Real-world effectiveness of CDK4/6i in first-line treatment of HR+/HER2- advanced/metastatic breast cancer: updated systematic review

Abstract

Aim: Since 2021, additional real-world evidence (RWE) has emerged on the effectiveness of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as first-line treatment of HR-positive/HER2-negative (HR+/HER2-) advanced/metastatic breast cancer (A/MBC), necessitating this updated review.

Methods: MEDLINE^®, Embase^®, and Cochrane Databases (07/06/2019-01/09/2024), and key congresses (2020-2024) were searched. Studies reporting first-line CDK4/6i use, over 100 participants, and progression-free survival (PFS) and/or overall survival (OS) data were included.

Results: This update included 82 unique studies, 42.7% for palbociclib, 7.3% for ribociclib, and 3.7% for abemaciclib; 46.3% assessed multiple CDK4/6i. In studies including multiple CDK4/6is, median PFS was 23.4-31.0 months for palbociclib, 19.8-44.0 for ribociclib, and 14.0-39.5 for abemaciclib. When reached, median OS was 38.0-58.0 months, 40.4-52.0 months, and 34.4 months, respectively. These real-world PFS and OS results were within the range of single-arm and CDK4/6i versus endocrine therapy (ET) studies, where CDK4/6i demonstrated greater benefits than ET alone.

Conclusion: First-line CDK4/6i RWE demonstrates significant clinical benefits in HR+/HER2- A/MBC. These data are important to guide clinical decision-making, as they include patients who are not adequately represented in clinical trials. Studies with longer follow-up are needed to assess long-term benefits of all three CDK4/6i therapies in HR+/HER2- A/MBC.

Keywords: CDK4/6 inhibitors; HR+/HER2−; breast; metastasis; quality assessment; real-world evidence; systematic literature review.

Figure 1

Study attrition diagram for (A) single-arm studies (B) comparative CDK4/6i versus ET studies, and (C) comparative CDK4/6i versus CDK4/6i studies. ^aThe GOIRC-04-2019 and REACHAUT studies had multiple associated records using single-arm and comparative analyses and are thus counted in both study design categories. ^bAny CDK4/6i regimen was defined as that in which a CDK4/6i—whether palbociclib, ribociclib, or abemaciclib—was evaluated, but the results were not specific to any single CDK4/6i. ^cThe RIBANNA study had multiple associated records, including ET and CDK4/6i comparator arms, resulting in its inclusion in both comparative study design categories. AI, aromatase inhibitor; CDK4/6i, cyclin-dependent kinase 4/6 inhibitors; CT, chemotherapy; ET, endocrine therapy; OS, overall survival; PFS, progression-free survival; PPII, proton pump inhibitor.

Figure 2

Regional distribution of included studies. ^aThe GOIRC-04-2019 study had multiple associated records, one evaluating palbociclib in North America and the other evaluating any CDK4/6i regimen in Europe. As such, this study is accounted for in both categories. ^bStudies were classified as “Multiple CDK4/6i” if two or more specified CDK4/6i were included in the study. CDK4/6i, cyclin-dependent kinase 4/6 inhibitors.

Figure 3

Forest plot of hazard ratios for effectiveness outcomes for overall first-line palbociclib in comparative RWE studies versus ET. AI, aromatase inhibitor; CI, confidence interval; NA, not applicable; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching; sIPTW, stabilized inverse probability of treatment weighting.

Figure 4

Forest plot of hazard ratios for effectiveness outcomes for overall first-line comparative RWE studies assessing two or more specified CDK4/6i. ^aHazard ratio has been inverted from that originally published by Weipert et al. for abemaciclib vs palbociclib: 1.29 (95% CI: 0.85-1.96). (60) ^bHazard ratio has been inverted from that originally published by Weipert et al. for ribociclib vs palbociclib: 1.04 (95% CI: 0.61-1.77) (60). AI, aromatase inhibitor; CI, confidence interval; ET, endocrine therapy; IPTW, inverse probability of treatment weighting; NA, not applicable; NR, not reported; OS, overall survival; PFS, progression-free survival.