A meta-analysis of randomized controlled trials indicates that adding CDK4/6 inhibitors to adjuvant endocrine therapy (ET) for hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer (EBC) shows a trend toward improved invasive disease-free survival (IDFS), but no statistically significant benefit in distant relapse-free survival (DRFS). The research, encompassing data from 12,647 patients across three major trials, also reveals a significant increase in adverse events (AEs) associated with the addition of CDK4/6 inhibitors. These findings underscore the complexities of integrating CDK4/6 inhibitors into EBC treatment and highlight the need for further research to refine patient selection and optimize treatment strategies.
Meta-Analysis Details
The meta-analysis included three Phase III trials: PALLAS, monarchE, and PENELOPE-B. These trials evaluated the addition of either palbociclib or abemaciclib to ET in the adjuvant or post-neoadjuvant settings for HR+/HER2- EBC. The primary endpoint was IDFS, with secondary endpoints including DRFS and the incidence of AEs. Data were analyzed using pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs).
Efficacy Outcomes
While the pooled analysis suggested a trend toward improved IDFS with CDK4/6 inhibitors (HR 0.85, 95% CI 0.71-1.01; P = 0.071), this did not reach statistical significance. The lack of significant improvement in DRFS (HR 0.83, 95% CI 0.58-1.19; P = 0.311) raises questions about the overall benefit of adding these agents to standard endocrine therapy. The IDFS benefit was largely driven by the monarchE trial, which had a median follow-up of only 19.1 months, potentially limiting the robustness of its conclusions.
Safety Concerns
The addition of CDK4/6 inhibitors was significantly associated with an increased risk of AEs of any grade (OR 9.36, 95% CI 3.46-25.33, P < 0.001) and grade ≥3 (OR 11.06, 95% CI 5.38-22.74, P < 0.001). Specific AEs with increased incidence included neutropenia, anemia, thrombocytopenia, diarrhea, upper respiratory infections, and fatigue. Early treatment discontinuation due to AEs was also significantly higher in the CDK4/6 inhibitor arms (OR 22.11, 95% CI 9.45-51.69, P < 0.001).
Discordant Trial Findings
The three trials included in the meta-analysis showed varying results, potentially due to differences in patient populations, treatment durations, and the specific CDK4/6 inhibitor used. For instance, PALLAS included patients based solely on anatomic stage (II and III), while monarchE and PENELOPE-B also considered biological characteristics. Palbociclib and abemaciclib have different pharmacological profiles, and the higher discontinuation rate observed with palbociclib in PALLAS may have contributed to the divergent findings.
Need for Better Patient Selection
The meta-analysis underscores the need for better patient selection to identify those most likely to benefit from CDK4/6 inhibitors in the adjuvant setting. Currently, no validated biomarkers can predict which patients will respond to these agents. Future research should focus on identifying predictive biomarkers and refining risk stratification to optimize the use of CDK4/6 inhibitors in EBC.
Ongoing and Future Research
Several ongoing trials are further evaluating the role of CDK4/6 inhibitors in EBC (NCT03701334, NCT03078751, and NCT03820830). These studies, along with further follow-up from the included trials, will provide additional insights into the efficacy and safety of CDK4/6 inhibitors in this setting. The financial impact and patient-reported outcomes also need to be carefully evaluated before these agents can be broadly incorporated into clinical practice.
