Abstract
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment1,2,3,4,5,6,7. Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting8. All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74–1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.
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Data availability
De-identified patient clinical data underlying the results reported in this Article will be made available to other researchers on reasonable request for academic use, within the limitations of the informed consent and the study’s consortium agreement. A detailed data proposal is required and will be considered on a case-by-case basis. Requests should be directed to BOOG study Center (info@boogstudycenter.nl) and will be reviewed by the study’s principal investigators. A response will be provided within 90 days. A signed data-access agreement with the sponsor is required before accessing shared data. The study protocol and SAP are provided with the paper.
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Acknowledgements
We thank all the patients who participated in this trial, as well as their families; all members of the steering committee and the study staff at all 74 hospitals of the SONIA trial; the independent Data Safety Monitoring Board; the Dutch Breast Cancer research Group (BOOG) for their support and sponsorship; the registration team of the Netherlands Comprehensive Cancer Organization (IKNL) for the collection of data for the Netherlands Cancer Registry; and all data managers for data collection throughout the trial. The Dutch Nationwide Pathology Databank (Palga) provided histopathology data. The Dutch Breast Cancer Association (BVN) was involved in the development and the execution of the trial. The trial was funded by the Netherlands Organization for Health Research (ZonMw) and Development and Dutch Health Insurers (ZN).
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A.J., G.S.S. and I.R.K. initiated the study. A.J., G.S.S., I.R.K. and V.v.d.N. designed the study with support from the study steering committee and The Dutch Breast Cancer Association (BVN). C.G.P. as director of BVN was involved in the development and the execution of the trial. A.E.v.L.-S. as director of the Dutch Breast Cancer research Group (BOOG) was involved in the project administration, funding acquisition and in the development and execution of the trial. A.B., A.v.O.-N., A.H.H., A.J., C.v.S.-v.d.M., C.S.T.-v.D., G.S.S., I.R.K., J.B.H., J.T., K.B., L.C.H., N.W., P.C.d.J., Q.C.v.R.-S. and S.V. contributed to recruitment of patients. A.C.P.S. and L.M. contributed to data collection and validation on behalf of the Netherlands Comprehensive Cancer Organization (IKNL). V.v.d.N. was the trial statistician. A.v.O.-N., N.W. and V.v.d.N. accessed and verified the data and contributed to the data analysis. H.M.B. contributed to the data analysis of the health-related quality-of-life and costing. A.J., G.S.S. and I.R.K. contributed to supervision of the study. A.J., A.v.O.-N., G.S.S., I.R.K. and N.W. wrote the initial draft of the article and decided to submit the manuscript. All of the authors participated in interpretation of the data and drafting of the manuscript. All of the authors reviewed and approved the final, submitted version.
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G.S.S. reports institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen; and consultancy for Biovica, Novartis and Seagen. H.M.B. received grants from CADTH, ZIN and Medical Delta; and participated in a data safety monitoring board or advisory board for Pfizer. A.H.H. received consulting fees from Gilead and Lilly; and received payment or honoraria from Lilly. Q.C.v.R.-S. has participated in a data safety monitoring board or advisory board for Roche. I.R.K. reports institutional research grant support from Novartis and Gilead. The other authors declare no competing interests.
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Extended data figures and tables
Extended Data Fig. 1 Trial profile.
The figure presents an overview of the course of the trial for all study participants. Of note, the number of deaths reported here are only those deaths that were reported to be the reason for discontinuation of first- or second-line therapy (i.e., patients who died in the absence of objective disease progression while on study treatment). The number of PFS2 events (n = 591) is different from the number of patients that discontinued second-line endocrine therapy (n = 502), since not all patients with a PFS2 event discontinued second-line treatment and not all patients who discontinued second-line treatment experienced a PFS2 event. NSAI, non-steroidal aromatase inhibitor; CDK4/6i, cyclin-dependent kinase 4 and 6 inhibitor.
Extended Data Fig. 2 PFS1 in ITT population.
Kaplan–Meier plots for PFS after one treatment line (PFS1) in the CDK4/6i-first and CDK4/6i-second group in the ITT population. Cox proportional hazard models were used to calculate hazard ratios between the study groups and were stratified according to the stratification factors used in randomization. The difference was assessed using the stratified log-rank test. P values are two-sided. Events, number of PFS1 events; n, number of patients randomized.
Supplementary information
Supplementary Information
This file contains Supplementary Table 1 (Overview protocol amendments), Supplementary Table 2 (Overview SAP adjustments), List of members of the SONIA consortium, Trial protocol (the first approved protocol version 1.2), Trial protocol (the last approved protocol version 1.11), and Statistical analysis plan.
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Sonke, G.S., van Ommen-Nijhof, A., Wortelboer, N. et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature (2024). https://doi.org/10.1038/s41586-024-08035-2
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DOI: https://doi.org/10.1038/s41586-024-08035-2
