Verzenio (abemaciclib)

Rhabdomyolysis due to CDK4/6 inhibitor-statin interactions is a rare but potentially life-threatening complication. Vigilant monitoring, timely intervention, and tailored treatment strategies are essential for preventing complications and improving patient outcomes.

This case highlights a rare but severe complication of ABE treatment. While CDK4/6 inhibitors are widely used as first-line agents in advanced breast cancer due to their high efficacy and generally favorable side-effect profile, clinicians should remain vigilant for NE, which requires prompt intervention.

The clinical deployment of ATP-competitive inhibitors-Palbociclib, Ribociclib, and Abemaciclib-has revolutionized the standard of care for hormone receptor-positive breast cancer. By recruiting the ubiquitin-proteasome system to catalytically degrade target proteins, CDK4/6-PROTACs eliminate both enzymatic activity and non-catalytic scaffolding functions, offering a mechanistically distinct strategy to overcome the structural limitations of traditional inhibitors. This review summarizes the progression from clinical inhibitors to strategies for overcoming resistance, offering insights into the future development of CDK4/6-targeted therapies.

High-resolution lineage tracing and multi-omic studies demonstrate that CDK4/6i resistance is shaped by clonal selection and adaptive remodeling of cell states, with the ESR1 mutation status and the specific inhibitor acting as key determinants of evolutionary trajectories. These findings suggest that both variables should be considered when designing sequential and combination treatment strategies to overcome CDK4/6i resistance.

P1, N=10, Terminated, Eli Lilly and Company | Completed --> Terminated; The study was terminated early as related study I3Y-MC-JPCM (NCT03706365) did not meet its primary endpoint.

In this comparative study, CDK4/6 inhibitor-based therapy was associated with significantly higher prevalence and severity of punctate epitheliopathy and vortex keratopathy, independent of aromatase inhibitor exposure and in the absence of measurable tear film dysfunction. These findings suggest a direct cytostatic effect on the corneal epithelium. Among respondents, symptom scores were uniformly low; however, the incomplete OSDI response rate in the CDKAI group limits definitive conclusions regarding symptom burden. Proactive corneal surface evaluation with fluorescein staining may be warranted during CDK4/6 inhibitor treatment.

P2, N=25, Recruiting, University Health Network, Toronto | Not yet recruiting --> Recruiting

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (such as palbociclib, ribociclib, and abemaciclib) exert their effects by arresting the cell cycle at the G1/S checkpoint. From the perspective of laboratory medicine, we further emphasize the importance of biomarker detection, therapeutic target assessment, and precision molecular subtyping in identifying patients most likely to benefit from CDK4/6 inhibitor-based therapies. In addition, we discuss the role of these agents in remodeling the TIME, evaluate current combination strategies aimed at overcoming resistance, and highlight future directions for advancing this rapidly evolving field.

P2, N=110, Recruiting, Dana-Farber Cancer Institute | N=180 --> 110

 Switching CDK4/6i and ET conferred a statistically significant improvement of PFS in patients with progression or recurrence on prior CDK4/6i-containing therapy. These findings underscore the variability in survival outcomes based on post-CDK4/6i therapy choices in HR+/HER2- MBC, with promising evidence for rechallenging strategies.

P2, N=19, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Apr 2026 --> Nov 2025