{"title":"Tasurgratinib 用于胆管癌或胃癌患者:首次人体I期研究的扩展部分。","authors":"Chigusa Morizane, Makoto Ueno, Tatsuya Ioka, Masahiro Tajika, Masafumi Ikeda, Kensei Yamaguchi, Hiroki Hara, Hiroshi Yabusaki, Atsushi Miyamoto, Satoru Iwasa, Manabu Muto, Tsutomu Takashima, Keiko Minashi, Yoshito Komatsu, Tomohiro Nishina, Takako Eguchi Nakajima, Atsuchi Takeno, Toshikazu Moriwaki, Masayuki Furukawa, Takatoshi Sahara, Hiroki Ikezawa, Maiko Nomoto, Shuya Takashima, Taisuke Uehara, Setsuo Funasaka, Masakazu Yashiro, Junji Furuse","doi":"10.1111/cas.16354","DOIUrl":null,"url":null,"abstract":"<p><p>Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)<sub>2</sub>-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7000,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.\",\"authors\":\"Chigusa Morizane, Makoto Ueno, Tatsuya Ioka, Masahiro Tajika, Masafumi Ikeda, Kensei Yamaguchi, Hiroki Hara, Hiroshi Yabusaki, Atsushi Miyamoto, Satoru Iwasa, Manabu Muto, Tsutomu Takashima, Keiko Minashi, Yoshito Komatsu, Tomohiro Nishina, Takako Eguchi Nakajima, Atsuchi Takeno, Toshikazu Moriwaki, Masayuki Furukawa, Takatoshi Sahara, Hiroki Ikezawa, Maiko Nomoto, Shuya Takashima, Taisuke Uehara, Setsuo Funasaka, Masakazu Yashiro, Junji Furuse\",\"doi\":\"10.1111/cas.16354\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)<sub>2</sub>-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.</p>\",\"PeriodicalId\":48943,\"journal\":{\"name\":\"Cancer Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-10-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cas.16354\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cas.16354","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
摘要
成纤维细胞生长因子受体(FGFR)是一个高度保守的跨膜受体酪氨酸激酶家族,在调控关键细胞过程中发挥着多种作用。在胃癌和胆管癌等几种癌症中都观察到了特定的 FGFR 突变。Tasurgratinib 是一种强效、选择性的 FGFR1-3 抑制剂,在一项 I 期、首次进入人体的单中心研究中,报告了 24 名日本实体瘤患者接受 Tasurgratinib(以前称为 E7090)治疗的剂量升级数据。根据该研究中观察到的安全性、药代动力学和药效学特征,该研究选择了每日一次 140 毫克的推荐剂量作为扩展部分(第二部分)的剂量,这是一项多中心扩展剂量探索研究,仅限于携带 FGFR 基因改变的肿瘤患者。第二部分对安全性和初步疗效进行了评估。此外,还评估了药效学药物基因组标记物(血清磷酸盐、FGF23 和 1,25-(OH)2-维生素 D、循环肿瘤 DNA)和药代动力学特征。共有 16 名患者参加了第二部分的研究,其中 6 人患有胆管癌,10 人患有胃癌。治疗过程中最常见的不良反应是高磷血症、掌跖红斑综合征和副癣。在胆管癌患者中观察到5例部分反应(83.3%),在胃癌患者中观察到1例部分反应(11.1%);两组患者的中位无进展生存期分别为8.26个月(95%置信区间[CI] 3.84,不可评估[NE])和3.25个月(95% CI 0.95,4.86),总生存期分别为22.49个月(95% CI 6.37,NE)和4.27个月(95% CI 2.23,7.95)。总之,对于携带FGFR2基因重排的胆管癌患者,塔舒瑞替尼140毫克具有可耐受的安全性和良好的临床疗效。
Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.
Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.
期刊介绍:
Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports.
Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.