Taselisib is an investigational medication studied for cancer treatment, though not currently approved for general clinical use. It was developed as a targeted therapy, aiming to interfere with specific molecular pathways that promote cancer growth.
How Taselisib Works
Taselisib functions as a phosphoinositide 3-kinase (PI3K) inhibitor, specifically targeting the alpha isoform (p110α) of this enzyme. The PI3K enzyme is a central component of the PI3K/Akt/mTOR signaling pathway, regulating cell growth, survival, proliferation, and metabolism. In many cancers, this pathway becomes overactive due to genetic alterations, including mutations in the PIK3CA gene encoding the p110α subunit.
The drug works by blocking the kinase activity of PI3K, disrupting signals that drive cancer cell proliferation. A distinct feature of taselisib is its ability to not only block this signaling but also to induce the degradation of the mutant p110α protein. This dual mechanism increases its effectiveness, particularly in cancer cells with PIK3CA gene mutations. By inhibiting this pathway, taselisib aims to halt tumor cell growth and promote programmed death.
Diseases Under Investigation
Taselisib has been primarily investigated for breast cancer, particularly in estrogen receptor (ER)-positive, HER2-negative cases harboring PIK3CA gene mutations. These mutations are observed in approximately 40% of ER-positive breast cancers, making the PI3K pathway an attractive target. PIK3CA mutations can activate the PI3K pathway, contributing to tumor growth and potential resistance against standard endocrine therapies.
Beyond breast cancer, taselisib was explored in early-phase “basket” studies for other advanced solid tumors with PIK3CA mutations. While some responses were noted in specific cancers like head and neck squamous cell carcinoma and cervical cancer, its overall activity as a single agent in non-breast cancers was limited. It was frequently studied in combination with other agents, such as fulvestrant, palbociclib, or HER2-directed therapies, to enhance its therapeutic effect.
Current Status in Development
Developed by Roche and Genentech, taselisib progressed through various clinical trial stages. Early Phase I studies in patients with advanced solid tumors determined appropriate dosing, identified common side effects, and provided preliminary evidence of activity in tumors with PIK3CA mutations. It then moved into Phase II trials, including studies in HER2-negative, hormone receptor-positive breast cancer where it was combined with fulvestrant, showing clinical activity.
A Phase III trial, SANDPIPER, investigated taselisib with fulvestrant for postmenopausal women with ER-positive, HER2-negative, PIK3CA-mutant metastatic breast cancer. Although SANDPIPER demonstrated a modest improvement in progression-free survival (around two months), Roche announced in June 2018 that it would not pursue further development. This decision was based on the drug’s modest clinical benefit and tolerability profile, leading to discontinuation of its manufacturing and development.
Potential Side Effects
Clinical trials identified a range of potential side effects, consistent with other PI3K inhibitors. Gastrointestinal issues are commonly reported, including diarrhea (sometimes severe), nausea, vomiting, decreased appetite, and stomatitis (mouth inflammation).
Metabolic changes, such as hyperglycemia (elevated blood sugar), were prominent. Rash, fatigue, and asthenia (weakness) were also reported.
Higher-grade adverse events were observed, sometimes leading to treatment discontinuation or dose reductions. While challenging, many effects are reversible with temporary interruption and can often be managed with supportive care.