Evaluating the Role of CDK4/6 Inhibitors in Potential Early Luminal Breast Cancer Treatment

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Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become increasingly well-recognized as a proven strategy in the treatment of advanced hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. There is growing interest in the potential role of CDK4/6 inhibitors as a possible early luminal breast cancer treatment.

Gil-Gil and colleagues reviewed relevant and recent studies focused on the use of CDK4/6 inhibitors for the treatment of early breast cancer in both the adjuvant and neoadjuvant settings, focusing on studies with CDK4/6 inhibitors associated with endocrine therapy for the treatment of early breast cancer. They specifically assessed the results of large, recently conducted phase 3 adjuvant trials in which the results diverged. They also examined the relevance of biomarkers as response-predictive factors for CDK4/6 inhibitors, radiotherapy and CDK4/6 inhibitor combinations, and the accumulated evidence for the role of these drugs in the treatment of early breast cancer. After evaluating the studies’ dissonant results, the investigators evaluated factors influencing the trial design that may have impacted outcomes.

To date, 4 major trials have explored the role of CDK4/6 inhibitors in the adjuvant setting of pre- and postmenopausal women or men with stage II or III HR-positive/HER2-negative early breast cancer. For ribociclib, the NATALEE trial is still underway and currently recruiting patients for an estimated sample size of 5000. Both studies that explored the use of palbociclib (PALLAS and PENELOPE-B) and MONARCH-E, which explored the use of abemaciclib, have presented interim or final results.

The parameters of these 3 studies differed in a number of relevant respects, including the definition of high-risk patients and the previous use of chemotherapy. The PALLAS study included 5760 patients stratified according to stage, chemotherapy, age, and geographic region, and up to 13% were node-negative. The PENELOPE-B trial included 1250 patients who had residual invasive disease at surgery following adequate neoadjuvant chemotherapy and were evaluated as high risk based on their clinical-pathological stage/estrogen grade score. Patients in this trial were stratified by nodal status at surgery, age at first diagnosis, centrally measured Ki67, global region of participating sites, and risk status. MONARCH-E comprised 5637 patients stratified for prior chemotherapy, menopausal status, and region, with high-risk early invasive breast cancer (node-positive disease) defined as the presence of pathologic lymph node involvement, and at least 1 additional risk factor for N1, histologic grade 3, Ki-67 >20%, or tumor size ≥5 cm. Previous use of chemotherapy ranged from 83% in PALLAS and 95% in MONARCH-E to 100% in PENELOPE-B.

Gil-Gil and colleagues conclude that differences in patient characteristics, CDK4/6 inhibitor schedule, treatment duration, and discontinuation rates may have contributed to the differences in outcomes among the 3 adjuvant CDK4/6 inhibitor trials. They highlighted the results for abemaciclib in MONARCH-E, specifically the significant reduction in the 2-year invasive disease-free survival rate related to the prevention of long-term recurrences and no significant benefit in patients treated with palbociclib. They stressed, however, that existing data are not yet adequate to interpret the early invasive disease-free survival benefits in the results of MONARCH-E or to establish the safety profile.

Source:

Gil-Gil M, Alba E, Gavilá J, et al. The role of CDK4/6 inhibitors in early breast cancer. Breast. 2021;58:160-169.

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