First-line CDK4/6 inhibitor-based combinations for HR+/HER2- advanced breast cancer: A Bayesian network meta-analysis
Xianan Guo1,2,3, Yunxiang Zhou1,2,3, Kun Zhang1,2,3
1Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Background:
International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA).
Methods:
We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines.
Results:
Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA = 78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA = 94.1%), abemaciclib+NSAI (SUCRA = 69.9%), and ribociclib+NSAI (SUCRA = 68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision.
Conclusions:
Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).
Insights
Ribociclib plus fulvestrant is the top choice for first-line advanced breast cancer treatment. This network meta-analysis compared cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to guide therapy selection.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- International guidelines advocate for cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).
- A lack of direct drug comparisons necessitates further analysis to determine optimal treatment strategies.
- Network meta-analysis (NMA) is employed to systematically compare available therapies.
Purpose of the Study:
- To conduct a network meta-analysis (NMA) to identify the most effective and safest first-line therapy for HR+/HER2- advanced breast cancer (ABC).
- To compare various endocrine therapies, including those combined with CDK4/6 inhibitors, based on progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs).
Main Methods:
- A comprehensive literature search was performed across major databases (PubMed, Embase, Web of Science, Cochrane) up to September 30, 2023.
- Included studies were randomized controlled trials (RCTs) evaluating first-line endocrine treatments for HR+/HER2- ABC.
- Bayesian network meta-analysis (NMA) was conducted following PRISMA guidelines, extracting hazard ratios (HRs) for PFS and OS, and relative risks (RRs) for ORR and AEs.
Main Results:
- Thirteen RCTs involving 10 treatments were analyzed, with most studies demonstrating a low risk of bias.
- Ribociclib plus fulvestrant showed the highest ranking for progression-free survival (PFS) (SUCRA=85.0%), followed by dalpiciclib plus nonsteroidal aromatase inhibitor (NSAI) (SUCRA=78.9%).
- For overall survival (OS), ribociclib plus fulvestrant ranked highest (SUCRA=94.1%), followed by abemaciclib plus NSAI (SUCRA=69.9%) and ribociclib plus NSAI (SUCRA=68.5%). Ribociclib demonstrated the lowest rate of grade 3/4 adverse events (AEs), while dalpiciclib had the worst safety profile.
Conclusions:
- Ribociclib plus fulvestrant emerges as a likely superior first-line treatment option for HR+/HER2- advanced breast cancer.
- Dalpiciclib plus NSAI demonstrated high efficacy but was associated with the poorest safety profile.
- Abemaciclib plus NSAI and ribociclib plus NSAI are promising alternatives, whereas palbociclib showed inferior outcomes in this NMA.
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