Efficacy of subsequent treatments after disease progression on CDK4/6 inhibitors therapy in patients with hormone receptor-positive metastatic breast cancer: A Kaplan-Meier derived individual-patient data meta-analysis

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are standard-of-care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). Yet, disease progression is common in these patients. In the absence of established guidelines for optimal sequencing post-progression, we conducted a pooled analysis of patient data to assess the efficacy of subsequent treatment options following disease progression on CDK4/6i therapy. Methods: We conducted a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for randomized controlled trials (RCTs) and observational cohort studies reporting subsequent treatment post-CDK4/6i progression in patients with HR+HER2-mBC from 2016 to December 2023. We performed a pooled analysis of Kaplan-Meier-derived individual patient data for progression-free survival (PFS) and overall survival (OS). Subgroups analysis according to drug type, and a sensitivity analysis including only RCTs were also conducted. Statistical analysis was performed with R Statistical Software. Results: Of 12,895 identified records, 18 studies (7 RCTs and 11 cohort studies) comprising 4,868 patients with HR+HER2-mBC were included. Maintaining treatment with a CDK4/6i postCDK4/6i progression was associated with longer PFS (HR: 0.64; 95% CI: 0.54–0.76; p,0.01; n=1,397) and prolonged OS (HR: 0.70; 95% CI: 0.61–0.79; p,0.01; n=2,369) compared with ET monotherapy. The PFS benefit was seen in both continuing the prior CDK4/6i (HR 0.62; 95%CI: 0.54–0.72; p,0.01; n=1,178) or switching to a different CDK4/6i (HR 0.49; 95%CI: 0.30–0.82; p,0.01; n=638). Subsequent therapy with PI3K/AKT/mTOR inhibitors plus ET also achieved longer PFS (HR: 0.74; 95% CI: 0.61–0.90; p,0.01; n=744), but significantly shorter OS (HR 1.36; 95%CI: 1.09–1.71; p,0.01; n=1,564) compared with ET monotherapy. PFS with chemotherapy was not different from ET monotherapy (HR 0.93; 95%CI: 0.76–1.13; p=0.45; n=879) but exhibited shorter OS (HR 1.55; 95%CI: 1.38–1.72; p, 0.01; n=2,476). Sensitivity analyses including only RCTs, confirmed the greater PFS of maintaining CDK4/6i plus ET compared with ET monotherapy (HR: 0.69 95% CI: 0.57–0.83; p,0.01; n=751). Conclusions: This extensive data pool of RCTs and cohort studies suggests the potential clinical benefit of continued CDK4/6i after disease progression compared to ET monotherapy. Data from phase III trials will further aid in understanding this question. Our data also supports current guideline recommendations of ET-based therapies over chemotherapy as the preferred treatment sequencing in HR+ HER2- mBC. Research Sponsor: None.