Abstract PS1-10-21: Switching CDK4/6 inhibitors due to Toxicity in first-line treatment of HR+/HER2- metastatic breast cancer: Incidence and Outcomes from the ESME Cohort

Abstract Background: CDK4/6 inhibitors (CDK4/6i) have markedly changed the treatment landscape for hormone receptors-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC). According to current European guidelines, switching between CDK4/6i is advised when patients experience unacceptable toxicity during therapy. This study aimed to examine patterns of CDK4/6i use and switching strategies due to toxicity in the first line (L1) setting, using data from the ESME cohort, a large real-world database. Methods: The ESME MBC cohort is a national cohort collecting individual-level patient data from 18 French Comprehensive Cancer Centers (NCT03275311). For this study, we included all patients aged 18 years or older with newly diagnosed HR+/HER2- MBC who began L1 endocrine treatment (ET) combined with a CDK4/6i. Among these, patients who discontinued CDK4/6i due to toxicity and subsequently reinitiated a different CDK4/6i were selected to evaluate progression-free survival (PFS) following the second CDK4/6i exposure. Results: Between January 1, 2013, and December 31, 2023, 22,965 women treated for HR+/HER2- MBC were enrolled in the ESME database. Among them, 5,553 patients (24%) received L1 ET combined with a CDK4/6i. At the time of analysis, 4,058 patients had discontinued their initial CDK4/6i therapy, 67%, 16% and 17% due to disease progression, toxicity, or other reasons, respectively. Of these, 2,744 (68%), 787 (19%) and 527 (13%) were treated with palbociclib, ribociclib, and abemaciclib, respectively. Aromatase inhibitors were the most commonly used ET partner (78%), followed by fulvestrant (20%). During L1, 231 patients (5.7%) switched CDK4/6i due to toxicity, after a median treatment duration of 2.9 months (range: 0.1-57.6), occurring under palbociclib, ribociclib and abemaciclib in 50 (1.8%), 108 (13.7%), and 73 (13.8%) patients, respectively. The leading causes of discontinuation were gastrointestinal toxicity (28%), hematologic toxicity (26%), and liver toxicity (21%). The median age at the time of CDK4/6i switch was 66 years (range: 32-90), 37% having de novo MBC and 34% presenting with visceral metastases. At the time of analysis, 95 patients were still on treatment while 136 (59%) had discontinued the second CDK4/6i, 40 (29%) due to toxicity after a median rechallenge duration of 3.4 months (range: 0.1-40.0). The toxicity profile was consistent with that observed during L1 therapy, primarily hematologic toxicity (30%), gastrointestinal toxicity (22%), and liver toxicity (10%).With a median follow-up of 28.3 months 95% CI: 23.3-32.9, the median PFS on the second CDK4/6i was 17.9 months 95% CI: 14.7-21.9, and the 3-year overall survival rate was 71.7% 95% CI: 63.1-78.6. Conclusion: This extensive multicenter retrospective study offers real-world evidence that switching to a second CDK4/6i after toxicity in L1 treatment is feasible. However, one third of this patients’ population discontinued the second CDK4/6i due to toxicity. Citation Format: T. Papazyan, A. Lusque, W. Jacot, T. Grinda, A. Mailliez, E. Brain, T. Bachelot, C. Levy, M. Arnedos, A. Goncalves, V. Massard, M. Mouret-reynier, T. De la Motte Rouge, T. Petit, A. Savoye, I. Desmoulins, M. Leheurteur, L. Bosquet, M. Campone, J. Frenel. Switching CDK4/6 inhibitors due to Toxicity in first-line treatment of HR+/HER2- metastatic breast cancer: Incidence and Outcomes from the ESME Cohort abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-21.