For first-line treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in combination with aromatase inhibitors (AIs) has become the standard of care. There are currently three CDK 4/6 inhibitors approved for first-line use in combination with hormonal therapy: palbociclib, ribociclib, and abemaciclib. Ribociclib was approved in this setting on the basis of results from the phase III MONALEESA-2 trial (N = 668), in which the combination of ribociclib and letrozole resulted in a 44% reduction in the risk of progression or death compared to letrozole alone in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer who had not previously been treated for metastatic disease.
Updated results from the MONALEESA-2 trial after 26.4 month of follow-up, showed continued treatment benefit of ribociclib plus letrozole, irrespective of potential biomarkers. The progression-free survival (PFS) with ribociclib plus letrozole was 25.3 months, compared to 16.0 months for letrozole plus placebo (HR 0.568, P = 9.63×10-8). The nearly 10 months benefit was consistent across all prespecified patient subgroups.
Furthermore, biomarker analysis found that the PFS benefit of ribociclib was maintained across biomarkers evaluated, including PIK3CA or TP53 mutation status; expression of Rb, Ki67, or p16; and CDKN2A, CCND1, and ESR1 mRNA levels. However, patients with wildtype receptor tyrosine kinase genes appear to have a slightly more pronounced benefit on ribociclib compared to those with mutated genes.
The overall response rate (ORR) among the total patient population was 42.5% with ribociclib plus letrozole arm and 28.7% with letrozole and placebo arm. In patients with measurable disease at baseline, the ORRs were 54.5% and 38.8%, respectively.
Importantly, with longer follow up, no new toxicities or evidence of cumulative toxicity of the ribociclib combination was observed. Adverse events (AEs) of any grade occurred in 25.4% of patients receiving ribociclib plus letrozole, and 15.5% of patients receiving letrozole alone. QTc prolongation, an AE known to be associated with ribociclib, occurred in 3.6% of patients in the ribociclib plus letrozole group, and 0.6% of patients in the letrozole plus placebo group. QTc changes were asymptomatic and managed with ribociclib dose reductions. The most common all-grade AE leading to ribociclib dose reduction was neutropenia (24.9%).
The investigators concluded that these results support the continued safety and efficacy of ribociclib plus letrozole as a first-line treatment for patients with metastatic HR-positive, HER2-negative breast cancer. Further follow-up, including analysis of overall survival, is awaited.