An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer.
An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-23-0011
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发表时间：
2023-08-01
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GDC-0927是一种新型的、有效的、非类固醇的、口服生物利用的、选择性的雌激素受体(ER)降解剂，可在ER+乳腺癌异种移植模型中诱导肿瘤消退。这项I期剂量递增多中心研究招募了患有ER+/HER2−转移性乳腺癌的绝经后妇女，以确定GDC-0927的安全性、药代动力学和推荐的II期剂量。用[18F]-氟雌二醇(FES)正电子发射计算机断层扫描评价药效学。42例患者每天接受一次GDC-0927治疗。未达到MTD。无论因果关系如何，最常见的不良事件(AE)是恶心、便秘、腹泻、关节痛、疲劳、潮热、背痛和呕吐。无死亡、4/5级不良反应或与治疗相关的严重不良反应。两名患者经历了2级的特别关注的深静脉血栓形成和颈静脉血栓形成，两者都被认为与GDC-0927无关。在给药后，观察到大约1.6倍的累积，与观察到的半衰期和给药频率一致。没有完全或部分反应。药效学得到了FES摄取减少90%和ER表达减少约40%的支持，这表明ER降解不是ER拮抗的机制驱动因素。12名患者(29%)获得临床收益；17名患者(41%)显示出稳定的疾病的最佳总体反应。雌激素受体和孕激素受体蛋白的基线水平以及突变的ESR1循环肿瘤DNA与临床益处无关。GDC-0927似乎耐受性良好，药物动力学支持每日一次给药。有证据表明，在有或没有ESR1突变的晚期/转移性ER+/HER2−乳腺癌患者中，有靶点参与和抗肿瘤活性的初步证据。
GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2− metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2− breast cancer with and without ESR1 mutations.