Efficacy of CDK4/6 inhibitors combined with endocrine therapy in HR+/HER2− breast cancer: an umbrella review

Abstract

Background The use of Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors has profoundly changed the challenge of endocrine therapy (ET) resistance in hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer. However, there is currently no comprehensive evaluation of the evidence for the efficacy of CDK4/6 inhibitors. We conducted an umbrella review to explore the impact of CDK4/6 inhibitor combined with ET on breast cancer by summarizing and assessing the meta-analysis (MA) and systematic review (SR) evidence. Methods Cochrane, PubMed, Embase, and Web of Science databases were searched from inception to August 1st, 2022. Eligible studies were assessed for methodological quality, report quality, and evidence quality using the AMSTAR-2 scale, PRISMA 2020, and GRADE grading systems, respectively. We summarized all efficacy outcomes of CDK4/6 inhibitors for breast cancer and reported them in narrative form. Results Our study included 24 MAs and SRs. The strongest evidence demonstrated that CDK4/6 inhibitor combined with ET significantly improved progression-free survival (PFS), overall survival (OS) in advanced breast cancer (ABC). A large body of moderate to high evidence showed a significant association between combination therapy and objective response rate (ORR), and clinical benefit response (CBR) benefit in ABC. Low evidence suggested some degree of benefit from combination therapy in second progression-free survival (PFS2) and time to subsequent chemotherapy (TTC) outcomes in ABC and invasive disease-free survival (IDFS) outcomes in early breast cancer. Conclusions Based on current evidence, CDK4/6 inhibitors combined with ET have great confidence in improving PFS, OS, ORR, and CBR outcomes in patients with ABC, which provides more rational and valid evidence-based medicine for CDK4/6 inhibitor promotion and clinical decision support.

A Canadian real world prospective observational study assessing the impact of hormone therapy ± targeted therapy in the treatment of HR+ HER2- advanced breast cancer

“…Consequently, most of the participants had priority access of CDK4/6i to 1st line due to local regulations in Canada (access to second line and beyond limited to clinical trials and expanded access, among others). Remarkably, in this population, CDK4/6i indication was extended beyond 1st line, leading more patients to a delayed use of palliative CT (15.1% and 43.2% in 2nd line and 3rd line respectively), as reported by others [40][41][42]. Use of CDK4/6i was slightly higher (20.9%) to other TTs in 3rd line (ET: 15.5%, mTORi: 16.2%, Other: 4.1%), but all clearly below CT (43.2%) (Fig.…”