A recent meta-analysis, encompassing three phase III trials with a total of 12,647 patients, has evaluated the efficacy and safety of adding CDK4/6 inhibitors to standard endocrine therapy (ET) in the adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (EBC). The study, published in PubMed Central, aimed to determine if the survival benefits observed with CDK4/6 inhibitors in metastatic breast cancer translate to the adjuvant setting.
The analysis focused on invasive disease-free survival (IDFS) as the primary outcome. Results indicated a potential favorable effect of adjuvant CDK4/6 inhibitors combined with ET compared to standard ET alone (HR 0.87, 95% CI 0.76–0.98, p = 0.03). However, trial sequential analysis (TSA) suggested that the current evidence is insufficient to definitively support this result, indicating a need for more trials to validate the findings.
Subgroup Analysis
Further analysis of predefined subgroups revealed that patients with stage N2/N3 nodal status were the only subpopulation to derive statistically significant survival benefit from the combination treatment (HR 0.83, 95% CI 0.71–0.97, p = 0.02). No significant IDFS prolongation was observed in other subgroups based on TNM stage, tumor stage, histologic grade, prior neoadjuvant chemotherapy, ethnicity, age, or menopausal status.
Safety and Tolerability
The meta-analysis also assessed the safety profile of the combination therapy. Results showed a significantly higher risk of grade 3/4 adverse events (AEs) in the CDK4/6 inhibitor arm compared to the ET-alone arm (RR 4.14, 95% CI 3.33–5.15, p < 0.00001). Specifically, grade 3/4 hematologic AEs were more common with CDK4/6 inhibitors (RR 45.96, 95% CI 13.57–155.70, p < 0.00001), leading to an increase in treatment discontinuation due to AEs (RR 19.14, 95% CI 9.25–39.58, p < 0.00001).
Conflicting Trial Outcomes
The three trials included in the meta-analysis – monarchE (abemaciclib), PALLAS (palbociclib), and PENELOPE-B (palbociclib) – reported inconsistent primary outcomes. This discrepancy may be attributed to differences in study populations, trial designs, and follow-up durations. For instance, monarchE and PENELOPE-B specifically enrolled EBC patients at high risk of recurrence, while PALLAS included a substantial proportion of lower-risk patients. Differences in treatment duration (two years in monarchE and PALLAS vs. one year in PENELOPE-B) and follow-up time may have also contributed to the varying results.
Implications for Clinical Practice
While the meta-analysis suggests a potential benefit of adjuvant CDK4/6 inhibitors in HR+/HER2- EBC, particularly for patients with N2/N3 nodal involvement, the evidence remains inconclusive. The increased risk of adverse events and treatment discontinuation associated with CDK4/6 inhibitors warrants careful consideration. Further research is needed to identify definitive clinicopathologic features or genomic signatures that can predict therapeutic responses to adjuvant CDK4/6 inhibitors, allowing for better patient selection and treatment tailoring.
Ongoing Research
Several ongoing studies (NCT03701334 and NCT03820830) are expected to provide additional data on the role of CDK4/6 inhibitors in the adjuvant setting. Translation analyses from the included studies are also eagerly awaited to elucidate the relationship between high-risk clinicopathologic features and therapeutic responses to CDK4/6 inhibitors. The findings from these studies will be crucial in determining the ultimate role of CDK4/6 inhibitors in the adjuvant treatment of HR+/HER2- EBC.
