Dennis Slamon, MD, PhD
As reported in The New England Journal of Medicine by Dennis Slamon, MD, PhD, of the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues, interim analysis of the phase III NATALEE trial has shown improved invasive disease–free survival with the addition of adjuvant ribociclib (a CDK4/6 inhibitor) to a nonsteroidal aromatase inhibitor in patients with hormone receptor–positive, HER2-negative early breast cancer.1
As stated by the investigators, “ribociclib has been shown to have a significant overall survival benefit in patients with … [hormone receptor]-positive, … HER2-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.”
Study Details
In the international open-label trial, 5,101 patients with stage II or III disease were randomly assigned between January 2019 and April 2021 to receive adjuvant ribociclib at 400 mg/d for 3 weeks followed by 1 week off for 3 years plus a nonsteroidal aromatase inhibitor (n = 2,549) or a nonsteroidal aromatase inhibitor alone (n = 2,552); aromatase inhibitor treatment consisted of letrozole at 2.5 mg/d or anastrozole at 1 mg/d for ≥ 5 years. Premenopausal women and men also received goserelin every 28 days. Randomization was stratified by disease stage (II or III), menopausal status (premenopausal women and men or postmenopausal women), previous adjuvant or neoadjuvant chemotherapy, and geographic location (North America/Western Europe/Oceania or rest of the world). Approximately 60% of patients in each group had stage III disease, approximately 71% had received prior endocrine therapy, and 43% and 48% had received prior neoadjuvant and prior adjuvant chemotherapy, respectively; in both groups, 44% were premenopausal women, 0.4% were men, and 56% were postmenopausal women. The primary endpoint was investigator-assessed invasive disease–free survival.
Invasive Disease–Free Survival
At the time of the prespecified interim analysis, the median follow-up was 34 months. At 3 years, the invasive disease–free survival rate was 90.4% with ribociclib plus a nonsteroidal aromatase inhibitor vs 87.1% with a nonsteroidal aromatase inhibitor alone (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.62–0.91, P = .003).
In stratification groups, hazard ratios for 3-year invasive disease–free survival for ribociclib plus a nonsteroidal aromatase inhibitor vs an aromatase inhibitor alone were 0.76 (95% CI = 0.53–1.10) among patients with stage II disease and 0.74 (95% CI = 0.59–0.93) for stage III disease; 0.72 (95% CI = 0.53–0.98) among men and premenopausal women and 0.78 (95% CI = 0.61–1.00) among postmenopausal women; 0.79 (95% CI = 0.61–1.01) among patients with prior neoadjuvant chemotherapy, 0.67 (95% CI = 0.49–0.93) among those with prior adjuvant chemotherapy, and 1.04 (95% CI = 0.58–1.87) among those who received neither; and 0.76 (95% CI = 0.59–0.97) among 1,563 vs 1,565 patients from North America/Western Europe/Oceania and 0.76 (95% CI = 0.56–1.02) among 986 vs 987 patients from the rest of the world. In additional subgroups, hazard ratios were 0.76 (95% CI = 0.60–0.95) among patients with and 0.77 (95% CI = 0.56–1.08) among patients without prior endocrine therapy; 0.80 (95% CI = 0.59–1.08) among 1,199 vs 1,236 patients with a Ki67 index ≤ 20% and 0.75 (95% CI = 0.75–1.00) among 920 vs 938 patients with a Ki67 index > 20%; 0.63 (95% CI = 0.34–1.16) among 285 vs 328 patients with N0 status and 0.77 (95% CI = 0.63–0.94) among 2,261 and 2,219 patients with N1–3 status.
At 3 years, the distant disease–free survival rate was 90.8% vs 88.6% (HR = 0.74, 95% CI = 0.60–0.91) and the recurrence-free survival rate was 91.7% vs 88.6% (HR = 0.72, 95% CI = 0.58–0.88). At the time of analysis, death had occurred in 2.4% of the ribociclib/aromatase inhibitor group vs 2.9% of the aromatase inhibitor–alone group (HR = 0.76, 95% CI = 0.54–1.07).
Adverse Events
The most common adverse events of any grade in the ribociclib/aromatase inhibitor group were neutropenia (62.1% vs 4.5% in aromatase inhibitor–alone group), arthralgia (36.5% vs 42.5%), and nausea (23.0% vs 7.5%). Grade 3, 4, and 5 adverse events occurred in 56.9%, 5.2%, and 0.5% of the ribociclib/aromatase inhibitor group and 16.1%, 1.6%, and 0.2% of the aromatase inhibitor–alone group. The most common grade 3 or 4 adverse events in the ribociclib/aromatase inhibitor group included neutropenia (50.2% vs 0.8% in the aromatase inhibitor–alone group), increased alanine aminotransferase (7.3% vs 0.6%), and increased aspartate aminotransferase (4.4% vs 0.5%). QT-interval prolongation of any grade was observed in 5.2% vs 1.2% of patients in the aromatase inhibitor–alone group.
KEY POINTS
- The addition of ribociclib to a nonsteroidal aromatase inhibitor significantly improved invasive disease–free survival in patients with hormone receptor–positive, HER2-negative, stage II or III, early-stage breast cancer.
- Benefits were observed in distant disease–free survival and recurrence-free survival.
Serious adverse events occurred in 13.3% vs 9.9% of patients. Adverse events led to discontinuation of ribociclib in 18.9% of patients, most commonly liver-related events (8.9%). No deaths were considered related to treatment.
The investigators concluded: “Ribociclib plus a [nonsteroidal aromatase inhibitor] significantly improved invasive disease–free survival among patients with [hormone receptor]-positive, HER2-negative stage II or III early breast cancer.”
DISCLOSURE: The study was funded by Novartis. Dr. Slamon sits on the board of directors for 1200 Pharma, BioMarin Pharmaceutical, and Tori BioTherapeutics; has received institutional grants from 1200 Pharma, Novartis, Pfizer, and Tori BioTherapeutics; has served as a consultant for AstraZeneca AB, Novartis, and Pfizer; and owns stock in Amgen, BioMarin Pharmaceutical, Merck, Pfizer, Seagen, and Vertex Pharmaceuticals. For full disclosures of the study authors, visit nejm.org.
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