board of Daiichi Sankyo.

作者声明以下财务利益/个人关系可能被认为是潜在的竞争利益：Y成田：来自Chugai，MSD，Amgen，ONO Pharmaceutical，Astellas，Sanofi，Taiho，Eisai，Daiichi Sankyo，Novartis和辉瑞的研究资金；来自益力多Honsha，Taiho，Eli Lilly，Daiichi Sankyo，Ono Pharma和Bristol Meyers Squibb的讲座，演讲和演讲局的酬金；参加第一三共咨询委员会。

T Ogata: personal fees from ONO Pharmaceutical, personal fees from BMS, personal fees from Taiho, personal fees from Daichi-Sankyo, outside the submitted work. H Kodama: honoraria for lectures, presentations, and speaker bureaus from Taiho. K Honda: grants from Pfizer, outside the submitted work; T Masuishi: grants and personal fees from MSD, grants and personal fees from Amgen, grants and personal fees from ONO Pharmaceutical, grants and personal fees from Daiichi Sankyo, grants from Novartis, grants from Pfizer, personal fees from Taiho, personal fees from Bristol Myers Squibb, personal fees from Eli Lilly, personal fees from Takeda, grants from Boehringer-Ingelheim, grants from Syneos Healthe Clinical, personal fees from Chugai, personal fees from Nippon Kayaku, grants from Cimic Shift Zero, personal fees from Merck Bio Pharma, personal fees from Bayer, personal fees from Yakult Honsha, personal fees from Sanofi, personal fees from ONO Pharmaceutical, outside the submitted work.

T绪方：提交作品之外的小野制药的个人费用，BMS的个人费用，太和的个人费用，大池三共的个人费用。H Kodama：太和的讲座，演讲和演讲局的酬金。K本田：辉瑞公司的赠款，在提交的作品之外；T Masuishi：MSD的赠款和个人费用，安进的赠款和个人费用，小野制药的赠款和个人费用，第一三共的赠款和个人费用，诺华的赠款，辉瑞的赠款，太和的个人费用，百时美施贵宝的个人费用，礼来的个人费用，武田的个人费用，勃林格殷格翰的赠款，Syneos Health Clinical的赠款，中盖的个人费用，日本佳彦的个人费用，Cimic零转移的赠款，默克生物制药的个人费用，拜耳的个人费用，养乐多的个人费用，个人费用赛诺菲的费用，小野制药的个人费用，提交的作品之外。

H Taniguchi: grants and personal fees from Takeda, grants from Daiichi Sankyo, grants and personal fees from ONO Pharmaceutical, personal fees from Eli Lilly, personal fees from Merck Biopharma, personal fees from Chugai, outside the submitted work; Dr. Kadowaki reports grants and personal fees from.

H Taniguchi：武田的赠款和个人费用，第一三共的赠款，大野制药的赠款和个人费用，礼来的个人费用，默克生物制药的个人费用，Chugai的个人费用，提交的作品之外；Kadowaki博士报告了来自的赠款和个人费用。

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Reprints and permissionsAbout this articleCite this articleNarita, Y., Ogata, T., Ishizuka, Y. et al. Trifluridine/tipiracil with and without ramucirumab for advanced gastric cancer: a comparative observational study.

转载和许可本文引用本文Narita，Y.，Ogata，T.，Ishizuka，Y。等人。三氟尿苷/替吡拉西联合和不联合雷莫昔单抗治疗晚期胃癌：一项比较观察性研究。

Sci Rep 14, 12658 (2024). https://doi.org/10.1038/s41598-024-61975-7Download citationReceived: 05 January 2024Accepted: 13 May 2024Published: 03 June 2024DOI: https://doi.org/10.1038/s41598-024-61975-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1412658（2024）。https://doi.org/10.1038/s41598-024-61975-7Download引文接收日期：2024年1月5日接受日期：2024年5月13日发布日期：2024年6月3日OI：https://doi.org/10.1038/s41598-024-61975-7Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsChemotherapyGastric cancerRamucirumabTrifluridine/tipiracil

关键词血液疗法癌症拉莫昔单抗三氟啶/替吡拉西

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CancerGastroenterologyGastrointestinal diseasesOncology

癌症消化道疾病

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