Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor, which is currently under investigation in patients with a variety of solid tumors, including BC. In this article, we focus on the main characteristics of buparlisib and its potential application in the treatment of BC.
Buparlisib has demonstrated preliminary activity in preclinical models, providing a rationale for its use in clinical practice.29 Preclinical data showed that this drug, at high concentrations, might cause cell death in various cellular systems, irrespective of the level of PI3K addiction. Moreover, this agent may interfere with microtubule assembling, inducing cell cycle arrest at G2–M phase. However, at doses and schedules used in clinical settings, these effects may not occur.30
In early-phase clinical studies, buparlisib showed encouraging tolerability profile, but modest clinical efficacy as a single agent.31 As the PI3K pathway is involved in resistance to anticancer treatments, a more promising therapeutic strategy likely consists in combining buparlisib, and PI3K inhibitors in general, with other agents in order to restore sensitivity to such treatments.32–35 Different trials testing the combination of this PI3K inhibitor with various anticancer drugs are ongoing and are summarized in Table 1.
(To view a larger version of Table 1, click here.)
MATERIALS AND METHODS
We searched PubMed for articles published anytime until September 23, 2017, using the terms “buparlisib” AND “breast cancer”, and identified 45 full-text articles in English. Of these articles, 10 publications were reviews. Five publications reported original data from Phase I clinical trials involving buparlisib in BC, and one publication related to Phase III trial of buparlisib in BC was identified.
The combination of a PI3K inhibitor and endocrine treatment was tested in a Phase IB study of buparlisib plus letrozole in patients with HR+/HER2− metastatic BC whose disease was refractory to ET.36 In this study, 46 patients were evaluable for response and 1 achieved complete response, 1 partial response, and 25 patients had stable disease. Clinical activity did not correlate with PIK3CA mutational status, thus suggesting that other alterations in the pathway might be responsible for PI3K pathway dependence.36
In the Phase III randomized, double-blind, placebo-controlled, multicenter BELLE-2 study, postmenopausal patients with HR+/HER2− metastatic BC, who had progressed on/after aromatase inhibitor therapy, were randomized 1:1 to receive either buparlisib (100 mg/day) or placebo, starting on day 15 of cycle 1, plus fulvestrant (500 mg) on days 1 and 15 of cycle 1, and thereafter on day 1 of 28-day cycles.37
PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent) were stratification factors. The objective of the trial was to assess the predictive value of single PI3K–AKT–mTOR pathway alterations on the clinical response of buparlisib. The primary endpoints were PFS in the overall population, in patients with known (either activated or non-activated) PI3K pathway status, and in patients with PI3K pathway activation.37
One thousand one hundred forty-seven patients were included in this trial; 576 received buparlisib plus fulvestrant and 571 received placebo plus fulvestrant.37 Median PFS was 6.9 vs 5.0 months in the overall population, receiving either buparlisib or placebo, respectively (p=0.00021). Patients with known PI3K status had a median PFS of 6.8 months when treated with buparlisib and 4.5 months with placebo (p=0.0033). In patients with PI3K pathway activation, median PFS was 6.8 vs 4.0 months in the buparlisib and placebo groups, respectively (p=0.014). Patients receiving buparlisib experienced more frequently grade 3–4 increased alanine aminotransferase (25% vs 1%), increased aspartate aminotransferase (18% vs 3%), hyperglycemia (15% vs <1%), and rash (8% vs none).37 Twenty-three percent of patients treated with buparlisib had serious adverse events as compared to 16% of patients who received placebo. Finally, this study showed that PI3K inhibition combined with ET is effective in patients with HR+/HER2− metastatic BC, but the toxicity associated with this combination is not negligible.37
PI3K pathway activation in preclinical models of BC is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Furthermore, buparlisib has shown synergistic activity when combined with paclitaxel in preclinical and clinical models. Therefore, the double-blind, placebo-controlled, adaptive Phase II/III BELLE-4 trial randomized (1:1) patients with untreated metastatic HER2− BC to receive either buparlisib or placebo with paclitaxel.38 PI3K pathway activation and HR status were the stratification factors. The primary endpoint was PFS in the overall and PI3K pathway-activated populations. An adaptive interim analysis following the Phase II part of the study was planned to decide whether to go or not to Phase III (in the overall or PI3K pathway-activated population).38 Four hundred sixteen patients were entered in the trial. At adaptive interim analysis, PFS did not increase with buparlisib over placebo, either in the overall or in the PI3K pathway-activated population. Therefore, the study was stopped for futility.38