Efficacy of Subsequent Treatments After Disease Progression on CDK4/6 Inhibitors in Patients With Hormone Receptor–Positive Advanced Breast Cancer

PURPOSE Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy (ET) are the standard of care in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer (aBC). Yet, disease progression remains common. In the absence of established postprogression sequencing guidelines, we conducted a pooled analysis of Kaplan-Meier (KM)–derived patient data to assess the efficacy of subsequent treatment options after disease progression on CDK4/6i therapy. METHODS We conducted a systematic review and meta-analysis searching PubMed, Embase, Cochrane, and conference proceedings for randomized trials and cohort studies published from 2016 to December, 2023. Studies assessing subsequent treatment postprogression on CDK4/6i in patients with HR+ HER2– aBC were included. We performed a pooled analysis of KM-derived individual patient data. Outcomes of interest were progression-free survival (PFS) and overall survival (OS). This study is registered in PROSPERO, CRD42023491090. RESULTS Of 12,895 identified records, 18 studies comprising 4,899 patients were included. Maintaining treatment with a CDK4/6i plus ET post–CDK4/6i progression was associated with longer PFS (hazard ratio [HR], 0.61 [95% CI, 0.53 to 0.70]; P < .01) and prolonged OS (HR, 0.68 [95% CI, 0.60 to 0.77]; P < .01) compared with ET monotherapy. The PFS benefit was seen in both continuing the previous CDK4/6i (HR, 0.67 [95% CI, 0.56 to 0.79]; P < .01) and switching to a different CDK4/6i (HR, 0.68 [95% CI, 0.54 to 0.85]; P < .01). Subsequent therapy with everolimus plus ET achieved similar PFS (HR, 1.10 [95% CI, 0.90 to 1.35]; P = .35) and significantly shorter OS (HR, 1.52; [95% CI, 1.21 to 1.90], P < .01) as compared with ET monotherapy. CONCLUSION This extensive data pool suggests significant benefit of CDK4/6i regimens after disease progression as compared with ET monotherapy. Our data also support current guideline recommendations of ET-based therapies over chemotherapy for treatment sequencing.