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. 2025 Oct;10(10):105803.
doi: 10.1016/j.esmoop.2025.105803. Epub 2025 Sep 17.

Real-world treatment patterns and effectiveness after disease progression on CDK4/6 inhibitors for HR-positive/HER2-negative metastatic breast cancer in the ESME-MBC cohort

R Varnier  1 , D Pérol  2 , W Jacot  3 , A Mailliez  4 , V Diéras  5 , F Dalenc  6 , A Gonçalves  7 , C Levy  8 , M Arnedos  9 , J-S Frenel  10 , C Bailleux  11 , V Massard  12 , E Brain  13 , B Sauterey  14 , A-M Savoye  15 , L Bosquet  16 , J-C Thery  17 , T Petit  18 , T Bachelot  2 , T Grinda  19 , I Ray-Coquard  20
Affiliations

Real-world treatment patterns and effectiveness after disease progression on CDK4/6 inhibitors for HR-positive/HER2-negative metastatic breast cancer in the ESME-MBC cohort

R Varnier et al. ESMO Open. 2025 Oct.

Abstract

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have improved the prognosis of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but their impact on the efficacy of second-line treatments remains poorly described.

Materials and methods: This retrospective study included patients from the Epidemiological Strategy and Medical Economics database who initiated endocrine therapy ± CDK4/6i as first-line treatment for HR-positive/HER2-negative MBC between 2008 and 2019 across 18 French cancer centres and subsequently received second-line therapy. Objectives were to describe treatment patterns, time to progression (TTP), and post-progression survival after CDK4/6i, and to compare chemotherapy efficacy between CDK4/6i-exposed and historical CDK4/6i-naive patients, using propensity score adjustments.

Results: Among 13 577 HR-positive/HER2-negative MBC patients, 538 received CDK4/6i and 4030 received endocrine therapy alone as first-line treatment. Following CDK4/6i exposure, 47% of patients received chemotherapy as first subsequent treatment {median TTP 5.94 months [95% confidence interval (CI) 5.23-7.10 months]; 5.00 months (95% CI 3.68-6.63 months) for taxanes, 6.43 months (95% CI 3.87-12.29 months) for anthracyclines, 7.62 months (95% CI 6.13-8.30 months) for fluoropyrimidines}, 26% received endocrine therapy alone [6.14 months (95% CI 4.43-10.03 months)], 16% received phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors [5.16 months (95% CI 3.90-6.48 months)], and 9% underwent CDK4/6i rechallenge [9.57 months (95% CI 6.0 months-not applicable)]. In the comparative analysis, chemotherapy appeared slightly less effective in CDK4/6i-exposed patients than in CDK4/6i-naive patients, with a median TTP of 5.77 months (95% CI 5.13-6.67 months) versus 7.77 months (95% CI 7.428.07 months), respectively. This difference remained significant after adjusting for patient characteristics (hazard ratio 1.26, P = 0.003), except for comparison with fluoropyrimidine-based regimens, which showed comparable efficacy across groups.

Conclusions: This study highlights the variability in second-line treatment strategies following CDK4/6i and suggests the presence of cross-resistance reducing the efficacy of subsequent chemotherapy.

Keywords: CDK4/6 inhibitor; breast cancer; cross-resistance; second-line therapy; treatment patterns.

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Conflict of interest statement

