Real-world overall survival and healthcare utilization with CDK4/6 inhibitor based regimens versus chemotherapy in previously treated HR+/HER2+ metastatic breast cancer: A TriNetX Global Collaborative Network analysis

Background: In the phase II monarcHER trial, abemaciclib plus trastuzumab with or without endocrine therapy improved overall survival (OS) versus chemotherapy plus trastuzumab in heavily pretreated hormone receptor-positive (HR+)/HER2+ metastatic breast cancer. Robust real-world evidence (RWE) comparing CDK4/6 inhibitor-based regimens with chemotherapy in this setting remains limited. Methods: We conducted a retrospective cohort study using de-identified electronic health records from the TriNetX Global Collaborative Network to compare two regimens in adults with highly pretreated HR+/HER2+ metastatic breast cancer: (1) CDK4/6 inhibitor plus endocrine and anti-HER2 therapy, and (2) chemotherapy plus anti-HER2 therapy. Prior exposure to anti-HER2 regimens was present, but explicit progression events and line counts were unavailable. The primary endpoint was overall survival (OS) up to 1200 days; secondary endpoints included neutropenia, heart failure (as a proxy for cardiotoxicity), and emergency department (ED) visits. Propensity score matching (1:1) was used to balance cohorts on demographics and comorbidities. Survival probabilities and hazard ratios (HRs) were estimated using Kaplan-Meier methods, log-rank tests, and Cox proportional hazards models. Results: PSM resulted in 140 patients per cohort with balanced baselines. Median follow-up was 573 days for chemotherapy and 479 days for CDK4/6 inhibitor therapy. Over 1200 days, death occurred in 36.4% (51/140) of the chemotherapy cohort and 17.1% (24/140) of the CDK4/6 inhibitor cohort, a 19.3% absolute risk reduction (95% CI, 9.2-29.4) favoring CDK4/6 inhibitors. Over the 1200-day, CDK4/6 inhibitor-based regimens significantly lowered the hazard of death compared to chemotherapy (HR, 0.52; 95% CI, 0.32-0.84; p=0.007). Neutropenia and heart failure were similar, but ED visits were more frequent with chemotherapy (HR 1.59; p=0.012). Conclusions: In this real-world, propensity-matched analysis of previously treated HR+/HER2+ metastatic breast cancer, CDK4/6 inhibitor-based endocrine and anti-HER2 therapy was associated with substantially lower mortality risk (HR 0.52; 19.3% absolute risk reduction) and reduced ED utilization compared with chemotherapy plus anti-HER2 therapy over a 1200-day window. These findings support the OS benefit seen in monarcHER and reinforce targeted endocrine strategies as clinically relevant alternatives to chemotherapy in heavily pretreated HR+/HER2+ metastatic breast cancer, despite the limitations of retrospective, non-randomized real-world evidence.