Crossing the toxicity threshold: a repeated landmark analysis of early toxicities and treatment modification during first-line CDK4/6 inhibitor therapy.

Authors

Tuğba Önder, Öztürk Ateş, Mehmet Emin Yılmaz, Ayşe Ocak Duran

Published in

Cancer chemotherapy and pharmacology. Volume 96. Issue 1. Sep 24, 2026. Epub Sep 24, 2026.

Abstract

Whether early treatment-related toxicities during cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy reflect treatment activity or simply longer treatment exposure remains unclear. Previous studies have largely evaluated toxicities cumulatively, potentially introducing immortal time bias into toxicity-outcome associations. We evaluated the prognostic significance of early toxicities and treatment modifications using repeated landmark analyses in patients receiving first-line CDK4/6i therapy for HR+/HER2- metastatic breast cancer.
This retrospective study included 404 patients receiving first-line CDK4/6i plus endocrine therapy. Repeated landmark analyses at 8, 12, and 24 weeks evaluated associations of early toxicities and treatment modifications with subsequent progression-free survival (PFS) and overall survival (OS).
During treatment, any-grade neutropenia occurred in 88.1% of patients, hepatotoxicity in 22.5%, QTc prolongation in 17.6%, and dose modification in 37.4%. At both the 8- and 12-week landmarks, grade 1-2 neutropenia was consistently associated with improved PFS and OS in multivariable analyses (all p<0.05; 8-week PFS: 33.2 vs. 22.1 months; OS: 90.6 vs. 40.8 months). Grade 3-4 neutropenia showed less consistent associations with survival but remained associated with improved OS at 12 weeks. Dose modification was independently associated with shorter PFS at the 12- and 24-week landmarks (all p<0.05). Associations between neutropenia and survival were attenuated at the 24-week landmark.
Grade 1-2 neutropenia was the most consistent toxicity-based predictor of favorable survival and may represent a potential clinical marker of treatment activity. Associations with grade 3-4 neutropenia were less consistent. Dose modification was associated with shorter PFS, whereas hepatotoxicity and QTc prolongation showed no consistent independent prognostic associations.

PMID:
42786218
Bibliographic data and abstract were imported from PubMed on 25 Sep 2026.

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