Gedatolisib for the treatment of hormone receptor-positive/HER2-negative advanced breast cancer: a European perspective.

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) represents the most common disease subtype. Although the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) has substantially improved patient outcomes, treatment resistance inevitably develops. Therapeutic options after progression on CDK4/6i-based regimens provide limited clinical benefit, particularly in patients without actionable target mutations. The PI3K/AKT/mTOR pathway drives endocrine and CDK4/6i resistance and of tumor progression, representing an attractive therapeutic target in this setting. Gedatolisib is a novel intravenous dual PI3K/mTOR inhibitor that simultaneously targets all class I PI3K isoforms and both mTOR complexes. Preclinical studies demonstrated broad antitumor activity irrespective of PIK3CA mutational status and enhanced activity when combined with ET and CDK4/6i. Early clinical trials reported preliminary antitumor activity, although associated with a considerable toxicity profile. More recently, the phase III VIKTORIA-1 trial demonstrated clinically meaningful PFS improvements with gedatolisib-based regimens in patients with HR+/HER2- metastatic BC pretreated with CDK4/6i, regardless of PIK3CA mutational status. This review summarizes the biological rationale, pharmacological profile, clinical development, and potential therapeutic positioning of gedatolisib in the evolving treatment landscape of HR+/HER2- metastatic BC.