1 Dana-Farber Cancer Institute, Boston, MA.
2 Brigham and Women's Hospital, Boston, MA.
J Clin Oncol. 2019 Mar 20;37(9):741-750. doi: 10.1200/JCO.18.01207. Epub 2019 Feb 4.
Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.
This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.
Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).
Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
磷酸肌醇 3-激酶（PI3K）信号在神经胶质瘤中高度活跃。我们评估了泛 PI3K 抑制剂 Buparlisib 在具有 PI3K 途径激活的复发性神经胶质瘤患者中的药代动力学、药效学和疗效。
这是一项多中心、开放性、多臂、II 期临床试验，入组了首次或第二次复发时具有 PI3K 途径激活的神经胶质瘤患者。在队列 1 中，计划在进展后再次手术的患者在手术前接受 Buparlisib 治疗 7-13 天，以评估脑穿透和切除肿瘤组织中 PI3K 途径的调节。在队列 2 中，不适合再次手术的患者在进展或无法耐受毒性时接受 Buparlisib 治疗。每日一次口服 Buparlisib 100mg，连续 28 天给药。主要终点是肿瘤组织中 PI3K 途径的抑制作用以及队列 1 中的 Buparlisib 药代动力学和队列 2 中的 6 个月无进展生存期（PFS6）。
共治疗了 65 例患者（队列 1，n=15；队列 2，n=50）。在队列 1 中，14 例患者中有 6 例（42.8%）达到了磷酸化 AKT 免疫组化评分的降低，但对核糖体蛋白 S6 和增殖的影响不显著。肿瘤与血浆药物浓度比为 1.0。在队列 2 中，50 例患者中有 4 例（8%）达到了 6 个月的 PFS6，中位 PFS 为 1.7 个月（95%CI，1.4-1.8 个月）。与治疗相关的最常见的 3 级或更高级别的不良事件是脂肪酶升高（n=7[10.8%]）、疲劳（n=4[6.2%]）、高血糖（n=3[4.6%]）和 ALT 升高（n=3[4.6%]）。
Buparlisib 在具有 PI3K 激活的复发性神经胶质瘤患者中具有最小的单药疗效。尽管 Buparlisib 实现了显著的脑穿透，但由于肿瘤组织中 PI3K 途径的不完全阻断，临床疗效不明显。综合结果表明，仍有必要对实现更完全的途径抑制的 PI3K 抑制剂进行进一步研究。
