The introduction of the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors abemaciclib and ribociclib to the adjuvant setting marks a significant advancement in the treatment of hormone-receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer (HR+, HER2- EBC). The paper also highlights strategies to enhance patient medication adherence and the involvement of multidisciplinary care teams to support treatment delivery. As research continues to evolve, additional follow-ups of the monarchE and NATALEE trials and future trials will further refine patient selection and treatment sequencing, ultimately improving outcomes and enhancing the quality of life for patients with HR+, HER2- EBC.

Based on current published data, abemaciclib is the preferred CDK4/6 inhibitor that should be used in eligible patients (unless contraindicated). To ensure optimal dose intensity and adherence to treatment schedule, use of literature and patient information material can improves compliance. Treatment modification requires early reporting of adverse effects, a responsibility of the patient and caregiver (relatives).

Endocrine therapies, including fulvestrant and novel oral selective estrogen receptor degraders (SERDs) like elacestrant, show promise, especially in patients with ESR1 mutations. Targeted therapies such as PI3K/AKT/mTOR inhibitors, exemplified by alpelisib and capivasertib, offer potential by addressing downstream signaling pathways involved in resistance. Additionally, FGFR inhibitors like erdafitinib are under investigation for their role in overcoming specific resistance mechanisms...Ongoing clinical trials are expected to provide deeper insights, guiding the development of more effective post-progression therapeutic strategies. This evolving landscape highlights the need for continuous research and individualized patient care to improve survival and quality of life in HR + mBC patients.

However, there has been a decrease in studies reporting adverse reactions to abemaciclib-related kidney injuries. Thus, this study was aimed at assessing its safety profile using a large-scale pharmacovigilance database.MethodsAbemaciclib-related adverse drug reaction reports from the Food and Drug Administration Adverse Event Reporting System were obtained and scrutinized, and adverse drug reactions were selected using reporting odds ratio, the proportional reporting ratio methods, empirical Bayes geometric mean and UK Medicines and Healthcare products Regulatory Agency methods.ResultsWe selected 10,757 matched reports associated with abemaciclib, among which we found eight adverse reactions about kidney injuries correlated with abeamciclib, such as increased blood creatinine, renal disorder, decreased glomerular filtration rate, increased blood urea, hydronephrosis, abnormal renal function test, increased creatinine renal clearance and increased cystatin C. A demographic analysis of reported cases of abemaciclib-associated renal injury revealed that the majority were female, aged ≥46 years and had taken the drug ≥30 days.ConclusionThis study highlights the characteristics of adverse reactions with abemaciclib and those associated with renal damage, which are crucial for safety studies on the clinical use of this drug.

Consistent with this observation, 18F-FLT PET was able to differentiate the resistance to Palbociclib from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in OVCAR-3 model. This work highlights the utility of 18F-FLT PET as a quantitative, non-invasive biomarker which provides whole-body information. 18F-FLT PET has potential to be a biomarker in novel CDK inhibitor clinical trials to evaluate Palbociclib resistance and identifying responding and non-responding patients.

P1, N=12, Completed, Children's Oncology Group | Active, not recruiting --> Completed

This case highlights the potential benefits of CDK4/6 inhibitors combined with endocrine therapy in the management of HR+, HER2-negative metastatic breast cancer, particularly in cases with skin involvement. These agents have reshaped the therapeutic landscape, providing prolonged disease control and improved patient outcomes.

We performed adisproportionality analysis to evaluate CDKI-related adverse events (AEs) inolder adults administered abemaciclib, palbociclib, and ribociclib. Our results aligned with clinicalobservations, emphasizing possible CDKI-related AEs. Conducting future clinicalresearch is essential to confirm AE-related differences among CDKIs in olderindividuals.

This extended follow-up analysis of PROs in PALOMA-2 shows continued QoL maintenance for patients with ER+/HER2- mBC receiving long-term palbociclib plus letrozole treatment.

P2, N=9, Terminated, University of Alabama at Birmingham | Trial completion date: Apr 2026 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2025 --> Jul 2024; Abemaciclib efficacy

P2, N=100, Recruiting, Universitaire Ziekenhuizen KU Leuven | Trial completion date: Oct 2026 --> Jan 2028 | Trial primary completion date: Oct 2026 --> Jan 2028

Importantly, it also showed good pharmacokinetic properties in rats, meanwhile, B15 effectively inhibited tumor growth in vivo (TGI = 85.3 %) without causing significant toxicity. Overall, our results introduce a promising strategy of dual CDK4/6 and BRD4 inhibitors for the treatment of NSCLC.

P2, N=333, Active, not recruiting, Pfizer | Phase classification: P3 --> P2 | Trial completion date: Dec 2028 --> Jan 2028 | Trial primary completion date: Dec 2025 --> Jun 2025

P1, N=34, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2025 --> Dec 2025

P1, N=102, Recruiting, Shandong Suncadia Medicine Co., Ltd. | Trial primary completion date: Dec 2024 --> Jun 2025

P1, N=24, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jul 2025 --> Oct 2024

The PBPK model successfully simulated the PK profiles and CDK4/6 occupancy for ABE and its three metabolites in plasma and CSD, and determined the optimal dosing in brain MBC. Overall,The PBPK model can provide important insights for personalized dosing strategies, contributing to improved treatment efficacy and safety for patients, particularly those with brain MBC.

