Buparlisib in PI3K Pathway–Activated Recurrent Glioblastoma
In a phase II trial reported in the Journal of Clinical Oncology, Wen et al found minimal activity of the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.
The study included 2 cohorts. In cohort 1, 14 evaluable patients scheduled for reoperation 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, 50 patients not eligible for reoperation received buparlisib until disease progression or unacceptable toxicity. Buparlisib was given at 100 mg on a continuous 28-day schedule.
Effects on PI3K Activation and Treatment Outcomes
In cohort 1, with regard to the effect on markers of PI3K activation, a reduction of phosphorylated AKTS473 immunohistochemistry scores was achieved in 6 (42.8%) of 14 patients, but no significant effects on phosphoribosomal protein S6S235/236 or proliferation were observed. The tumor-to–plasma drug level ratio was 1.0.
In cohort 2, no patients had a radiographic response. Six-month progression-free survival was observed in 4 (8%) of 50 patients, and the median progression-free survival was 1.7 months. Disease stabilization was observed in 43.8% of patients in cohort 2.
The most common treatment-related grade ≥ 3 adverse events were lipase elevation (10.8%), fatigue (6.2%), hyperglycemia (4.6%), and elevated alanine transaminase (4.6%).
The investigators concluded, “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.”
Patrick Y. Wen, MD, of the Center for Neuro-Oncology, Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Ivy Foundation Early Phase Clinical Trials Consortium, DFHCC/MIT Bridge Project, and Novartis. The study authors' full disclosures can be found at jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
