Gedatolisib after CDK4/6 inhibition in HR-positive/HER2-negative advanced breast cancer: pharmacology, phase III evidence, and therapeutic positioning.

INTRODUCTION

Progression following CDK4/6 inhibition remains a therapeutic challenge in hormone receptor-positive, HER2-negative advanced breast cancer. Gedatolisib, an FDA-approved pan-class I PI3K/mTORC1/2 inhibitor, introduces a treatment strategy for disease without a detected PIK3CA mutation.

AREAS COVERED: This review critically evaluates gedatolisib pharmacology, clinical evidence, safety, biomarkers, and therapeutic positioning. PubMed/MEDLINE, publisher platforms, ClinicalTrials.gov, regulatory sources, and oncology conference records were searched through July 2026, with updates through September 2026. In phase III VIKTORIA-1, median progression-free survival was 9.3 versus 2.0 months with gedatolisib-fulvestrant-palbociclib versus fulvestrant (hazard ratio 0.24) and 7.4 versus 2.0 months with gedatolisib-fulvestrant versus fulvestrant (hazard ratio 0.33). Experimental regimens were not directly compared in a powered analysis. Stomatitis, metabolic toxicity, palbociclib-associated neutropenia, and weekly intravenous administration complicate treatment delivery.

EXPERT OPINION: Gedatolisib expands post-CDK4/6 treatment options, but optimal positioning requires individualized patient selection without assuming triplet superiority. Mature survival outcomes, validated predictive biomarkers, comparative sequencing evidence, and VIKTORIA-2 findings will determine its long-term clinical value.