Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) and endocrine therapy (ET) has been a major advance for the treatment of hormone receptor–positive (HR+), ERBB2 (formerly HER2)–negative (ERBB2−) advanced or metastatic breast cancer.
Randomized phase 3 studies demonstrated that the addition of CDK4/6i reduced the hazard risk of disease progression by approximately half compared with hormonal monotherapy (an aromatase inhibitor, tamoxifen, or fulvestrant) in the first-line (1L) and/or second-line (2L) setting. Hence, the US Food and Drug Administration and European Medicines Agency approved 3 CDK4/6i, in both 1L and 2L settings. However, differences among the CDK4/6i regarding mechanisms of action, adverse effect profiles, and overall survival (OS) are emerging. Both abemaciclib and ribociclib have demonstrated efficacy in high-risk HR+ early breast cancer. While ET with or without CDK4/6i is accepted as standard treatment for persons with advanced HR+ ERBB2− metastatic breast cancer, several key issues remain. First, why are there discordances in OS in the metastatic setting and efficacy differences in the adjuvant setting? Additionally, apart from HR status, there are few biomarkers predictive of response to CDK4/6i plus ET, and these are not used routinely. Despite the clear OS advantage noted in the 1L and 2L metastatic setting with some CDK4/6i, a subset of patients with highly endocrine-sensitive disease do well with ET alone. Therefore, an unanswered question is whether some patients can postpone CDK4/6i until the 2L setting, particularly if financial toxicity is a concern. Finally, given the lack of endocrine responsiveness following progression on some CDK4/6i, strategies to optimally sequence treatment are needed.
Conclusions and Relevance
Future research should focus on defining the role of each CDK4/6i in HR+ breast cancer and developing a biomarker-directed integration of these agents.
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Accepted for Publication: February 24, 2023.
Published Online: June 29, 2023. doi:10.1001/jamaoncol.2023.2000
Corresponding Authors: Ciara Catherine O’Sullivan, MB Bch BAO(Hons), MRCPI (email@example.com), and Matthew Philip Goetz, MD (firstname.lastname@example.org), Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Author Contributions: Drs Goetz and Robertson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Obtained funding: Goetz.
Administrative, technical, or material support: O’Sullivan, Clarke, Goetz.
Supervision: Goetz, Robertson.
Conflict of Interest Disclosures: Dr O’Sullivan reported research funding to institution from Lilly, Seagen, Minneamrita Therapeutics, Biovica, nference, ACCRU, Bavarian Nordic, Sermonix Pharmaceuticals, and AstraZeneca, and serving as an adviser for AstraZeneca outside the submitted work. Dr Clarke reported relationships with American Gene Technologies, Inc, and Bayer Pharmaceuticals outside the submitted work. Dr Goetz reported grants from National Cancer Institute (P50CA116201) during the conduct of the study; consulting fees to Mayo from ARC Therapeutics, AstraZeneca, Biotheranostics, Blueprint Medicines, Lilly, RNA Diagnostics, Sanofi Genzyme, and Seattle Genetics; and grant funding to Mayo from Lilly, Pfizer, Sermonix Pharmaceuticals, and Atossa outside the submitted work. Dr Robertson reported grants from AstraZeneca to institution for clinical trials and personal fees from AstraZeneca for consultancy outside the submitted work.
Funding/Support: This work was supported by the George M. Eisenberg Foundation, and National Cancer Institute funding to the Mayo Clinic Breast Specialized Program of Research Excellence (SPORE) (P50CA116201) and the Mayo Clinic Cancer Center (P30CA15083) (Dr Goetz).
Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.
Additional Contributions: The authors would like to thank Mark Korinek, BS, Advanced Image Processing at Mayo Clinic, Rochester, Minnesota, for his assistance with the Figure. No compensation was received for this contribution.
Additional Information: Search strategy and selection criteria: References for this Review were identified through searches of PubMed with the search terms “Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i); abemaciclib; ribociclib; palbociclib; endocrine resistance; metastatic hormone receptor positive (HR+), HER2-negative (-) advanced or metastatic breast cancer (MBC)” from 2012 until February 2022. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.
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