Inavolisib: a second-generation PI3Kα inhibitor in HR+/HER2-negative breast cancer

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype.
• PIK3CA mutations activate PI3K/AKT/mTOR signaling, contributing to therapeutic resistance and relapse in up to 40% of patients.
• There is a critical need for more selective and tolerable targeted therapies for this patient population.

Purpose of the Study:

• To review the pharmacology, development, and therapeutic role of inavolisib, a novel PI3Kα-selective inhibitor.
• To evaluate the efficacy and safety of inavolisib in combination therapy for HR+/HER2- breast cancer.
• To discuss the potential of inavolisib in precision oncology.

Main Methods:

• Review of preclinical studies on inavolisib's pharmacology, including its dual inhibitory and degradation activity against mutant p110α.
• Analysis of data from the Phase III INAVO120 trial, assessing the addition of inavolisib to palbociclib and fulvestrant.
• Examination of safety data, identifying common adverse events.

Main Results:

• Inavolisib demonstrated improved isoform selectivity and reduced off-target toxicity compared to earlier agents in preclinical studies.
• The addition of inavolisib to palbociclib and fulvestrant nearly doubled progression-free survival and extended overall survival by seven months in the INAVO120 trial.
• The safety profile of inavolisib was manageable, with hyperglycemia and stomatitis being the most frequent adverse events.

Conclusions:

• Inavolisib represents a significant advancement for PIK3CA-mutated HR+/HER2- breast cancer due to its PI3Kα selectivity and mutant p110α degradation.
• Its demonstrated clinical activity and improved tolerability position inavolisib as a key therapeutic candidate.
• Ongoing trials are exploring inavolisib in resistant disease, HER2-positive settings, and novel combinations, highlighting its evolving role in precision oncology.