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Abstract：
BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.
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.
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.
摘要：
背景：在大多数晚期人类表皮生长因子受体2阳性（HER2+）乳腺癌患者中，抗HER2治疗由于获得性耐药性的发展而失败，可能通过磷酸肌醇-3-激酶（PI3K）信号介导。我们调查了添加taselisib，一种α选择性强效口服PI3K抑制剂，以不同的HER2为导向的方案，以改善疾病控制。
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。
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。
