Ribociclib regimen provides durable benefit, reduces recurrence in breast cancer subgroup
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SAN ANTONIO — The addition of ribociclib to endocrine therapy conferred durable benefit to patients with hormone receptor-positive, HER2-negative early breast cancer, according to findings presented at San Antonio Breast Cancer Symposium.
An improvement in invasive DFS persisted across subgroups and the combination exhibited a manageable toxicity profile, updated results from the randomized phase 3 NATALEE trial showed.
“With almost 80% of patients having completed ribociclib therapy — or stopping it for other reasons — the separation of the invasive disease-free survival curves indicates this is not a temporary benefit, but one that will persist and perhaps increase even after stopping the medication,” researcher Gabriel N. Hortobagyi, MD, FACP, professor of medicine in the department of breast medical oncology at The University of Texas MD Anderson Cancer Center, told Healio.
Ribociclib (Kisqali, Novartis) — a cyclin-dependent kinase (CDK) 4/6 inhibitor — is approved for treatment of metastatic breast cancer.
The open-label NATALEE trial evaluated the efficacy and safety of ribociclib plus endocrine therapy for men and women with hormone receptor-positive, HER2-negative early breast cancer.
“[Hormone receptor-positive, HER2-negative] breast cancer tends to have an indolent course, meaning that more than half of the recurrences are detected more than 5 years after diagnosis,” Hortobagyi said. “This is thought to be related, in part, to tumor dormancy, and our current treatments do not address this problem. So, 20 years after diagnosis, patients receiving appropriate treatment have recurrence rates between 15% and 50%, depending on the stage at diagnosis. That is unacceptable and clearly indicates an unmet need.”
The trial included 5,101 patients with stage IIA, IIB or III breast cancer.
Researchers assigned 2,549 to ribociclib —dosed at 400 mg daily on a 3-weeks-on, 1-week-off schedule for 36 months — plus endocrine therapy (letrozole 2.5 mg daily or anastrozole 1 mg daily for at least 5 years). The other 2,552 received endocrine therapy alone. Endocrine therapy continued regardless of ribociclib discontinuation.
Men and premenopausal women also received goserelin dosed at 3.6 mg every 28 days.
Invasive DFS served as the primary endpoint. Secondary endpoints included RFS, distant DFS and OS.
Previously reported results showed the addition of ribociclib to standard adjuvant therapy with a nonsteroidal aromatase inhibitor conferred a significant improvement in invasive DFS for patients with stage II or stage III hormone receptor-positive, HER2-negative early breast cancer at risk for recurrence, including those with node-negative disease.
At SABCS, Hortobagyi presented the final protocol-specified analysis for invasive DFS.
At data cutoff, 42.8% of those assigned the combination had completed 3 years of ribociclib, 35.5% discontinued ribociclib or both treatment components early, and 20.7% remained on ribociclib. Among those assigned endocrine therapy alone, 68.5% remained on treatment.
After median follow-up of 33.3 months, the addition of ribociclib to the endocrine therapy combination continued to confer a statistically significant benefit in invasive DFS (HR = 0.74; 95% CI, 0.62-0.89).
Researchers reported a higher rate of 3-year invasive DFS in the combination group (90.7% vs. 87.6%).
The DFS benefit persisted across subgroups, including patients with stage II disease (HR = 0.7; 95% CI, 0.49-0.98; 3-year invasive DFS, 94.2% vs. 92.6%) and stage III disease (HR = 0.75; 95% CI, 0.61-0.92; 3-year invasive DFS, 88.1% vs. 83.8%), as well as those with node-negative disease (HR = 0.72; 95% CI, 0.41-1.26; 3-year invasive DFS, 93.2% vs. 90.6%).
Ribociclib-treated patients also achieved improved RFS (HR = 0.72; 95% CI, 0.6-0.87; 3-year RFS, 92.1% vs. 89.1%) and distant DFS (HR = 0.74; 95% CI, 0.62-0.9; 3-year distant DFS, 92.9% vs. 90.2%).
“The benefit observed is a 25% reduction in recurrences,” Hortobagyi said. “That is in keeping with other recently developed active treatments, including aromatase inhibitors.
“The absolute benefit associated with this relative risk reduction is greater for patients at higher risk of recurrence and smaller for those with more modest risk,” he added. “This allows us to discuss with greater nuance the benefit-risk ratio for individual patients.”
OS results remained immature, with 84 events (3.3%) in the combination group and 88 events (3.4%) in the endocrine therapy alone group (HR = 0.89; 95% CI, 0.66-1.2).
No new safety signals emerged since the previous interim analysis, Hortobagyi said.
Approximately one in five (19.5%) patients assigned the combination had discontinued ribociclib at data cutoff, an increase of less than 1 percentage point since the previous interim analysis.
“After 3 years of therapy, there were no new adverse events identified and tolerance to treatment was acceptable, leading to good compliance,” Hortobagyi said. “This is important, because a drug you don’t take can’t possibly help you.”
Hortobagyi noted development of CDK4/6 inhibitors is still in its “early days.”
“Much more needs to be learned, including mechanisms of resistance, how to prevent or reverse the emergence of resistance, and how to develop biomarkers to identify patients who will benefit and those who will not,” he said.
“There also is much research being done with additional cell cycle inhibitors, including CDK2 and CDK7 inhibitors, among others,” he added. “These might be useful in combination with or in sequence after CDK4/6 inhibitors.”
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Hortobagyi G, et al Abstract GS03-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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