Abstract Introduction: CDK4/6 inhibitors (CDK4/6i) have transformed the therapeutic landscape of hormone receptors-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC). However, the clinical benefit of rechallenging with a CDK4/6i, either by maintaining the same agent or switching to another, after progression on first-line (1L) combined endocrine treatment (ET) remains unclear. Our study aimed to assess factors predicting the real-world effectiveness of CDK4/6i rechallenge after progression on 1L ET, using data from the ESME cohort, a large nationwide database of patients with MBC. 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 1L ET with a CDK4/6i between January 2013 and December 2023. From this subpopulation, patients who had discontinued CDK4/6i due to disease progression and were later re-treated with a CDK4/6i in subsequent lines of therapy were selected to assess real world outcome including progression-free survival (PFS) and overall survival (OS) following the second CDK4/6i exposure. Multivariable analyses were conducted using Cox proportional hazards model including line of therapy, age, tumor grade, de novo MBC status, visceral metastases, number of metastatic sites, use of different CDK4/6i, and duration of initial CDK4/6i. Results: Among 2,711 patients who progressed on 1L ET + CDK4/6i, 177 (4.4%) underwent a CDK4/6i rechallenge during their treatment course. The initial CDK4/6i was palbociclib, ribociclib, and abemaciclib in 76.8%, 17.0% and 6.2% of patients, respectively, ET being mostly (86.4%) an aromatase inhibitor. After a 1L CDK4/6i-based treatment exceeding 24 months in 32.2% of patients, rechallenge occurred in 2L or later lines (3L++) in 77 (43.5%) and 100 (56.5%), respectively. At rechallenge, the median age was 63 years (range 28-89), 68.9% patients were postmenopausal, and 61.6% had visceral metastases. In 80.2% of cases, a different CDK4/6i was used, mosly abemaciclib (54.8%), in combination with fulvestrant (61.6%).With a median follow-up of 22.7 months 95%CI: 18.4-26.2 post-rechallenge, the second CDK4/6i was discontinued in 121 patients (68.4%) mainly due to disease progression (82.6%), followed by toxicity (10.0%) and other reasons (7.4%). In the whole population, the median PFS at rechallenge was 6.2 months 95% CI: 4.6-7.1. Rechallenge resulted in a PFS of 6.9 months 95%CI: 4.5-10.6 in the 2L setting and 5.7 months 95%CI: 3.2-6.7 in 3L++ setting. Using a different CDK4/6i results median PFS was 5.7 months 95%CI: 4.1-6.7 and 7.8 months 95%CI: 3.8-9.6 when the same CDK4/6i was used. Multivariable analysis showed a worse PFS for Rechallenge in third 3L++ was the only factor associated with PFS (adjusted HR: 1.47, 95%CI: 0.98-2.21, p-value=0.06). Conclusion: This large multicenter retrospective study provides real-world evidence that switching with a second CDK4/6i after progression is feasible and may offer clinical benefit in selected patients. Citation Format: T. PAPAZYAN, A. Lusque, A. Mailliez, T. Bachelot, T. Grinda, A. Goncalves, E. Brain, A. Savoye, M. Arnedos, C. Levy, I. Desmoulins, T. De La Motte Rouge, C. Pflumio, M. Mouret-Reynier, V. Massard, M. Leheurteur, L. Bosquet, W. Jacot, M. Campone, J. Frenel. Factors predicting the effictiveness of CDK4/6 inhibitor rechallenge following progression on first-line endocrine therapy combined with a CDK4/6 inhibitor in ER+ metastatic breast cancer in the French ESME Database 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 PS1-11-29.
PAPAZYAN et al. (Tue,) studied this question.