Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer

www.nature.com/scientificreports OPEN Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer Coralea Kappel 1, Mitchell J. Elliott 1, Vikaash Kumar 1, Michelle B. Nadler 1, Alexandra Desnoyers 2 & Eitan Amir 1,3* Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7–97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1–2 vomiting OR 1.87 [95% CI 1.37–2.56] and OR 2.27 [95% CI 1.59–3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3–4 diarrhea OR 118.06 [95% CI 7.28–1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3–4 infections. Abemaciclib had significantly less grade 3–4 transaminitis and grade 3–4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes. Inhibition of cyclin dependent kinase 4 (CDK4) and cyclin dependant kinase 6 (CDK6) in combination with endocrine therapy is the first-line standard of care for hormone receptor positive and erb-B2-negative (HR+/ HER2−) locally advanced or metastatic breast cancer (MBC)1–3. In phase III trials, CDK4/6 inhibitors trials, palbociclib, ribociclib, and abemaciclib have shown a consistent improvement in progression-free survival (PFS) when combined with an aromatase inhibitor (AI), fulvestrant, or tamoxifen4,5 with the hazard ratios for PFS ranging between 0.50 and 0.59. In contrast, while individual trials for ribociclib with endocrine therapy have reported statistically significant improvement in overall survival (OS), such improvements have not been reported for palbociclib or a bemaciclib6–11. This is reflected in the National Comprehensive Cancer Network guidelines where ribociclib is the only category 1 preferred first-line treatment option for HR+/HER2− MBC in combination with an AI; whereas both abemaciclib and ribociclib are category 1 preferred first-line in combination with fulvestrant3. CDK4/6 inhibitors can be associated with significant symptom burden that may limit tolerability and impact patients’ health-related quality of life12. In a pooled analysis of clinical trials, more than 70% of older patients had their treatment dose reduced and more than 15% discontinued t reatment13. Tolerability is a key metric for CDK4/6 inhibitors given the duration of treatment can extend over 2 years, especially when used in the firstline setting. 1 Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. 2Hôpital Charles-Lemoyne, Greenfield Park, QC, Canada. 3Princess Margaret Cancer Centre, 610 University Ave, 700U, 7‑721, Toronto, ON M5G 2M9, Canada. *email: Scientific Reports | (2024) 14:3129 | https://doi.org/10.1038/s41598-024-53151-8 1 Vol.:(0123456789) www.nature.com/scientificreports/ A robust analysis of both relative efficacy and relative tolerability is therefore of interest to help clinicians and patients make informed decisions about the optimal agent to be used. Methods Search strategy and study selection A network meta-analysis, registered in PROSPERO (registration number CRD42023392416) was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (PRISMA)14. Inclusion criteria comprised phase 3 randomized controlled trials (RCTs) in which patients with HR+/HER2− metastatic breast cancer were treated with a CDK4/6 inhibitor in combination with endocrine therapy (AI, fulvestrant or tamoxifen) compared to endocrine therapy alone in the first or second-line setting. There was no limitation on year or language of publication. Meta-analyses, single-arm trials, and observational studies were excluded. Only studies of human subjects were included. When more than one publication was identified for the same clinical trial, data from the most recent or complete report were included. A search strategy was constructed using ClinicalTrials.gov. Titles and abstracts identified by these strategies were screened independently by two reviewers (C.K. and E.A.) for inclusion; disagreements were resolved by consensus. The following variables from all eligible manuscripts were extracted: year of publication, median duration of follow-up, study sample size and the treatment in the experimental and control groups. For each approved CDK4/6 inhibitor, data was extracted on efficacy and on pre-specified common and serious treatment related adverse events. For efficacy outcomes, the study-reported hazard ratios (HR) and respective 95% confidence intervals (CI) for overall survival (OS) were extracted. For safety and tolerability, the data extracted included treatment-related death, treatment discontinuation due to adverse event and selected adverse events (AEs). For hematological toxicities, data were extracted on grade 3–4 neutropenia, anemia, and thrombocytopenia. For GI toxicities, data were extracted on both grade 1–2 and grade 3–4 diarrhea, nausea, and vomiting. Additional data was extracted on grade 1–2 stomatitis, grade 1–2 fatigue and/or asthenia, grade 3–4 venous thromboembolism (VTE), grade 3–4 transaminitis, grade 3–4 dyspnea and/or cough, grade 3–4 infection, grade 3–4 prolonged QT and grade 1–2 alopecia. The number of events and the number of patients at risk were extracted individually for both the CDK4/6 inhibitor and control groups in each trial. Outcome measures were obtained from the most recently published manuscripts and cross-referenced with data in the clinicaltrials.gov registry to ensure consistency. Data synthesis and statistical analysis When mor (...truncated)