The efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in the adjuvant treatment of patients with high-risk invasive HR+/HER2-early breast cancer: A comprehensive updated meta-analysis of randomized cli

This paper aimed to evaluate the effectiveness of incorporating CDK 4/6 inhibitors (CDK4/6i) into ET for the adjuvant treatment of HR + HER2-resected early-stage breast cancer (ESBC) patients, employing meta-analysis. In this paper, we compiled randomized clinical trials focusing on CDK4/6i used in the adjuvant treatment of high-risk invasive HR-positive and HER2-ESBC patients. A meta-analysis was performed in line with the PRISMA guidelines. We identified four clinical trials that met our inclusion criteria and were published between 2020 and 2024. These trials involved a combined sample size of 17,749 patients diagnosed with breast cancer. The data obtained from the pooled analysis revealed a remarkable beneficial trend in terms of invasive disease-free survival (iDFS) for the use of ET in combination with CDK4/6i compared to the group receiving ET alone (HR = 0.81, 95 % CI: 0.67-0.98, p = 0.03). Of note, CDK4/6 inhibitors demonstrated a notably beneficial effect in both grade 2 (HR = 0.69, 95 % CI: 0.59-0.81, p < 0.001) and grade 3 (HR = 0.76, 95 % CI: 0.65-0.89, p < 0.001). Significant improvements were noted in terms of distant relapse-free survival (dRFS) in the groups treated with abemaciclib and ribociclib (HR = 0.65, 95 % CI: 0.56-0.76, p < 0.001; HR = 0.72, 95 % CI: 0.58-0.89, p = 0.003, respectively). CDK4/6i didn't yield a statistically significant difference in overall survival (OS) (HR = 0.96, 95 % CI: 0.77-1.19, p = 0.69). The use of CDK4/6i with ET was associated with an increased risk of adverse events, particularly anemia and neutropenia, compared with ET alone (OR = 9.12, 95 % CI = 5.04-16.48, p < 0.001). The findings of this paper demonstrate a significant improvement in iDFS when ET is combined with CDK4/6i, compared to ET alone. Specifically, treatments with abemaciclib and ribociclib showed notable enhancements in dRFS.

Keskinkilic M ，Arayici ME ，Basbinar Y ，Ellidokuz H ，Yavuzsen T ，Oztop I ... -  《-》

Comparative overall survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR+/HER2- metastatic breast cancer in the US real-world setting.

Randomized controlled trials have shown inconsistent overall survival (OS) benefit among the three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as first-line (1L) treatment of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). Several real-world studies compared CDK4/6i effectiveness, with inconsistent findings. This study compared overall survival (OS) of patients with HR+/HER2- mBC receiving 1L palbociclib, ribociclib, or abemaciclib, in combination with an aromatase inhibitor (AI), in US clinical practice. This retrospective study used real-world data from the Flatiron Health electronic health record-derived deidentified longitudinal database. Patients with HR+/HER2- mBC aged ≥18 years at mBC diagnosis started 1L CDK4/6i therapy (index treatment) between February 2015 and November 2023, with a potential ≥6-month follow-up. OS was defined as months from start of index treatment to death. Stabilized inverse probability of treatment weighting (sIPTW; primary analysis) was used to balance baseline patient characteristics. Multivariable Cox proportional hazards model was carried out as a sensitivity analysis. Of 9146 eligible patients, 6831, 1279, and 1036 received palbociclib plus AI, ribociclib plus AI, or abemaciclib plus AI, respectively. After sIPTW, baseline characteristics were balanced between treatment groups. After sIPTW, no significant OS differences were found between treatment groups [ribociclib versus palbociclib: adjusted hazard ratio (aHR) 0.98, 95% confidence interval (CI) 0.87-1.10, P = 0.7531; abemaciclib versus palbociclib: aHR 0.95, 95% CI 0.84-1.08, P = 0.4292; abemaciclib versus ribociclib: aHR 0.97, 95% CI 0.82-1.14, P = 0.6956]. Sensitivity analysis including a subanalysis of patients who started index treatment in 2017 or later also showed no significant OS differences between treatment groups. This large real-world study suggested that there were no significant OS differences between 1L ribociclib, abemaciclib, and palbociclib in combination with an AI for patients with HR+/HER2- mBC. These findings together with other factors such as safety and quality of life are helpful in the selection of CDK4/6i combination therapy for patients with HR+/HER2- mBC.

Rugo HS ，Layman RM ，Lynce F ，Liu X ，Li B ，McRoy L ，Cohen AB ，Estevez M ，Curigliano G ，Brufsky A ... -  《ESMO Open》

Real-world experience with CDK4/6 inhibitors in hormone receptor-positive metastatic and recurrent breast cancer: findings from an Asian population.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.

Chen BF ，Tsai YF ，Chao TC ，Lien PJ ，Lin YS ，Feng CJ ，Chen YJ ，Cheng HF ，Liu CY ，Lai JI ，Tseng LM ，Huang CC ... -  《-》

Unveiling the Potential of Cyclin-Dependent Kinases 4 and 6 Inhibitors Beyond Progression in Hormone Receptor Positive/Human Epidermal Growth Factor Negative Advanced Breast Cancer - A Clinical Review.

Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) have revolutionized the management of hormone receptor-positive (HR +) breast cancer. However, resistance to CDK4/6i remains an unavoidable challenge, with limited evidence to guide the choice of subsequent treatments. Continuation of CDK4/6 inhibition raises as a compelling treatment option and is currently an active area of research. This approach encompasses multifaceted strategies regarding CDK4/6i sequence (same or switched agent), endocrine therapy (ET) partner and potential combination with a third drug. Continuing CDK4/6 inhibition while targeting ET resistance in tumours still dependent on ER activity (i.e., ESR1 mutation) through a ctDNA-guided approach has the potential of becoming practice-changing, pending the results of ongoing phase III studies. Conversely, the efficacy of this strategy in cases of radiological progression in a biomarker-unselected population appears to be rather unsatisfactory. While some benefit, albeit modest, has been observed from switching to a different CDK4/6i after progression (e.g. ribociclib after palbociclib in the MAINTAIN trial and abemaciclib after both palbociclib and ribociclib in the postMONARCH trial), the current evidence (mainly with palbociclib) clearly argues against maintaining the same CDK4/6i. Biomarker analyses to optimally identify patients suitable for this approach yielded inconsistent findings that do not apply to daily clinical decision making. Attractive preliminary efficacy has recently emerged from combining a third agent (immunotherapy, AKT/ PIK3CA/mTOR inhibitor, new ET agents, CDK2 inhibitors) to CDK4/6i and ET, but further validation in larger ongoing trials is required to also determine the optimal timing for incorporating these agents into the therapeutic timeline. To date, CDK4/6i after CDK4/6i progression is far from being a standard of care. However, selected patients with indolent disease, prolonged exposure to previous CDK4/6i treatment (especially palbociclib) and without actionable molecular alterations, may be suitable for suchmaintenance strategy beyond progression. In this challenging and rapidly evolving treatment landscape, ongoing studies can refine the optimal approach and identify clinical and molecular factors to select the best treatment for the right patient.

Benvenuti C ，Grinda T ，Rassy E ，Dixon-Douglas J ，Ribeiro JM ，Zambelli A ，Santoro A ，Pistilli B ... -  《-》

Real-World Experience with CDK4/6 Inhibitors in the First-Line Palliative Setting for HR+/HER2- Advanced Breast Cancer.

Patel R ，Mathews J ，Hamm C ，Kulkarni S ，Gupta R ，Opperman T ，Chiong JD ，Nasser A ... -  《-》