A phase 2 trial of buparlisib in patients with platinum‐resistant metastatic urothelial carcinoma

Abstract

BACKGROUND: 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 panisoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Cancer 2020;126:4532-4544.

Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor

“…Herein, we describe our efforts to further explore the relationship between isoform specificity and TI. Initial clinical studies with the pan class I PI3K inhibitor buparlisib (NVP-BKM120, AN2025) 6 had produced favorable results in patients with solid tumors, but these studies also highlighted the tolerability profile of 6 to be challenging, Figure . − However, three features associated with 6 complicated the interpretation of the clinical efficacy and tolerability readouts in the context of PI3K inhibition . Firstly, a cytotoxic off-target effect had been identified for 6 , which resulted from interfering with tubulin dynamics (microtubule stabilization) and lead to cell cycle arrest .…”

“…The potency ranges relevant to the above cytotoxicity and the class I PI3K activities of 6 were considered to overlap, making the contribution of each to the efficacy and tolerability difficult to separate. Secondly, 6 was found to penetrate the central nervous system (CNS), and it remained unclear if the treatment related mood disorders observed with 6 were as a result of central PI3K inhibition, interfering with microtubule dynamics, or an unidentified off-target activity. − Thirdly, 6 is 2.3- to 4.5-fold more potent as a PI3Kα inhibitor relative to the other class IA isoforms (based upon Rat1 cellular assays measuring S473P-Akt, Table ), and the narrow TI with respect to PI3Kα-mediated effects on glucose homeostasis was considered to potentially limit the extent to which the β- and δ-isoforms could be robustly inhibited …”

Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells

“…Previous studies indicate that dysregulation of the PI3K/Akt/mTOR pathway plays an essential role in the tumorigenesis of BC and targeting the PI3K/Akt/ mTOR pathway is a potential therapeutic strategy for BC. To date, the e ects of several PI3K/Akt/mTOR inhibitors have been examined clinically in BC, such as everolimus, GSK2126458, and buparlisib [13][14][15]. PF-04691502 is a novel dual PI3K/mTOR inhibitor that has antitumour e ects against various cancers.…”

Biomarkers for therapy selection in metastatic urothelial cancer

“…When everolimus was tested in combination with the TKI pazopanib, TSC1, TSC2, or mTOR mutations were identified in the only complete responder (CR), and two of the three partial responders [202] , and subsequent analysis of the CR revealed two distinct activating mTOR mutations, both validated in vitro and conferring sensitivity to mTOR inhibition [203] . However, follow-up studies have failed to yield clinically relevant efficacy for mTOR inhibition in UC treatment, including additional inhibitors such as sapanisertib, which showed minimal response for TSC1/2-mutated mUC patients [204] .…”