PDF(Pubmed)
Abstract：
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
摘要：
SacituzumabGovitecan（SG）是一种抗体-药物偶联物，已在表达TROP-2的上皮癌患者中表现出功效。在颅内乳腺癌的异种移植模型中，SG抑制肿瘤生长并增加小鼠存活率。我们在圣安东尼奥的德克萨斯大学健康科学中心进行了一项前瞻性机会窗试验（NCT03995706），以检查患有脑转移（BCBM）或复发性胶质母细胞瘤（rGBM）的乳腺癌开颅手术患者中SG的肿瘤内浓度和颅内活性。我们招募了25名年龄≥18岁的诊断为BCBM和rGBM的患者，在切除前一天以10mg/kg的剂量静脉注射SG，并在恢复后的21天周期的第1天和第8天继续。BCBM和rGBM队列的PFS分别为8个月和2个月，分别。OS分别为35.2个月和9.5个月，分别。≥3级AE包括中性粒细胞减少症（28%），低钾血症（8%），癫痫发作(8%)，血栓栓塞事件（8%），尿路感染（8％）和下肢肌肉无力（8％）。在术后组织中，BCBM的总SN-38中位数为249.8ng/g，rGBM为104.5ng/g，从而实现主要终点。生物标志物分析表明通过在靶位点直接释放来递送有效载荷,并且低氧变化不驱动间接释放。BCBM队列的OS次要终点为35.2个月，rGBM为9.5个月。ORR的非计划探索性终点为BCBM的38%和29%，分别。在100%的BCBM和78%的rGBM肿瘤中观察到Trop-2表达的探索性终点。总之,发现SG具有良好的耐受性，可充分渗透到颅内肿瘤中，并有望在CNS内发挥初步活性。试验注册：临床试验（NCT03995706）作为神经/SacituzumabGovitecan/乳腺癌转移/胶质母细胞瘤/Ph0：https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706。
