Crossing the milestone: landmark-based conditional survival after first-line CDK4/6 inhibitor therapy in HR+/HER2-metastatic breast cancer.

BACKGROUND: In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed long-term disease control; however, survival trajectories remain markedly heterogeneous. While a subset of patients experiences early progression reflecting endocrine-resistant and biologically aggressive disease, others maintain durable endocrine-sensitive control for several years. As a result, baseline survival estimates calculated from treatment initiation become progressively less representative for patients who remain progression-free during ongoing therapy. We therefore evaluated landmark-based conditional survival outcomes in a real-world cohort of patients receiving first-line CDK4/6i-based therapy. METHODS: We retrospectively evaluated 390 patients with HR+/HER2- mBC treated with first-line CDK4/6i plus endocrine therapy. Landmark analyses were performed at 6, 12, 24, and 36 months following treatment initiation. Conditional progression-free survival (cPFS), conditional overall survival (cOS), and post-landmark OS according to progression status were estimated using Kaplan-Meier analyses from each landmark time point. Baseline clinicopathological factors were additionally evaluated using landmark-specific logistic regression analyses. RESULTS: Median progression-free survival (PFS) and overall survival (OS) from treatment initiation were 29.2 months (95% CI, 24.6-33.9) and 68.0 months (95% CI, 55.7-80.4), respectively. Disease progression had occurred in 11.5%, 26.1%, 50.8%, and 70.4% of patients by the 6-, 12-, 24-, and 36-month landmarks, respectively. Among patients remaining progression-free at these time points, median cPFS was 27.15, 28.08, 34.58, and 41.90 months, respectively, suggesting increasingly durable conditional disease control with successive progression-free milestones. Landmark progression status strongly stratified subsequent survival outcomes, with significantly inferior post-landmark OS observed among patients with progression at all evaluated landmarks (all log-rank p < 0.001). Endocrine resistance, visceral disease, and adverse tumor biology were consistently associated with an increased risk of progression. However, estimates beyond the 36-month landmark were less precise owing to the limited risk set and greater censoring. CONCLUSIONS: Landmark-based conditional survival analysis provides clinically meaningful, time-updated prognostic information in HR+/HER2- mBC treated with first-line CDK4/6 inhibitors. Crossing successive progression-free milestones identifies a subgroup with increasingly durable long-term disease control while maintaining favorable post-landmark survival. These findings support the integration of milestone-based conditional survival estimates alongside conventional baseline survival metrics in the CDK4/6i era.