Efficacy of adjuvant CDK4/6 inhibitors in hormone receptor-positive breast cancer: a systematic review and meta-analysis

ABSTRACTBackground The combination of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and standard endocrine therapy (ET) in the adjuvant treatment of hormone receptor (HR)-positive/HER2-negative breast cancer (BC) has yielded conflicting results. We performed a pooled analysis of the adjuvant efficacy of CDK4/6 inhibitors by including data from the NATALEE trial, the most recent trial on this topic.Methods We searched major databases and congress proceedings until 7 June 2023 to identify randomized controlled trials (RCT) comparing adjuvant CDK4/6 inhibitor plus ET combination versus ET in HR-positive/HER2-negative early-stage BC.Results Four RCTs involving a total of 17,749 patients were included. According to the pooled analysis of these four studies, significant improvement in invasive disease-free survival (iDFS) was observed with the addition of CDK4/6 inhibitors to standard ET (HzR: 0.81, 95% CI 0.67–0.97). IDFS benefit was irrespective from menopausal status, Ki-67 index, tumor grade, and previous chemotherapy. CDK4/6 inhibitors plus ET had a significant improvement in iDFS in stage 3 whereas there was a trend toward better iDFS in stage 2 (HzR for stage 3: 0.67, 95% CI 0.58–0.78; HzR for stage 2: 0.74, 95% CI 0.55–1.01).Conclusions Addition of CDK4/6 inhibitors to standard ET in the adjuvant treatment of HR-positive/HER2-negative early-stage BC improves iDFS.KEYWORDS: Breast cancerCDK 4/6 inhibitorsendocrine therapyadjuvantmeta-analysis Article highlights Conflicting evidence exists regarding the efficacy of CDK4/6 inhibitors in the adjuvant treatment of HR-positive/HER2-negative breast cancer.Primary endpoint not met in RCTs with palbociclib; positive results observed in studies with abemaciclib and ribociclib.Joint analysis of 17,749 patients, including PALLAS, PENELOPE-B, MonarchE, and NATALEE studies, was conducted in this meta-analysis.Adding CDK4/6 inhibitors to standard endocrine therapy improves iDFS in HR-positive/HER2-negative early-stage breast cancer.The benefit was observed regardless of menopausal status, tumor grade, Ki-67 index, prior chemotherapy, or lymph node involvement.Stage 3 patients experienced significant iDFS benefit, while stage 2 patients showed a non-significant difference with a trend favoring CDK4/6 inhibitors.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Author contributionsY Ergun contributed to study design/conception, data collection and analysis, manuscript writing and review. M Dogan contributed to manuscript writing and review. G Ucar, P Karacin and C Karacin contributed to literature search and data extraction.Reviewer disclosuresA reviewer on this manuscript has disclosed being a Consultant for Novartis. Another reviewer has disclosed working with Agendia, Amgen, APOGHEVA, Aristo, Astra Zeneca, Celgene, Clovis Oncology, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, Merck & Co, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Stemline, Tesaro Bio, Teva, Veracyte, Viatris, FOMF, Aurikamed, Clinsol, Pomme Med, medconcept, and MCI. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2023.2258791Additional informationFundingThis paper was not funded.