P1, N=48, Active, not recruiting, Nader Sanai | Trial completion date: Jan 2025 --> Mar 2026

Moreover, we showed that the CDK6 inhibitor palbociclib effectively suppresses the pro-growth and chemoresistant effects induced by IGF2BP3 overexpression. These results suggested that the IGF2BP3/m6A/CDK6 axis plays a pivotal role in bladder cancer progression and chemoresistance, and that targeting this pathway with CDK6 inhibitors such as palbociclib may offer a promising therapeutic strategy for overcoming cisplatin resistance in bladder cancer.

In patients with heavily pretreated metastatic RCC, abemaciclib monotherapy had no clinically meaningful activity without new toxicity signals. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2α inhibitors and immunotherapy.

Therefore, how to screen out the prime population for intensive adjuvant therapy of ribociclib needs to worth explored. In this paper, we discussed that the adaptive neoadjuvant endocrine therapy can screen out the prime population for intensive adjuvant therapy of ribociclib.

P2, N=30, Recruiting, Harbin Medical University | Not yet recruiting --> Recruiting

P=N/A, N=2615, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P2, N=60, Recruiting, University of Washington | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Mar 2025 --> Mar 2027

P2, N=96, Recruiting, Abramson Cancer Center at Penn Medicine | Trial primary completion date: Nov 2024 --> Jul 2027

Given the tumor's limited sensitivity to chemotherapy, she was treated with neoadjuvant endocrine therapy (ET) using fulvestrant, palbociclib, and leuprolide. This case supports the potential role of endocrine-based targeted therapy in managing pediatric LGSOC, offering a viable alternative for patients with limited treatment options. Further research is needed to optimize treatment strategies and improve survival outcomes in this rare population.

Targeted therapeutic drugs, such as Abemaciclib (targeting the RB1 pathway) with an IC50 value of 1.744 µM, and Alflutinib Mesylate (targeting the EGFR pathway) with an IC50 value of 0.9150 µM, exhibited significant cytotoxic effects in the MPT2 organoid models. This study highlights the novel application of PDOs for studying the molecular landscape of MPTs and identifying effective therapeutic targets, offering a promising platform for guiding personalized treatment strategies for this rare and challenging cancer.

P=N/A, N=1443, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | Trial completion date: Mar 2029 --> Mar 2039

P3, N=209, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

P3, N=405, Active, not recruiting, ETOP IBCSG Partners Foundation | Recruiting --> Active, not recruiting | Trial completion date: Nov 2027 --> Jan 2029 | Trial primary completion date: Jan 2025 --> Jan 2026

P2, N=220, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2024 --> Jun 2025

P=N/A, N=68, Active, not recruiting, Mayo Clinic | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Mar 2021 --> Mar 2026

The sensitivity of three common drugs (homoharringtonine, lapatinib, and palbociclib) in LUAD could be evaluated by the CR-relevant risk model. Ultimately, the experimental results confirmed that the expression trends of CDK1 and HLA-DMA in our collected clinical samples were in line with the expression trends in the TCGA-LUAD dataset. In conclusion, a CR-relevant risk model based on CDK1 and HLA-DMA was constructed by using bioinformatics analysis, which might supply a new insight into the improved prognosis of LUAD.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Mar 2025 --> Sep 2025

The biochemical assays revealed that abemaciclib hindered the progression of breast cancer cells MDA-MB-231 and MCF-7 and enhanced RT (10 Gy) by provoking cell cycle arrest throughout the restraint of CDK4 and CDK6 expression and increasing apoptosis, in addition to decreasing the PI3K/AKT/mTOR and NF-κβ/TGF-β pathway expression; inhibiting CK18 and COX2 activity; boosting the protein concentration of BAX and P53; and decreasing Bcl-2, IL-6, IL-1β, MMP2, and MMP9, modulating oxidative stress markers. These results implied potential effects of radiation and CDK4/6i abemaciclib on breast cancer cell lines.

P1, N=18, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Mar 2026 --> Mar 2029 | Trial primary completion date: Mar 2025 --> Mar 2027

P=N/A, N=36, Recruiting, Fudan University

P3, N=1400, Not yet recruiting, Novartis Pharmaceuticals | N=3100 --> 1400

P=N/A, N=3250, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

Here we examine the composition, communication, and phenotypes of tumor-associated cells in serial biopsies from stage II and III high-risk estrogen receptor positive (ER+ ) breast cancers of patients receiving endocrine therapy (letrozole) as single agent or in combination with ribociclib, a CDK4/6-targeting cell cycle inhibitor. Exogenous IL-15 improves CDK4/6 inhibitor efficacy by augmenting T-cell proliferation and cancer cell killing by T cells. In summary, response to ribociclib in stage II and III high-risk ER +  breast cancer depends on the composition, activation phenotypes and communication network of immune cells.

P1, N=54, Active, not recruiting, Abramson Cancer Center at Penn Medicine | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Dec 2024 --> Aug 2025

These analyses of NATALEE show that adding adjuvant ribociclib to an NSAI does not negatively impact HRQOL in patients with HR+/HER2- EBC.