More recently, the development of short-acting CDK4/6 inhibitors, particularly trilaciclib, has provided the first clinically approved example of pharmacologic myeloprotection in small-cell lung cancer...Cyclotherapy should not be regarded as a failed hypothesis prematurely tested, but as an evolving paradigm requiring refined biological stratification and temporal optimization. Properly implemented, it may redefine cytoprotection and expand the therapeutic latitude of modern oncology.

Structure-guided design based on the reported binding modes of palbociclib and the EYA2 inhibitor ETC-616 enabled the identification of EC21 as a lead compound...Importantly, EC21 exhibited pronounced antitumor activity in a syngeneic breast cancer mouse model and reduced EYA2 protein levels in tumor tissues without apparent toxicity. Collectively, these findings demonstrate that pharmacological stabilization of the CDK6-EYA2 interaction represents a feasible strategy for inducing EYA2 degradation and provides a potential therapeutic approach for EYA2-driven breast cancer.

This integrative analysis characterized the ribociclib pharmacokinetic and exposure-QTcF relationship, revealed the population effect on both pharmacokinetic and QTcF response, and justified the 400-mg dose in EBC. This work illustrates the utility and impact of quantitative pharmacology in justifying different doses across different patient populations for oncology therapies.

The incidence of anemia (43.9% versus 28.3%, p = 0.01), ≥grade 3 anemia (9.8% versus 1.9%, p = 3.10E-03), ≥grade 3 thrombocytopenia (9.8% versus 1.9%, p = 3.10E-03), ≥grade 3 ALT (6.1% versus 0.4%, p = 3.10E-03) and AST (7.3% versus 1.9%, p = 0.02) dysfunction occurred more frequently in the high-altitude group. Patients with HR+/HER2- ABC in the high-altitude region experienced inferior survival outcomes and individualized tolerability to CDK4/6i, which may inform scientific research and the management of CDK4/6i in Chinese patients with HR+/HER2- ABC.

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

Ribociclib-induced vitiligo-like depigmentation is an under-recognized adverse effect. Early recognition and multidisciplinary management are key to optimizing oncologic care without compromising therapeutic benefit.

Together, these findings position palbociclib as a versatile therapeutic backbone in CRC. By simultaneously targeting cell cycle and oncogenic signaling networks, palbociclib-based combinations induce synergistic and durable responses, offering a compelling rationale for tailored therapeutic strategies in molecularly defined CRC.

CDK4/6 inhibitor-based neoadjuvant therapy results in meaningful tumour downstaging and biological subtype modulation in HR+/HER2- breast cancer. The frequent conversion from Luminal B to Luminal A and the marked suppression of Ki-67 support the cytostatic, differentiation-driven mechanism of CDK4/6 inhibition. Although pCR rates remain modest compared with chemotherapy, the consistent biological and morphological responses highlight this approach as a lower-toxicity alternative or complement to chemotherapy in selected patients. Prospective studies incorporating proliferative dynamics and nodal outcomes are warranted.

P2, N=28, Completed, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University | Recruiting --> Completed

The results of the screen revealed that a PI3K inhibitor, copanlisib, combined with a CDK4/6 inhibitor, ribociclib, exhibited strong synergistic anti-Ewing sarcoma activity. In two xenograft models of Ewing sarcoma, we demonstrated that the combination significantly prolonged survival compared to treatment with either vehicle or single-agent therapy alone. Our findings identify a new candidate therapy combination for Ewing sarcoma and provide a resource of additional potential synergistic combinations for future validation.