{"title":"First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors","authors":"Wei Li, Yongsheng Wang, Anwen Xiong, Ge Gao, Zhengbo Song, Yiping Zhang, Dingzhi Huang, Feng Ye, Qiming Wang, Zhihui Li, Jiaye Liu, Chunwei Xu, Yinghui Sun, Xijie Liu, Fei Zhou, Caicun Zhou","doi":"10.1038/s41392-024-02006-9","DOIUrl":null,"url":null,"abstract":"<p>Oncogenic <i>RET</i> alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with <i>RET</i>-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable <i>RET</i> alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of <i>RET</i> alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target <i>RET</i> alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with <i>RET</i>-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).</p>","PeriodicalId":40,"journal":{"name":"Inorganic Chemistry","volume":"48 1","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inorganic Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41392-024-02006-9","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, INORGANIC & NUCLEAR","Score":null,"Total":0}
引用次数: 0
Abstract
Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).
致癌基因 RET 改变是各种癌症的重要组织诊断治疗靶点。我们在RET改变的实体瘤患者中开展了SY-5007（一种强效、选择性RET抑制剂）的首次人体1期研究。主要终点是安全性、最大耐受剂量（MTD）和推荐的 2 期剂量（RP2D）。次要终点包括药代动力学和初步抗肿瘤活性。该研究共招募了122名患者（17名处于剂量递增阶段，105名处于剂量扩大阶段），其中包括91名非小细胞肺癌患者、23名甲状腺髓样癌患者、7名甲状腺乳头状癌患者和1名胃癌患者。96.7%的患者报告了治疗相关不良事件（TRAE），最常见的≥3级TRAE为高血压（22.1%）、腹泻（16.4%）、高甘油三酯血症（6.6%）和中性粒细胞减少（6.6%）。SY-5007的暴露量与剂量成正比。在116例有疗效的患者中，总客观应答率（ORR）为57.8%，其中治疗无效患者为70.0%，既往接受过治疗的患者为51.3%。中位无进展生存期（PFS）为21.1个月。无论肿瘤类型和既往治疗情况如何，都能观察到疗效。对61例可检测到循环肿瘤DNA（ctDNA）RET改变的患者进行的生物标志物分析显示，ORR为57.4%，中位PFS为13.8个月。ctDNA快速清除RET改变与更快的反应和更好的疗效相关。在复发患者中，57.1%（12/21）的患者出现了脱靶诱导耐药，未发现靶上RET改变。总之，SY-5007在RET改变的实体瘤患者中耐受性良好，并显示出良好的疗效。连续的ctDNA监测可揭示治疗反应和潜在的耐药机制（NCT05278364）。
期刊介绍：
Inorganic Chemistry publishes fundamental studies in all phases of inorganic chemistry. Coverage includes experimental and theoretical reports on quantitative studies of structure and thermodynamics, kinetics, mechanisms of inorganic reactions, bioinorganic chemistry, and relevant aspects of organometallic chemistry, solid-state phenomena, and chemical bonding theory. Emphasis is placed on the synthesis, structure, thermodynamics, reactivity, spectroscopy, and bonding properties of significant new and known compounds.
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