Disclosure DP reports consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Brenus Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead, Ipsen, Janssen, Novartis, Merck Sharp and Dohme, Pfizer, and Takeda; and support for attending meetings and/or travel from Novartis and Roche. WJ reports grants or contracts from AstraZeneca, and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Eisai, BMS, Lilly France, Daiichi Sankyo, MSD, Novartis, Pfizer, Roche, and Seagen; support for attending meetings and/or travel from AstraZeneca, Novartis, Chugai Pharma, Pfizer, Eisai, Pierre Fabre, Glaxo Smithkline, Roche, Lilly France, and Sanofi Aventis; and participation on a data safety monitoring board or advisory board from AstraZeneca, Eisai, BMS, Lilly France, Daiichi Sankyo, MSD, Novartis, Pfizer, Roche, Seagen, and Gilead. AM reports support for attending meetings and/or travel from Lilly, AstraZeneca, Pierre Fabre, Novartis, and MSD. VD reports personal consulting fees and participation on advisory boards or symposia from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Medac GmbH, Menarini, MSD, Novartis, Pfizer, Roche Genentech, and Seagen; personal support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Gilead, MSD, Novartis, Pfizer, Roche Genentech, and Seagen; institutional financial interests as coordinating principal investigator for AstraZeneca, Daiichi Sankyo (also IDMC member), and Lilly (also steering committee member); institutional financial interests as steering committee member for Roche Genentech and Seagen; and institutional and personal financial interests for Sanofi, including IDMC participation. FD reports institutional support for attending meetings and/or travel from Novartis, Pfizer, and Daiichi; and institutional support related to participation on advisory boards from Gilead, Roche, AstraZeneca, Novartis, MSD, and Menarini. AG reports institutional grants or contracts from Roche/Genentech, AstraZeneca, Daiichi Sankyo, MSD, Gilead, Novartis, and Pfizer; support for attending meetings and/or travel from Mylan and Menarini; and institutional support for his participation on a data safety monitoring board or advisory board from Novartis, AstraZeneca, MSD, Gilead, and Daiichi Sankyo. MA reports consulting fees from Menarini, Pfizer, MSD, Daiichi Sankyo, Novartis, AstraZeneca, Lilly, and Gilead; and support for attending meetings and/or travel from Gilead, Pfizer, AstraZeneca, Lilly, and Novartis. JSF reports consulting fees from AstraZeneca, GSK, Eisai, MSD, Lilly, Pfizer, Novartis, Daiichi Sankyo, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, GSK, Eisai, MSD, Lilly, Pfizer, Novartis, Daiichi Sankyo, and Seagen; support for attending meetings and/or travel from AstraZeneca, GSK, Eisai, MSD, Lilly, Pfizer, Novartis, Daiichi Sankyo, and Seagen; and participation on a data safety monitoring board or advisory board from AstraZeneca, GSK, Eisai, MSD, Lilly, Pfizer, Novartis, Daiichi Sankyo, and Seagen. CB reports grants or contracts from Novartis; consulting fees from Novartis, Lilly, and Pfizer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Novartis; and support for attending meetings and/or travel from Novartis and Lilly. VM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Exact Sciences, Pfizer, Novartis, MSD, Johnson & Johnson, Bayer, Astellas, Lilly, Gilead, Daiichi Sankyo, and Menarini Stemline; support for attending meetings and/or travel from AstraZeneca, Pfizer, Novartis, MSD, Johnson & Johnson, Lilly, and Gilead; and participation on a data safety monitoring board or advisory board from AstraZeneca, Exact Sciences, Pfizer, Novartis, MSD, Johnson & Johnson, Bayer, Lilly, Gilead, Daiichi Sankyo, and Menarini Stemline. EB reports consulting fees from Exact Sciences, Menarini, Pfizer, and Sandoz; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Daiichi, Eli Lilly, Exact Sciences, Incyte, Novartis, Pfizer, and Takeda; support for attending meetings and/or travel from AstraZeneca, Daiichi, Exact Sciences, Gilead, Novartis, and Pfizer; and participation on a data safety monitoring board or advisory board from Daiichi. LB is full-time employee at Unicancer. JCT reports institutional consulting fees from AstraZeneca and support for attending meetings and/or travel from Pfizer, Eisai, and PharmaMar. TP reports support for attending meetings and/or travel from Pfizer and Daiichi Sankyo; and participation on a data safety monitoring board or advisory board from Pfizer, Lilly, AstraZeneca, MSD, Menarini, and Daiichi Sankyo. TB reports institutional grants or contracts from AstraZeneca, Pfizer, SeaGen, and Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca/Daiichi, Novartis, Pfizer, and Lilly; support for attending meetings and/or travel from Roche, Daiichi, AstraZeneca, Pfizer, and Novartis; and participation on a data safety monitoring board or advisory board from AstraZeneca/Daiichi, SeaGen, Novartis, Pfizer, and Lilly. TG reports support for attending meetings and/or travel from AstraZeneca, MSD, Gilead, and Pfizer; consulting fees from AstraZeneca, Pfizer, MSD, and Cancerologie-pratique; research funding from Amgen; and personal grant from Philippe Foundation. IRC reports consulting fees from GSK, Lilly, AstraZeneca, and Pharma&; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eisai, Verastem, and MSD; and support for attending meetings and/or travel from OSE Pharma, AbbVie, and MSD. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Study flow chart. CDK4/6, cyclin-dependent kinase 4/6; ESME, Epidemiological Strategy and Medical Economics; HER2, human epidermal growth factor receptor2; HR, hormone receptor; MBC, metastatic breast cancer.
Figure 2
Figure 2
Sunburst diagram of treatment patterns. The Sunburst diagram depicts treatment transitions between regimens used from the first line (inner-most donut) to fourth line (outer slice) in patients who received CDK4/6i as the first treatment. CDK4/6i, cyclin-dependent kinase 4/6 inhibitors; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.
Figure 3
Figure 3
First subsequent treatment time to progression. CDK4/6, cyclin-dependent kinase 4/6; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.
Figure 4
Figure 4
TTSP for first subsequent chemotherapy according to previous exposition to CDK4/6i (IPTW analysis). (A) and stratified by chemotherapy regimen (B). The reported sample sizes are those weighted by the IPTW analysis and therefore differ from the raw sample sizes. 5-FU, 5-fluorouracil; CDK4/6i, cyclin-dependent kinase 4/6 inhibitors; IPTW, inverse probability of treatment weighting; TTSP, time to second progression.
See this image and copyright information in PMC

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