Lerociclib (DB16218): A Comprehensive Monograph on a Differentiated CDK4/6 Inhibitor

Executive Summary

Lerociclib is an investigational, orally bioavailable, small molecule drug that functions as a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). As a member of the third generation of CDK inhibitors, it represents a refined therapeutic agent designed to address the primary drivers of cell cycle progression in certain malignancies, most notably hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The mechanism of action is centered on the inhibition of the Cyclin D-CDK4/6-Retinoblastoma (Rb) protein pathway, a critical regulator of the G1-S phase transition in the cell cycle. By preventing the phosphorylation of Rb, lerociclib induces a durable G1 cell cycle arrest, thereby suppressing the proliferation of cancer cells dependent on this pathway.

The clinical development of lerociclib has been robust, culminating in two pivotal, randomized, double-blind, placebo-controlled Phase III trials—LEONARDA-1 and LEONARDA-2. These studies have successfully demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) in patients with HR+/HER2- advanced or metastatic breast cancer. LEONARDA-1 established its efficacy in combination with fulvestrant in an endocrine-resistant population, while LEONARDA-2 confirmed its benefit as a first-line therapy in combination with letrozole. The magnitude of benefit observed, with hazard ratios for disease progression or death consistently around 0.46, positions lerociclib's efficacy as highly competitive with established market leaders in the CDK4/6 inhibitor class.