PLX3397, also known as pexidartinib and marketed as Turalio, is an orally available, targeted therapy. It is designed to interact with and influence biological processes at a molecular level. The development of such therapies signifies an advancement in treating certain conditions by focusing on specific pathways involved in disease progression.
Understanding How PLX3397 Works
PLX3397 functions as a tyrosine kinase inhibitor, blocking the activity of specific enzymes called tyrosine kinases. These enzymes are involved in cell growth, division, and survival. By inhibiting them, the drug interferes with signaling pathways that contribute to disease development.
The drug specifically targets several receptor tyrosine kinases, including Colony-Stimulating Factor 1 Receptor (CSF1R), KIT, and FMS-like tyrosine kinase 3 (FLT3). CSF1R is involved in the proliferation and survival of certain cell types, such as macrophages. KIT and FLT3 are also receptors that, when activated, can promote abnormal cell growth. Inhibiting CSF1R can lead to the down-modulation of macrophages, osteoclasts, and mast cells, which are immune cells that can contribute to various diseases. This targeted inhibition helps reduce cell proliferation and accumulation.
Approved Use in Tenosynovial Giant Cell Tumor
Turalio received approval from the U.S. Food and Drug Administration (FDA) in August 2019 for the treatment of tenosynovial giant cell tumor (TGCT). This approval marked it as the first systemic therapy available for adult patients with symptomatic TGCT who experience severe morbidity or functional limitations and whose condition is not amenable to improvement with surgery.
Tenosynovial giant cell tumor is a rare, typically non-malignant tumor that originates from the synovium, bursae, or tendon sheaths. The disease causes abnormal growth and damage to these joint-lining tissues. Overproduction of colony-stimulating factor 1 (CSF1) is a key factor in the development of TGCT, leading to the recruitment and accumulation of immune cells, particularly macrophages, which contribute to tumor mass formation.
PLX3397 is effective in TGCT because it specifically inhibits CSF1R, which is often overexpressed in this condition. By blocking CSF1R, the drug suppresses the growth of these tumors and can improve patient symptoms and functional outcomes. The FDA’s approval was based on the ENLIVEN trial, a phase III study showing a significant overall response rate compared to placebo. The recommended dose is 250 mg orally twice daily with a low-fat meal, a change from the previous regimen to help manage potential side effects.
Ongoing Research for Other Conditions
Beyond its approved use in tenosynovial giant cell tumor, PLX3397 is under investigation for its potential to treat other medical conditions in various clinical trials. These investigational uses are not yet approved therapies.
One area of research includes certain types of cancers, such as glioblastoma (GBM), an aggressive brain tumor. Studies have explored PLX3397’s ability to cross the blood-brain barrier and target CSF1R and KIT, which are expressed in glioblastoma cells and the surrounding microenvironment. While early phase II studies in recurrent glioblastoma did not show significant efficacy as a single agent, ongoing research is exploring its use in combination therapies or with biomarkers to identify more responsive patient populations.
Research also explores its role in acute myeloid leukemia (AML) and other solid tumors. The rationale behind these trials stems from the understanding that CSF1R signaling can contribute to tumor growth, survival, and the recruitment of tumor-associated macrophages in various malignancies.
Managing Potential Side Effects
PLX3397 treatment can lead to potential side effects, requiring careful monitoring due to the possibility of serious adverse events. Liver toxicity is a significant concern, with reported cases of serious and potentially fatal liver injury, including vanishing bile duct syndrome. Healthcare providers are required to monitor liver tests before starting treatment, weekly for the first eight weeks, then every two weeks for the next month, and every three months thereafter.
Common side effects include changes in hair color, reported in 67% of patients in clinical trials. Other reported adverse reactions include fatigue, nausea, and diarrhea. Patients may also experience elevated cholesterol levels and changes in blood cell counts, such as decreased neutrophils and lymphocytes.
Side effect management often involves dose adjustments or temporary treatment interruption based on severity. If liver injury occurs, the dose may be reduced or the drug discontinued. Due to the risk of serious liver problems, PLX3397 is available only through the restricted Turalio Risk Evaluation and Mitigation Strategy (REMS) Program, which mandates specific monitoring and management protocols.