Division of Urology, Department of Surgery, McGill University, Montreal, Quebec, Canada.
Broad Institute of Massachusetts Institute of Technology, Cambridge, Massachusetts.
Cancer. 2020 Oct 15;126(20):4532-4544. doi: 10.1002/cncr.33071. Epub 2020 Aug 7.
The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC.
Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome.
Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy.
Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients.
The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.
磷脂酰肌醇 3-激酶（PI3K）/Akt/雷帕霉素靶蛋白（mTOR）通路在尿路上皮癌（UC）患者中经常被激活。在目前的研究中，作者进行了一项 2 期研究，评估了泛同工型 I 类 PI3K 抑制剂 buparlisib 对铂类难治性转移性 UC 患者的疗效。
招募了两个队列：一个是最初未经基因选择的队列，另一个是随后的 PI3K/Akt/mTOR 通路改变肿瘤患者的扩展队列。主要终点是 2 个月无进展生存率。Simon 2 期最小最大设计认为≥80%的无进展生存率有希望。次要终点包括安全性和 PI3K 通路激活标志物与结局的相关性。
初始队列中可评估的 13 名患者中有 6 名出现疾病稳定，1 名出现部分缓解，这低于进入 2 期所需的 9 名患者的截止值。3 名疾病稳定的患者和 1 名部分缓解的患者携带体细胞 TSC1 改变。随后有 4 名患者加入扩展队列：3 名 TSC1 改变的患者和 1 名 PIK3CA 激活突变的患者。在 8 周时没有患者达到疾病控制，并且停止了入组。在可评估毒性的 19 名患者中，17 名出现与治疗相关的毒性，其中 2 名不得不停止治疗。
在肿瘤携带 TSC1 功能丧失改变的转移性 UC 患者中，buparlisib 被发现具有适度的活性；然而，这并不是对 buparlisib 反应的可靠预测因子。遗传共改变的模式可能影响药物敏感性。鉴于 buparlisib 的适度临床活性和显著毒性，UC 患者的 PI3K 抑制剂的未来试验应集中在基于基因组选择的患者中使用同工型选择性 PI3K 抑制剂。
医生笔记：PI3K/Akt/mTOR 通路在转移性 UC 患者中经常被上调。本试验研究了 PI3K 抑制剂 buparlisib 在治疗经过大量预处理的转移性 UC 患者中的作用。尽管该药物被发现具有适度的疗效，有 6 名患者在治疗 8 周时出现疾病稳定，1 名患者出现部分缓解，但也观察到显著的副作用。具有特定遗传改变的患者对治疗有反应。需要使用具有更好毒性特征和更具选择性的通路抑制剂的新型药物进一步研究 PI3K 通路抑制。
