Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.
Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
Signal Transduct Target Ther. 2024 Nov 4;9(1):300. doi: 10.1038/s41392-024-02006-9.
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).
致癌性 RET 改变是多种癌症中一种重要的、组织无关的治疗靶点。我们在有 RET 改变的实体瘤患者中进行了 SY-5007 的首次人体 1 期研究，这是一种有效的、选择性的 RET 抑制剂。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。共有 122 名患者入组（剂量递增阶段 17 名，剂量扩展阶段 105 名），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%的患者出现了与治疗相关的不良事件（TRAEs），最常见的≥3 级 TRAEs 是高血压（22.1%）、腹泻（16.4%）、高甘油三酯血症（6.6%）和中性粒细胞减少症（6.6%）。SY-5007 的暴露与剂量成正比。在 116 名可评估疗效的患者中，总客观缓解率（ORR）为 57.8%，初治患者为 70.0%，经治患者为 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如何，均观察到疗效。对 61 名有循环肿瘤 DNA（ctDNA）检测到 RET 改变的患者进行生物标志物分析显示，ORR 为 57.4%，中位 PFS 为 13.8 个月。快速清除 RET 改变的 ctDNA 与更快的反应和更好的结果相关。在复发患者中，观察到 57.1%（12/21）的脱靶诱导耐药，未发现靶向 RET 改变。总之，SY-5007 在有 RET 改变的实体瘤患者中耐受性良好，疗效有前景。连续的 ctDNA 监测可能揭示治疗反应和潜在的耐药机制（NCT05278364）。
