{"title":"抗 TIGIT 抗体 tiragolumab 联合 atezolizumab 治疗日本晚期或转移性实体瘤患者的 I 期研究。","authors":"Noboru Yamamoto, Takafumi Koyama, Jun Sato, Tatsuya Yoshida, Kazuki Sudo, Satoru Iwasa, Shunsuke Kondo, Kan Yonemori, Atsuko Kawasaki, Kyoko Satake, Shoyo Shibata, Toshio Shimizu","doi":"10.1007/s00280-023-04627-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926).</p><p><strong>Methods: </strong>Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity.</p><p><strong>Results: </strong>Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: C<sub>max</sub> 217 μg/mL; C<sub>min</sub> 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t<sub>1/2</sub>, 17.6 days. Best overall response was stable disease in two patients.</p><p><strong>Conclusion: </strong>Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials.</p><p><strong>Trial registration number: </strong>jRCT2080224926.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258096/pdf/","citationCount":"0","resultStr":"{\"title\":\"Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors.\",\"authors\":\"Noboru Yamamoto, Takafumi Koyama, Jun Sato, Tatsuya Yoshida, Kazuki Sudo, Satoru Iwasa, Shunsuke Kondo, Kan Yonemori, Atsuko Kawasaki, Kyoko Satake, Shoyo Shibata, Toshio Shimizu\",\"doi\":\"10.1007/s00280-023-04627-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926).</p><p><strong>Methods: </strong>Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity.</p><p><strong>Results: </strong>Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: C<sub>max</sub> 217 μg/mL; C<sub>min</sub> 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t<sub>1/2</sub>, 17.6 days. Best overall response was stable disease in two patients.</p><p><strong>Conclusion: </strong>Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials.</p><p><strong>Trial registration number: </strong>jRCT2080224926.</p>\",\"PeriodicalId\":9556,\"journal\":{\"name\":\"Cancer Chemotherapy and Pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258096/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Chemotherapy and Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00280-023-04627-3\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/11 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Chemotherapy and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00280-023-04627-3","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/11 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：Tiragolumab 是一种与抑制性免疫检查点 TIGIT（具有 Ig 和 ITIM 结构域的 T 细胞免疫受体）结合的单克隆抗体。在早期临床试验中，tiragolumab与程序性死亡配体1抑制剂atezolizumab联合治疗晚期/转移性实体瘤患者的耐受性良好，并显示出初步的抗肿瘤活性。我们报告了在日本患者中开展的替拉戈单抗联合阿特佐利珠单抗 I 期研究（jRCT2080224926）的结果：方法：年龄≥20岁的日本患者接受替拉戈单抗（600毫克）和阿替佐利单抗（1200毫克）静脉注射，每21天一次，直至出现不可接受的毒性或疾病进展。主要终点是替拉戈单抗和阿特佐利珠单抗的安全性和药代动力学（PK）参数。次要终点为抗肿瘤活性：3名患者入组，诊断为非小细胞肺癌、胰腺癌和胆管癌。未观察到限制剂量的毒性反应。两名患者出现了任何级别的治疗相关不良事件（AE）。没有≥3级的不良反应、严重不良反应、导致停药、改药或撤药的不良反应或导致死亡的不良反应。在第一周期，替拉戈单抗的平均 PK 参数如下Cmax为217微克/毫升；Cmin为54.9微克/毫升；从0到最后可测量浓度的浓度-时间曲线下面积为2000微克-天/毫升；t1/2为17.6天。两名患者的最佳总体反应是病情稳定：结论：日本晚期/转移性实体瘤患者对替拉戈单抗联合阿特珠单抗的耐受性良好，参加本研究的日本患者与参加全球III期研究的非日本患者在替拉戈单抗PK特征方面没有差异。这些结果可能支持将日本患者纳入正在进行的全球III期临床试验。
Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors.
Purpose: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926).
Methods: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity.
Results: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: Cmax 217 μg/mL; Cmin 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t1/2, 17.6 days. Best overall response was stable disease in two patients.
Conclusion: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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