Ribociclib plus letrozole improves OS in hormone receptor–positive, HER2-negative advanced breast cancer

A combined regimen of ribociclib plus letrozole as first-line treatment provides a statistically significant and clinically meaningful overall survival (OS) benefit vs placebo plus letrozole in postmenopausal patients with hormone receptor–positive and HER2-negative advanced breast cancer (BC), results of the phase III MONALEESA-2 study have shown.   

At a median follow-up of 80 months, median OS was prolonged by 12.5 months with ribociclib plus letrozole (63.9 months vs 51.4 months; hazard ratio [HR], 0.76; 95 percent confidence interval [Cl], 0.63 to 0.93; p=0.004) compared with placebo plus letrozole. [Hortobagyi GN, et al, ESMO 2021, abstract LBA17]

“This is the longest median follow-up reported for a cyclin-dependent kinase [CDK] 4/6 inhibitor to date, as well as the longest median OS reported to date in any phase III advanced BC trial,” highlighted investigator Dr Gabriel Hortobagyi of the University of Texas MD Anderson Cancer Center, Houston, Texas, US.

“The OS benefit of ribociclib plus letrozole began to emerge at 20 months and continued to increase over time, [with estimated 4-year and 6-year survival rates of 60.9 percent vs 55.2 percent and 44.2 percent vs 32.0 percent, respectively, for ribociclib plus letrozole vs placebo vs letrozole],” pointed out Hortobagyi.

“A consistent OS benefit with ribociclib plus letrozole was demonstrated across key subgroups by performance status, age, ethnicity, geographical location, prior neoadjuvant or adjuvant therapy, and number and location of metastatic sites. Of note, a wide Cl of OS HR was observed in a small number of patients in some subgroups,” Hortobagyi continued.

The MONALESSA-2 study included 668 postmenopausal patients with hormone receptor–positive and HER2-negative advanced BC who had not received previous systemic therapy for advanced disease. Prior adjuvant or neoadjuvant endocrine therapy (ET) was permitted. The patients were randomized (1:1) to receive ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg/day) or placebo plus letrozole.

The median treatment duration was approximately 2 years vs 1 year in the ribociclib-letrozole arm vs placebo-letrozole arm. Treatment was discontinued in 92.4 percent of the cohort patients at the end of 80-month follow-up, with disease progression being the most common (69.9 percent) reason. Notably, treatment was still ongoing in almost twice as many patients in the ribociclib-letrozole arm vs placebo-letrozole arm (9.0 percent vs 5.1 percent).

Among patients who discontinued the study regimen, 21.7 percent vs 34.4 percent of patients in the ribociclib-letrozole arm vs placebo-letrozole arm received a CDK 4/6 inhibitor in a subsequent line of treatment.

Time to first chemotherapy was delayed by approximately 1 year in the ribociclib-letrozole arm vs placebo-letrozole arm (median, 50.6 months vs 38.9 months; HR, 0.74; 95 percent CI, 0.61 to 0.91).

No new safety signals were identified in the trial, with the majority of adverse events (AEs) occurring in the first 12 months of treatment. The most common grade 3/4 AEs of special interest were neutropenia (63.8 percent for ribociclib-letrozole vs 1.2 percent for placebo-letrozole), hepatobiliary toxicity (14.4 percent vs 4.8 percent), prolonged QT interval (4.5 percent vs 2.1 percent), and interstitial lung disease/pneumonitis (0.6 percent vs 0 percent).

“The MONALEESA trials have demonstrated a consistent OS benefit with ribociclib regardless of ET partner, line of therapy, or menopausal status. Ribociclib combined with ET is the only first-line treatment with an OS benefit. It should therefore be considered the preferred treatment option for hormone receptor–positive, HER2-negative advanced BC,” concluded Hortobagyi.