Ribociclib Receives FDA Approval for Treating High-Risk Early-Stage Breast Cancer

On September 17, 2024, the United States Food and Drug Administration (FDA) approved a regimen for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage 2 and 3 breast cancer at high risk of recurrence, for adjuvant treatment: ribociclib (Valamor, Novartis) with an aromatase inhibitor. The Kisqali Femara Co-Pack, containing ribociclib and letrozole, was also approved for the same indication.

FDA Approval Based on the NATALEE Trial

Ribociclib's efficacy was evaluated in NATALEE, a randomized, open-label, multicenter trial involving 5101 adults with hormone receptor-positive, HER2-negative early-stage breast cancer.

How Is a Patient With “High-Risk” Hormone-Positive, HER2-Negative Early Breast Cancer Defined?

This definition covers patients with breast cancer considered at high risk of recurrence. In the study, the high-risk patient group was defined as follows:

• Patients with lymph node involvement, excluding microscopic lymph node involvement
• Patients without lymph node involvement but with a tumor larger than 5 cm
• Patients with a tumor measuring 2-5 cm, grade 2, and either high genomic risk or a Ki67 level of 20% or higher
• Patients with a tumor measuring 2-5 cm and grade 3 disease

Patients meeting these criteria form a group requiring more intensive treatment because of their high risk of recurrence.

Study Details

Participants were randomly assigned in a 1:1 ratio to receive ribociclib (400 mg) plus an aromatase inhibitor (AI) or an AI alone. Patients could also receive goserelin when needed. Randomization was based on anatomical stage, previous chemotherapy (neoadjuvant or adjuvant), menopausal status (premenopausal women and men versus postmenopausal women), and region (North America/Western Europe/Oceania versus the rest of the world).

The study's primary efficacy endpoint was invasive disease-free survival (iDFS).

iDFS was defined as the time from randomization to the first occurrence of local or regional invasive breast cancer recurrence, distant metastasis, death from any cause, contralateral invasive breast cancer, or a primary invasive cancer outside the breast (excluding basal and squamous cell skin carcinomas).

Results

The interim analysis showed a statistically significant improvement in invasive disease-free survival (iDFS) in the group receiving ribociclib plus an AI.

• In the final iDFS analysis, the iDFS rate at 36 months in the ribociclib plus AI arm was 90.7% (95% CI: 89.3, 91.8), compared with 87.6% (95% CI: 86.1, 88.9) in the AI-only arm.
• These data were supported by a hazard ratio of 0.749 (95% CI: 0.628, 0.892).
• These results indicate that adding ribociclib significantly reduces the risk of cancer recurrence, meaning an approximately 25% reduction in recurrence risk (hazard ratio 0.749).

Overall survival (OS) was not yet mature at this point.

Side effects observed in NATALEE were consistent with the known safety profile of ribociclib in combination with an AI. Additional safety information is available in the prescribing information.

The recommended adjuvant ribociclib dose is 400 mg daily (two 200 mg film-coated tablets) for 21 days of each 28-day treatment cycle. Refer to the prescribing information for the recommended aromatase inhibitor dose.

Updated storage requirements are also available for Valamor/Kisqali. Kisqali must be refrigerated until dispensed to patients. After dispensing, patients are advised to store it at room temperature for up to 2 months.

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Comparing Ribociclib and Abemaciclib

Previously, adjuvant treatment for patients in a similar situation was investigated in monarchE, leading to approval in October 2021 of abemaciclib (Yulareb), which received FDA approval.

The 36-month invasive disease-free survival (iDFS) results from NATALEE and monarchE show important advances in early breast cancer treatment in both trials, although several differences stand out.

NATALEE Trial: NATALEE evaluated ribociclib plus an aromatase inhibitor in patients with hormone receptor (HR)-positive, HER2-negative stage II and III early breast cancer. At 36 months, the iDFS rate was 90.7% among patients receiving ribociclib and an aromatase inhibitor, compared with 87.6% among those receiving an aromatase inhibitor alone. This showed a 25% reduction in recurrence risk with ribociclib (HR: 0.749). The study also included a broader patient population, enrolling patients with no lymph node involvement but high-risk tumor characteristics.

monarchE Trial: monarchE evaluated abemaciclib plus endocrine therapy in patients with high-risk HR-positive, HER2-negative breast cancer. At 36 months, iDFS was 86% in the abemaciclib group and 79% in the endocrine therapy group. monarchE included only patients with lymph node involvement and showed a 37% reduction in recurrence risk (HR: 0.68).

In conclusion:

• Patient Characteristics: Both trials examined patients with hormone receptor-positive, HER2-negative breast cancer, but monarchE focused on higher-risk patients.
• Treatment Duration: Abemaciclib was given for 2 years in monarchE, while ribociclib was given for 3 years in NATALEE.
• Efficacy: CDK 4/6 inhibitors improved invasive disease-free survival (iDFS) rates in both studies. In monarchE, abemaciclib produced a greater improvement in the measured survival rates (a 7.6% increase in iDFS).
• Side Effects: Both medicines cause side effects, but a broader side-effect profile was observed with abemaciclib in monarchE.

These results show that CDK4/6 inhibitors significantly reduce recurrence risk in patients with high-risk breast cancer in both studies. NATALEE stands out for its broader patient population and lower ribociclib dose, while monarchE focused only on patients with positive lymph nodes.