FDA Approves Adjuvant Ribociclib in HR+/HER2– Breast Cancer

The FDA has approved adjuvant ribociclib (Kisqali) plus an aromatase inhibitor (AI) for the treatment of patients with hormone receptor–positive, HER2-negative stage II and III early breast cancer at high risk of recurrence, including those with node-negative disease.¹

The approval is based on data from the phase 3 NATALEE trial (NCT03701334), in which the combination demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) in patients with stage II or III hormone receptor–positive, HER2-negative early breast cancer vs endocrine therapy alone.¹

"The FDA approval of [ribociclib] for this early breast cancer population, including those with N0 disease, is a pivotal moment in improving our approach to care," Dennis J. Slamon, MD, director of Clinical/Translational Research, UCLA Jonsson Comprehensive Cancer Center and chairman of the Board of Translational Research In Oncology and NATALEE trial lead investigator, said in a news release.¹ "Today's approval allows us to offer treatment with a CDK4/6 inhibitor to a significantly broader group of people as a powerful tool that, combined with endocrine therapy, can help further minimize their risk of cancer returning."

Findings from the second interim analysis, which were presented at the 2023 ASCO Annual Meeting, demonstrated that patients who received the combination (n = 2549) achieved a 3-year iDFS rate of 90.4% vs 87.1% in patients who received endocrine therapy alone (n = 2552; HR, 0.748; 95% CI, 0.618-0.906; P = .0014). Median follow-up for iDFS was 27.7 months, and the benefit proved consistent across patient subgroups, regardless of disease stage, menopausal status, or nodal status.² The final iDFS analysis was performed with a median follow-up of 33.3 months and showed sustained iDFS benefit with ribociclib, with 3-year iDFS rates of 90.7% vs 87.6%, respectively (HR, 0.749; 95% CI, 0.628-0.892; P =.0006).³

Updated findings from an exploratory analysis that was performed with an additional 10.9 months of follow-up were presented at the 2024 ESMO Congress. The results demonstrated that at a median follow-up of 44.2 months in the intention-to-treat population, the 3-year iDFS rates were 90.8% with ribociclib plus an AI vs 88.1% with an AI alone. At 4 years, the respective iDFS rates were 88.5% vs 83.6% (HR, 0.715; 95% CI, 0.609-0.840; P <.0001).⁴

NATALEE was a multicenter, randomized, open-label trial comparing ribociclib plus endocrine therapy with endocrine therapy alone in adult patients with hormone receptor–positive, HER2-negative early breast cancer. Eligible patients needed to have anatomic stage IIA, IIB, or III disease following surgical resection, an ECOG performance status of 1 or 0, and have available archival tissue from surgical resection. Those who received prior treatment with a CDK4/6 inhibitor, those with distant breast cancer metastases beyond regional lymph nodes, and those with clinically significant, uncontrolled heart disease were excluded. Prior endocrine therapy up to 12 months prior to randomization was permitted.^4,5

Patients who had stage IIA disease included those with N1 disease or those with N0 disease that was grade 2 with evidence of high-risk characteristics, which included Ki-67 expression of 20% or higher, an Oncotype DX Breast Recurrence Score of at least 26, or high-risk characteristics via genomic risk profiling, or grade 3. For stage IIB, the disease must be N0 or N1 and for stage III, the disease must be N0, N1, N2, or N3.⁴

Eligible patients were randomly assigned to receive 400 mg of ribociclib daily in a 3-weeks-on-1-week off manner for 3 years plus an AI, or an AI alone. In both arms, standard-of-care endocrine therapy consisted of letrozole or anastrozole for a duration of at least 5 years plus goserelin in men and premenopausal women.⁴

iDFS using STEEP criteria served as the primary end point of the study. Secondary end points included recurrence-free survival, distant disease-free survival (DDFS), overall survival (OS), patient-reported outcomes, pharmacokinetics, and safety and tolerability. Locoregional recurrence-free survival and gene expression and alterations in circulating tumor DNA/RNA samples were exploratory end points.⁴

Additional findings from the ESMO 2024 presentation demonstrated that ribociclib led to a continued improvement in DDFS (HR, 0.715; 95% CI, 0.604-0.847; P <.0001) and a positive trend for OS (HR, 0.827; 95% CI, 0.636-1.047; P =.0766).⁴

Regarding safety adverse effects (AEs) of special interest in the combination arm included neutropenia (all grade, 62.8%; grade 3/4, 44.4%), liver-related AEs (26.7%; 8.6%), QT interval prolongation (5.4%; 1.0%), and interstitial lung disease/pneumonitis (1.6%; 0.0%).⁴

"With this approval, we are redefining treatment options for a broader population of people impacted by breast cancer and facing the persistent risk of recurrence," Victor Bultó, president, US, Novartis, said.¹ "We continue to transform cancer care with [ribociclib], building on its established profile in the metastatic setting and now helping a wide range of people as they strive to stay cancer-free following an early-stage diagnosis."

References

1. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed September 17, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer
2. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
3. Hortobagyi G, Stroyakovsky D, Yardley D, et. al. Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial. Presented at: 2023 San Antonio Breast Cancer Symposium. December 5-9, 2023; Abstract GS03-03.
4. Fasching PA, Stroyakovskiy D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2– early breast cancer: 4-year outcomes from the NATALEE trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. LBA13.
5. A trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer (NATALEE). ClinicalTrials.gov. Updated October 3, 2023. Accessed September 17, 2024. https://clinicaltrials.gov/ct2/show/NCT03701334