Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
The University of Chicago, Chicago, IL.
J Clin Oncol. 2019 Dec 20;37(36):3518-3527. doi: 10.1200/JCO.19.00646. Epub 2019 Nov 5.
Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer.
Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg).
Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing.
DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.
前列腺六跨膜上皮抗原 1（STEAP1）在前列腺癌中高度表达。DSTP3086S 是人源化 IgG1 抗 STEAP1 单克隆抗体，与有效的抗有丝分裂剂单甲基奥瑞他汀 E 相连。本研究评估了 DSTP3086S 在转移性去势抵抗性前列腺癌患者中的安全性和活性。
患者入组了一项 3+3 剂量递增研究，以评估 DSTP3086S（静脉注射 0.3 至 2.8mg/kg）每 3 周一次，随后在推荐的 II 期剂量或每周（0.8 至 1.0mg/kg）进行扩展队列。
77 例患者每 3 周接受 DSTP3086S 一次，7 例患者每周接受治疗。2 例在每 3 周剂量递增的患者中出现剂量限制的 3 级氨基转移酶升高。1 例接受 1.0mg/kg 每周治疗的患者出现 3 级高血糖和 4 级低磷血症。在最初的扩展队列评估中，每 3 周 2.8mg/kg 一次的剂量（n=10），但频繁的剂量减少导致在扩展阶段测试 2.4mg/kg（n=39）。在不同剂量（每 3 周）中常见的相关不良事件（>20%）是疲劳、周围神经病、恶心、便秘、厌食、腹泻和呕吐。DSTP3086S 的药代动力学呈线性。在接受>2mg/kg DSTP3086S 每 3 周一次的 62 例患者中，11 例（18%）前列腺特异性抗原下降≥50%；2 例（6%）基线有可测量疾病的患者达到影像学部分缓解；在 27 例基线有信息性不利循环肿瘤细胞≥5/7.5mL 血液的患者中，16 例（59%）转为有利循环肿瘤细胞<5。每周给药时未见前列腺特异性抗原或 RECIST 反应。
在推荐的 2.4mg/kg 每 3 周一次的 II 期剂量水平下，DSTP3086S 具有可接受的安全性。在 2.25 至 2.8mg/kg 每 3 周一次的剂量下观察到抗肿瘤活性，支持用 STEAP1 靶向抗体药物偶联物治疗 STEAP1 表达的转移性去势抵抗性前列腺癌的潜在益处。
