As reported in TheNew England Journal of Medicine by Seock‑Ah Im, MD, PhD, of Seoul National University College of Medicine, and colleagues, an interim analysis in the phase III MONALEESA-7 trial has shown an overall survival benefit with the addition of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor ribociclib to endocrine therapy in premenopausal or perimenopausal women with advanced hormone receptor–positive, HER2-negative breast cancer.1 A prior report from the trial showed that the addition of ribociclib to endocrine therapy significantly improved progression-free survival, the primary endpoint of the trial.2
In the double-blind trial, 672 women aged 18 to 59 years from 188 sites in 30 countries were randomly assigned between December 2014 and August 2016 to receive ribociclib at 600 mg daily for 21 consecutive days followed by 7 days off in 28-day cycles (n = 335) or a matching placebo (n = 337). Both groups received goserelin at 3.6 mg subcutaneously on day 1 of each 28-day cycle and either a nonsteroidal aromatase inhibitor (letrozole at 2.5 mg or anastrozole at 1 mg) or tamoxifen (20 mg) continuously once daily. Crossover between groups was not permitted. Patients had to have locoregionally recurrent or metastatic disease not amenable to curative therapy.
This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone receptor–positive, HER2-negative breast cancer.— Seock‑Ah Im, MD, PhD
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In the previously reported primary analysis, with a median follow-up of 19.2 months, median progression-free survival was 23.8 months in the ribociclib group vs 13.0 months in the placebo group (hazard ratio [HR] = 0.55, P < .0001).2
The second prespecified interim analysis of overall survival, the key secondary endpoint of the trial, was conducted after 192 patients had died, including 83 (24.8%) in the ribociclib group and 109 (32.3%) in the placebo group.1 The median duration of follow-up was 34.6 months. Kaplan-Meier estimated overall survival at 42 months was 70.2% in the ribociclib group vs 46.0% in the placebo group (HR = 0.71, P = .00973), with the P value crossing the prespecified stopping boundary (P = .01018) for superiority of ribociclib. Median overall survival could not be estimated in the ribociclib group vs 40.9 months in the placebo group (95% confidence interval [CI] = 37.8 to could not be estimated). Estimated overall survival was 82.7% vs 81.8% at 24 months and 71.9% vs 64.9% at 36 months.
Survival by Subgroup
Among the 495 patients who received an aromatase inhibitor (248 in the ribociclib group, 247 in the placebo group), median overall survival could not be estimated in the ribociclib group vs 40.7 months in the placebo group; estimated overall survival at 42 months was 69.7% vs 43.0% (HR = 0.70, 95% CI = 0.50–0.98). Among 177 patients who received tamoxifen (87 in the ribociclib group, 90 in the placebo group), median overall survival could not be estimated in either group; estimated survival at 42 months was 71.2% vs 54.5% (HR = 0.79, 95% CI = 0.45–1.38).
A total of 219 patients in the ribociclib group and 280 patients in the placebo group discontinued the study regimen. Among these patients, 68.9% vs 73.2% received subsequent therapy, most commonly chemotherapy alone (22.4% vs 28.6%) and hormone therapy alone (22.4% vs 20.4%). At 42 months, 65.8% of the total ribociclib group vs 49.0% of the total placebo group had not yet received a first subsequent chemotherapy (HR = 0.60, 95% CI = 0.46–0.77). For progression-free survival during receipt of subsequent treatment, the estimated percentage of patients who were alive without disease progression at 42 months while receiving second-line therapy was 54.6% vs 37.8% (HR = 0.69, 95% CI = 0.55–0.87).
Adverse events in the two groups at the current overall survival analysis were consistent with those reported in the primary analysis.2 Grade 3 or 4 adverse events of special interest were neutropenia, which occurred in 63.5% of the ribociclib group vs 4.5% of the placebo group; hepatobiliary toxic effects, which occurred in 11.0% vs 6.8%; and prolonged QT interval, which occurred in 1.8% vs 1.2%.
The investigators concluded: “This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone receptor–positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up.”
DISCLOSURE: Dr. Im has served in a consulting or advisory role for Amgen, AstraZeneca, Eisai, Hanmi Pharmaceutical, Novartis, Pfizer, and Roche/Genentech; has received research funding from AstraZeneca, Pfizer, and Roche/Genentech; has been reimbursed for travel, accommodations, or other expenses by Novartis and Roche/Genentech; and has held other roles or relationships with Roche. For full disclosures of all other study authors, visit www.nejm.org.
1. Im SA, Lu YS, Bardia A, et al: Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med 381:307-316, 2019.
2. Tripathy D, Im SA, Colleoni M, et al: Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol 19:904-915, 2018.