METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.
RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.
CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.
方法:将患有晚期HER2+乳腺癌的患者(n=68)纳入该开放标签,剂量递增Ib期研究。主要终点是定义各种含有taselisib的组合的最大耐受剂量(MTD)。次要终点是安全性。探索性终点包括循环肿瘤DNA分析。该研究包括四个队列:(A)taselisib+曲妥珠单抗emtansine(T-DM1),(C)他赛利布+曲妥珠单抗和帕妥珠单抗(TP),(D)taselisib+TP+紫杉醇,和(E)taselisib+TP+氟维司群。
结果:剂量递增后,taselisibMTD定义为每天一次4mg.治疗与显著的毒性有关,由于68例患者中有34例经历了归因于taselisib的≥3级不良事件(AE),最常见的全等级不良事件是腹泻,疲劳,和口腔粘膜炎.中位随访时间为43.8个月,队列A中MTD治疗人群的中位无进展生存期(PFS),C,E为6.3个月[95%置信区间(CI)3.2-不适用(NA)],1.7(95%CI1.4-NA)个月,和10.6个月(95%可信区间8.3-NA),分别。先前使用过T-DM1的队列A患者的中位PFS为10.4个月(95%CI2.7-NA)。
结论:Taselisib联合HER2靶向治疗的PIK3CA靶向与有希望的疗效和实质性毒性相关。