P2, N=46, Recruiting, University of Nebraska | Trial completion date: Sep 2031 --> Sep 2032 | Trial primary completion date: Sep 2025 --> Sep 2026

P2, N=333, Active, not recruiting, Pfizer | Trial primary completion date: Sep 2025 --> Mar 2026

P3, N=701, Active, not recruiting, Celcuity Inc | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2025 --> Jun 2026

P=N/A, N=2766, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P=N/A, N=100, Enrolling by invitation, London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's | Not yet recruiting --> Enrolling by invitation

Omission of SLNB in patients with small HR-positive/HER2-negative tumors results in a missed indication for CDK4/6i in <8 % with minimal impact on recurrence.

The advent of CDK4/6 inhibitors, namely, palbociclib, ribociclib and abemaciclib, has changed the management of oestrogen receptor (ER)-positive/HER2-negative advanced breast tumours. Nonetheless, the acquired resistance to CDK4/6 inhibitors remains a major therapeutic challenge. Thus, the identification of molecular drivers involved in the resistance to these drugs is crucial for the design of novel therapeutic approaches and the selection of patient-centred strategies in various types of tumours.

Clinical data indicate a higher incidence of nephrotoxic adverse reactions in patients receiving CDK4/6i compared to control groups, with abemaciclib showing the highest risk ratio...Preclinical studies suggest a complex effect on renal health; while some data indicate acute nephroprotection, long-term rodent models treated with palbociclib after ischemic AKI demonstrated impaired recovery, increased renal fibrosis, and cellular senescence, indicating potentially detrimental long-term chronic effects...Furthermore, these agents are susceptible to significant drug-drug interactions, particularly with CYP3A4 inhibitors/inducers and immunosuppressants, necessitating careful dose adjustments and monitoring, especially in solid organ transplant recipients. This review consolidates current evidence regarding the renal of CDK4/6i, emphasizing the need for vigilant monitoring and a multidisciplinary approach to optimize patient outcomes.

P2, N=162, Completed, MedSIR | Active, not recruiting --> Completed

Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

CARABELA trial results suggest that 12 months of letrozole/abemaciclib may not offer similar efficacy to that of chemotherapy in achieving RCB 0-I. However, in less proliferative tumors (RS <26 or Ki-67 <30%), outcomes were comparable, suggesting that letrozole/abemaciclib could replace (neo)adjuvant chemotherapy in selected patients.

The combination therapy provides a clinically significant improvement in survival and treatment responses, even though the toxicity is increased but manageable, and requires careful prescription.