Buparlisib, also known by the code name BKM120, is an orally administered drug being explored as a targeted therapy for various cancers. It belongs to a class of medications called PI3K inhibitors. This compound aims to offer a new treatment option by interfering with specific pathways that drive cancer cell growth and survival. Buparlisib is currently undergoing clinical trials to assess its safety and effectiveness.
How Buparlisib Targets Cancer
Buparlisib operates by inhibiting the activity of class I phosphatidylinositol-3-kinase (PI3K) enzymes. The PI3K/AKT/mTOR signaling pathway plays a significant role in cell growth, proliferation, survival, and metabolism. In many cancers, genetic alterations can lead to its constant activation, promoting tumor growth.
Buparlisib works by binding to the ATP-binding pocket of the PI3K enzyme. This action prevents the enzyme’s activation and the subsequent phosphorylation of its downstream targets, such as AKT. By disrupting these processes, buparlisib interferes with cellular functions necessary for cancer cell survival and proliferation, including protein synthesis, cell cycle progression, and the inhibition of apoptosis.
Targeting all class I PI3K isoforms, including PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, provides a broad-spectrum approach. This broad inhibition may help overcome resistance mechanisms that might arise with PI3K inhibitors that target only specific isoforms. Buparlisib has also been shown to induce apoptosis and inhibit proliferation in various cancer cell types, including breast, ovarian, and intestinal cancer, as well as glioma and lung cancer.
Cancers Treated with Buparlisib
Buparlisib has been investigated for various cancer types, often combined with other therapies. A primary focus is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, frequently studied alongside hormone therapies like fulvestrant due to common PI3K pathway alterations.
Beyond breast cancer, buparlisib has been explored for glioblastoma multiforme (GBM), an aggressive brain cancer with active PI3K pathways. Clinical trials are assessing its effects when combined with standard treatments such as temozolomide and radiation therapy. Other solid tumors under investigation include head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer, and colorectal cancer.
Novartis has also conducted phase II clinical studies for buparlisib in other malignancies, including:
- Follicular lymphoma
- Gastrointestinal stromal tumors
- Mantle cell lymphoma
- Prostate cancer
- Diffuse large B-cell lymphoma
- Ovarian cancer
- Hepatocellular carcinoma
- Bone marrow fibrosis
- Advanced endometrial cancer
- Melanoma
- Bladder cancer
- Pancreatic cancer
A phase II study in relapsed or refractory non-Hodgkin lymphoma showed modest activity, with overall response rates of 11.5% in diffuse large B-cell lymphoma, 22.7% in mantle cell lymphoma, and 25.0% in follicular lymphoma.
Potential Side Effects and Patient Safety
Clinical trials have identified several common and potentially serious side effects associated with buparlisib. Across various studies, common adverse events affecting over 20% of patients have included fatigue, nausea, decreased appetite, diarrhea, and vomiting. Other frequently reported side effects involve anxiety, depression, hyperglycemia (high blood sugar), increased aspartate aminotransferase, and decreased weight.
Many patients experienced Grade 3 or 4 adverse events, indicating more severe reactions. The most common treatment-related adverse events were fatigue, nausea, hyperglycemia, decreased appetite, and diarrhea. Side effects that led to study drug interruption or dose reduction included increases in aspartate aminotransferase and alanine aminotransferase, as well as hyperglycemia and fatigue.
Serious adverse events, though less common, have been reported and include pneumonitis, esophageal perforation, seizures, pancreatitis, mental status changes, and psychotic disorder. Neuropsychiatric effects, such as anxiety (18–25%) and depression (18–29%), have been noted in studies involving lymphoma and breast cancer, though these were generally manageable with dose adjustments or other medications. Hyperglycemia and transaminitis are also reversible toxicities associated with buparlisib.
Buparlisib’s Regulatory Journey
Buparlisib remains an investigational drug and has not received approval from major regulatory bodies such as the FDA or EMA for widespread clinical use. Its development has faced challenges, particularly concerning its toxicity profile in relation to its efficacy. For instance, while some studies showed buparlisib prolonged progression-free survival, these benefits were often accompanied by significant side effects.
Novartis, the developer, discontinued its breast cancer study program for buparlisib due to negative results, which indicated that despite some efficacy, the drug resulted in excessive side effects. A phase III trial (BELLE-4) combining buparlisib with paclitaxel for advanced HER2-negative breast cancer was stopped early due to futility, as the addition of buparlisib did not improve progression-free survival.
Despite these setbacks, buparlisib continues to be investigated for other indications, such as head and neck squamous cell carcinoma (HNSCC). A global phase II clinical trial combining buparlisib with paclitaxel for HNSCC has been completed with a manageable safety profile. Buparlisib currently holds fast-track status with the United States Food and Drug Administration, indicating ongoing interest in its potential.