Ibrance (palbociclib)

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.

P=N/A, N=1342, Completed, Pfizer | N=733 --> 1342

We discuss the case literature on the management of ophthalmic and eyelid metastases, including the role of radiotherapy. We outline the multi-disciplinary team (MDT) discussions and recommendations made in the present case, which ultimately found that the risks of radiation toxicity would outweigh the benefits. Adjuvant therapy with fulvestrant and palbociclib was recommended, with future consideration of a CDK 4/6 inhibitor in the event of metastatic recurrence.

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.

Our findings revealed a signalling pathway in which lung adenocarcinoma regulates stemness and tumourigenesis through HES1, and the targeting of this pathway by VR23 or napabucasin supports further preclinical development for CDK4/6 inhibitor combination therapy.

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.

Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance... Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor-positive, HER2-negative metastatic breast cancer...Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120... Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2- mBC.

P3, N=61, Terminated, SOLTI Breast Cancer Research Group | N=456 --> 61 | Trial completion date: Mar 2027 --> Mar 2026 | Active, not recruiting --> Terminated; The study was prematurely halted because enrollment was significantly delayed compared with the original projections due to the evolving therapeutic landscape.

Among 121 patients, 30 (24.8%) had BRCA1, 88 (72.7%) had BRCA2, and three (2.5%) had dual mutations; 66.9% received first-line therapy, with ribociclib in 69.4% and palbociclib in 29.8%. In multivariable analysis, ECOG ≥ 1 (HR 1.85; p = 0.010) and fulvestrant-based therapy (HR 1.74; p = 0.041) predicted shorter PFS; fulvestrant also predicted worse OS (HR 2.39; p = 0.008). CDK4/6 inhibitor-based therapy shows meaningful activity in gBRCAm HR+/HER2- MBC; the numerically poorer outcomes observed in BRCA2 carriers are hypothesis-generating and warrant validation in larger cohorts.

A review of the literature reveals that studies on the efficacy and tolerability of CDK 4/6 inhibitors have primarily focused on a limited number of patients aged 70 years or older. The results of these studies, similar to our study, generally indicate that efficacy and survival are similar to those in younger patients, and that dose reductions do not significantly impact survival. Furthermore, there are no studies in the literature yet that examine the relationship between the Charlson comorbidity index and survival in elderly patients with multiple comorbidities who are receiving CDK 4/6 inhibitors.

The combination of palbociclib and tamoxifen delayed deterioration in patients' QoL while they experienced reduced risk for disease progression.

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.