Pharmacologic Features, Clinical Applications, and Drug Safety Evaluation of Inavolisib in the Treatment of Metastatic Breast Cancer.

The clinical benefit of available treatments in metastatic hormone receptor (HR)+/HER2-breast cancer (BC) remains limited due to the onset of resistance mechanisms, hence the need for increasingly personalized therapies targeting specific molecular alterations. In these cancers, the estrogen receptor, CDK4/6, and the phosphoinositide 3-kinase pathway are key drivers of tumor growth and survival. In preclinical studies, targeting these pathways together has been shown to enhance treatment response and delay resistance; in clinical practice, however, implementation of this combination has been limited by its challenging safety profile that results in poor tolerability. PIK3CA mutations are found in around 40% of cases and are associated with a poor prognosis. In BCs with alterations in the AKT/PIK3CA pathway, capivasertib, alpelisib, and inavolisib have recently improved progression-free survival (PFS). Inavolisib (GC0077) differs from the other drugs targeting this pathway by its high potency and tolerability when combined with endocrine therapy, mostly with fulvestrant, and a CDK4/6 inhibitor. Its recent use in the first-line combined treatment for advanced HR+/HER2-negative BC has shown a PFS benefit compared to placebo in the INAVO120 trial, suggesting its role as a valid treatment option in PIK3CA-mutated patients. Further studies are warranted to confirm these results in terms of prolonging efficacy and maintaining durable responses - with a manageable safety profile - in clinical practice.