HR+/HER2– Early Breast Cancer | Image Credit: © Axel Kock – stock.adobe.com

Health Canada has granted a Notice of Compliance to Novartis for adjuvant ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of adult patients with hormone receptor–positive, HER2-negative, stage II/III early breast cancer at a high risk of recurrence.1

This regulatory decision was supported by data from the pivotal phase 3 NATALEE trial (​​NCT03701334), which showed a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) with the addition of ribociclib to endocrine therapy compared with endocrine therapy alone in a broad patient population.

Prior findings published in the New England Journal of Medicine, demonstrated that patients treated with ribociclib plus endocrine therapy (n = 2549) experienced a 25% reduction in the risk of invasive disease recurrence or death compared with AI alone (n = 2552; HR, 0.75; 95% CI, 0.62–0.91; P = .003).1,2 At a median follow-up of 27.7 months, the estimated 3-year iDFS rate was 90.4% in the ribociclib arm vs 87.1% in the control arm. Regarding safety, ribociclib was well tolerated across all subgroups.

Data from NATALEE also supported the September 2024 FDA approval of adjuvant ribociclib plus an AI for patients with stage II or III disease at high risk of recurrence, including those with node-negative tumors.3

“In the NATALEE trial, ribociclib demonstrated significant efficacy for a broad population of patients with early breast cancer,” Stephen K.L. Chia, MD, FRCPC, a medical oncologist with the BC Cancer, Vancouver Cancer Centre in Canada, and a steering committee member of the NATALEE trial, stated in a news release.1 “This approval provides a new and expanded treatment option for these patients to help reduce their risk of cancer returning. Patients deserve access to the most effective treatment options, and their individual needs should always be at the center of shared decision-making. In every situation, it’s critical to have an open, balanced risk-benefit discussion, in order to make the appropriate treatment decision that’s best suited for the patient to reduce the risk of their cancer returning.”

Notably, ribociclib remains the only CDK4/6 inhibitor to demonstrate a statistically significant overall survival (OS) benefit in 3 separate phase 3 trials in patients with advanced breast cancer, according to Novartis.

“While the risk of cancer returning peaks in the first 5 years after diagnosis, more than half of recurrences occur after this period, and the majority are metastatic and incurable,” Katarzyna Jerzak, MD, MSc, FRCPC, an associate scientist and medical oncologist at Sunnybrook Health Sciences Centre, added in the news release. “Ribociclib provides a new treatment option to help reduce the risk of recurrence and improve outcomes, particularly for patients at elevated risk. This approval expands our treatment arsenal with a targeted therapy that will have a meaningful impact on improving the care of patients diagnosed with early breast cancer in Canada.”

NATALEE Trial Overview and Design

NATALEE was a global, open-label trial that enrolled patients at least 18 years of age with histologically confirmed stage II or III hormone receptor–positive, HER2-negative early breast cancer, per local assessment.2 Patients with stage IIB or III disease were eligible regardless of nodal status, while those with stage IIA disease required 1 or more involved lymph nodes. Those with grade 2, node-negative tumors were permitted to enroll if they had a Ki-67 index of 20% or higher or high-risk genomic features. Prior neoadjuvant or adjuvant endocrine therapy for up to 12 months was allowed, but prior CDK4/6 inhibitor use was not.

Eligible patients were randomly assigned 1:1 to receive 400 mg of ribociclib daily in 28-day cycles for up to 36 months alongside an AI vs treatment an AI alone. Stratification factors included disease stage (II vs III), menopausal status (premenopausal vs postmenopausal), prior neoadjuvant/adjuvant chemotherapy (yes vs no), and geographic region (North America/Western Europe/Oceania vs rest of the world).

The study’s primary end point was iDFS per STEEP criteria. Key secondary end points included recurrence-free survival (RFS), distant disease-free survival (DDFS), OS, safety and tolerability, patient-reported outcomes, and pharmacokinetics.

Additional Efficacy and Safety Findings

The 3-year DDFS rate was 90.8% for the ribociclib arm vs 88.6% for the control arm (HR, 0.74; 95% CI, 0.60-0.91). The 3-year RFS rates were 91.7% and 88.6%, respectively (HR, 0.72; 95% CI, 0.58-0.88). At a median follow-up for OS of 30 months, 2.4% of patients in the ribociclib arm and 2.9% in the control arm had died (HR, 0.76; 95% CI, 0.54-1.07).2

Any-grade adverse effects (AEs) were reported in 97.9% of patients in the ribociclib arm vs 87.1% in the AI-alone arm. Serious AEs occurred in 13.3% and 9.9% of patients, respectively. Ribociclib was discontinued due to AEs in 18.9% of patients; both ribociclib and AI were discontinued in 3.3% of patients. AI discontinuation rates for any cause were comparable between groups. The most common any-grade AEs included neutropenia (62.1% vs 4.5%), arthralgia (36.5% vs 42.5%), and liver-related AEs (25.4% vs 10.6%). Grade 3 or higher neutropenia occurred in 43.8% of patients receiving ribociclib vs 0.8% of those receiving AI alone.

“Over 100,000 [patients] with [hormone receptor–positive, HER2-negative] metastatic breast cancer have been treated with [ribociclib] globally, and now we’re focused on expanding its use to those with stage II or III hormone receptor–positive/HER2-negative early breast cancer to reduce risk of recurrence,” Mark Vineis, country president of Novartis Canada, concluded in the news release.1 “We are actively committed to working with our health system partners to ensure timely access to [ribociclib] and supporting Canadians and healthcare professionals to improve health outcomes.”

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