First-line CDK4/6 inhibitors in HR+/HER2− metastatic breast cancer with chronic kidney disease stage 3b–5: a target trial emulation

Pivotal CDK4/6 inhibitor trials in HR+/HER2− metastatic breast cancer defined renal eligibility by serum creatinine, excluding all patients with chronic kidney disease (CKD) stage 4–5; no head-to-head data exist. Within the TriNetX Global Collaborative Network, we emulated three target trials as pairwise propensity-score-matched comparisons (1134/545/520 per arm) of women with CKD stage 3b–5 initiating first-line therapy. Co-primary outcomes were 2-year composite treatment failure and all-cause mortality. Compared with palbociclib, abemaciclib and ribociclib were each associated with lower treatment failure (hazard ratio: 0.79, 95% CI: 0.68–0.90; and 0.75, 0.60–0.94) and lower mortality (0.84, 0.71–0.99; and 0.69, 0.52–0.92); ribociclib and abemaciclib did not differ. Treatment-failure associations held in all sensitivity cohorts; mortality associations did not ( E -value for the confidence-interval bound, 1.11). Drug-specific safety signatures from pivotal trials were preserved. Acute kidney injury hazard was stable for abemaciclib (interaction p = 0.081) but fell for ribociclib versus palbociclib (hazard ratio from 1.29 to 0.75; interaction p = 0.012). Mapping onto a published single-cell kidney atlas places the renal transporters these agents inhibit at the site of creatinine secretion. These exploratory, unregistered analyses lack familywise error control, but the toxicity profiles may inform drug selection in advanced CKD; an isolated creatinine rise on abemaciclib may warrant cystatin C measurement before discontinuation.