Prediction of dose reductions and impact of reduced starting doses of CDK4 /6i on effectiveness in HR ‐positive/ HER2 ‐negative metastatic breast cancer: Real‐world data from the OPAL registry

Cancer patients prone to toxicities might benefit from dose reduction over fixed-dose recommendations. We develop a predictive index to identify patients with increased probability of dose reduction, intolerable toxicities, or therapy discontinuation (hereafter: dose reduction) in metastatic breast cancer (MBC) and compare real-world effectiveness of reduced (RSD) versus full starting dose (FSD) using this index. This analysis included 618 patients with HR-positive, HER2-negative MBC from the prospective, observational, multicenter registry OPAL (NCT03417115), receiving first-line palbociclib (n = 386) or ribociclib (n = 232) plus endocrine therapy. A logistic regression model was employed to derive the predictive index. Inverse probability of treatment weighting was used to emulate a head-to-head comparison of RSD and FSD by analyzing progression-free (PFS) and overall survival (OS). Within 6 months, 215 patients (35%) underwent dose reduction, including 109 (51%) with RSD. Predictors for dose reduction were age ≥65 years and Charlson comorbidity index (CCI) ≥1. Among patients with increased probability of dose reduction (index ≥1: ≥65 years and/or CCI ≥ 1), median PFS and OS were 30.1 [21.7, 54.0] and 57.6 [40.0, NA] months with RSD vs. 29.3 [24.9, 32.0] and 43.1 [38.8, 50.3] months with FSD. For low-probability patients (index = 0: