The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology to recommend ribociclib (Kisqali; Novartis) as a Category 1 preferred cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) adjuvant therapy. This recommendation applies to patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) when used in combination with an aromatase inhibitor (AI). This makes ribociclib the only CDK4/6i recommended for both all node-positive disease and patients without nodal involvement but with high-risk disease.
The NCCN's Category 1 designation indicates a high level of clinical evidence and uniform consensus among experts regarding the appropriateness of ribociclib for this patient population. The updated guidelines reflect the impact of longer-term results from the Phase 3 NATALEE trial (NCT03701334), presented at the European Society for Medical Oncology (ESMO) 2024 Congress. The NATALEE trial demonstrated a sustained efficacy benefit even after the completion of ribociclib treatment in a broad patient population, including those with node-negative disease and EBC indications.
NATALEE Trial Results
The NATALEE trial, a global, open-label, multicenter Phase 3 study, enrolled over 1500 adult patients with HR+/HER2- EBC. Participants were randomized to receive either ribociclib plus endocrine therapy (ET) or ET alone as adjuvant treatment. The ET consisted of a non-steroidal AI (anastrozole or letrozole) and goserelin, if applicable. The primary endpoint was invasive disease-free survival.
Data from the NATALEE trial showed that ribociclib combined with ET resulted in an approximate 25.1% reduction in the risk of disease recurrence compared to ET alone (HR = 0.749; 95% CI: 0.628, 0.892; P = .0006), including patients with high-risk node-negative disease. Furthermore, investigators observed a deepening benefit beyond three years, with a 28.5% reduction in the risk of recurrence in patients receiving the ribociclib regimen (HR = 0.715; CI 95% 0.609-0.840; P < .0001).
Clinical Implications
According to experts, the updated NCCN guidelines are expected to approximately double the number of patients who could benefit from treatment with a CDK4/6i in the adjuvant setting. Shreeram Aradhye, MD, President of Development and Chief Medical Officer at Novartis, stated that the NCCN guideline recommendation reaffirms the importance of offering eligible patients with early breast cancer, including those with limited nodal involvement and high-risk N0 disease, a CDK4/6i treatment like ribociclib in addition to endocrine therapy to reduce their risk of recurrence.
Ribociclib functions as a selective cyclin-dependent kinase inhibitor, slowing cancer progression by inhibiting CDK4 and CDK6 proteins. These proteins, when overactivated, can accelerate cancer cell growth and division. Ribociclib is administered orally for three weeks, followed by one week off treatment, in combination with any AI for four weeks.
The FDA approved ribociclib in combination with an AI for the treatment of HR+/HER2- stage 2 and 3 EBC at high risk of recurrence in September 2024. This approval was based on data presented at the ESMO 2024 Congress, which demonstrated a clinically meaningful reduction in the risk of disease recurrence and a well-tolerated safety profile.
