Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis.

Palbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent. We searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib. 8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3-4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively. Palbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.

Desnoyers A ，Nadler MB ，Kumar V ，Saleh R ，Amir E ... -  《-》

Influence of ethnicity on cyclin-dependent kinase inhibitor efficacy and toxicity: A systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard of care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (aBC). While the efficacy and safety profiles of CDK4/6i and ET have been extensively evaluated in phase II and III trials worldwide, it remains unclear whether the response to CDK4/6i and toxicity profile vary among Asian and non-Asian patients. Therefore, we aimed to assess the treatment efficacy of ET with and without CDK4/6i by comparing outcomes in Asian and non-Asian subgroups included in these clinical trials. In addition, we evaluated the toxicity profiles of the treatments by estimating the risk of treatment-related adverse events (AEs). We conducted a meta-analysis including the most recent randomized trial data systematically searched from PubMed, Embase, Web of Science, Cochrane CENTRAL (from inception to May 31st, 2024) or presented in abstracts or oral presentations at the ESMO, ASCO, and SABCS international congresses. We included studies comparing CDK4/6i (palbociclib, ribociclib, abemaciclib, dalpiciclib) + ET versus placebo + ET. Progression-free survival (PFS) and overall survival (OS), hazard ratios (HR), and 95 % confidence intervals (CI) were extracted for the two subgroups of interest. To evaluate the treatment-related toxicity profiles, we extracted the number of side effects to estimate the risk of treatment-emergent AEs. Eleven studies (n = 5129) were included in this meta-analysis. The addition of CDK4/6i to ET consistently improved PFS in both Asian (HR = 0.52, 95 % CI 0.47-0.60; p < 0.001) and non-Asian (HR = 0.58, 95 % CI 0.52-0.64; p < 0.001) groups. Similarly, the combination of CDK4/6i + ET led to an OS improvement in both Asian (HR = 0.75, 95 % CI 0.62-0.91; p = 0.003) and non-Asian (HR = 0.81, 95 % CI 0.73-0.89; p < 0.001) patients. The risk of treatment related toxicity was higher in the CDK4/6i + ET arm in both Asian and non-Asian groups. Interestingly, a numerically higher rate of treatment-related hematological toxicity was observed in Asian patients, although no significant interethnic difference was found in the relative risk of these events. The combination of CDK4/6i and ET significantly improves PFS and OS compared to ET alone in both Asian and non-Asian patients with HR+/HER2-aBC. Although the magnitude of benefit appears to be independent of ethnicity, future clinical trials should devise a standardized method for stratifying patients by ethnicity to more effectively assess potential differences in treatment benefits. PROSPERO registration number: CRD42024543217.

Buonaiuto R ，Caltavituro A ，Tafuro M ，Longobardi A ，Pavone G ，De Santis P ，Caputo R ，De Angelis C ，Del Mastro L ，Puglisi F ，Giuliano M ，Arpino G ，Pagliuca M ，De Laurentiis M ... -  《-》

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》

Hematological toxicity of cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer: a network meta-analysis and pharmacovigilance study.

Ding H ，Xu W ，Dai M ，Li S ，Xin W ，Tong Y ，He C ，Mi X ，Zhan Z ，Fang L ... -  《-》

Comparison of Safety and Treatment Continuity of Palbociclib and Abemaciclib for Hormone Receptor-Positive, HER2-Negative Metastatic/Recurrent Breast Cancer.

Go M ，Kimura M ，Yamada S ，Usami E ，Noguchi Y ，Yoshimura T ... -  《-》