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Adding the CDK 4/6 inhibitor ribociclib (Kisqali) to a first-line hormonal treatment prolonged survival by more than 1 year in postmenopausal women with HR-positive/HER2-negative (HR+HER2-) advanced breast cancer, according to results from the MONALEESA-2 trial.

Final overall survival (OS) results showed that patients treated with ribociclib plus the aromatase inhibitor (AI) letrozole (Femara) achieved a median OS of 63.9 months versus 51.4 months for patients treated with placebo plus letrozole (hazard ratio 0.76, 95% CI, 0.63-0.93), reported Gabriel N. Hortobagyi, MD, of the MD Anderson Cancer Center in Houston.

"This is the longest median survival reported to date in any advanced breast cancer phase III clinical trial," Hortobagyi said in a a presentation at European Society for Medical Oncology (ESMO) virtual meeting. "Ribociclib and letrozole should be considered the preferred treatment option for HR+HER- advanced breast cancer."

"The big message from today's MONALEESA-2 presentation is this impressive 12.5 months improvement in median overall survival," commented ESMO discussant Gonzalo Gomez-Abuin, MD, of Hospital Alemán in Buenos Aires. "MONALEESA-2 is the first study to break the 5-year median overall survival barrier in HR+HER- postmenopausal metastatic breast cancer. These are impressive results."

Hortobagyi noted that showed that ribociclib and letrozole compared with letrozole plus placebo significantly improved progression-free survival (PFS) for postmenopausal women (median 25.3 months vs 16.0 months, HR 0.568, 95% CI, 0.43-0.72). In addition, the phase III and trials both showed a statistically significant OS benefit with the addition of ribociclib to endocrine therapy compared with endocrine therapy alone in pre- and postmenopausal patients with HR+HER- advanced breast cancer.

"Taken together, the MONALEESA trials with ribociclib demonstrate a consistent overall survival benefit regardless of endocrine therapy partner, line of therapy, or menopausal status," Hortobagyi said.

MONALEESA-2 randomly assigned patients 1:1 to either ribociclib plus letrozole or placebo plus letrozole. Patients were excluded if they received a prior CDK 4/6 inhibitor, chemotherapy, or endocrine therapy.

At data cutoff in June 2021, the median duration of follow-up was 80 months, "the longest reported for a CDK 4/6 inhibitor to date," Hortobagyi said.

He noted that the OS benefit began to emerge after 20 months and continued to increase over time. At 4 years, the absolute OS benefit was 5.7% favoring ribociclib, which increased to 8.4% at 5 years, and 12.2% at 6 years, with 6-year survival rates of 44.2% and 32.0% for ribociclib and placebo, respectively.

"This finding makes us wonder whether the OS difference between the arms will remain the same or will be amplified with longer follow-up, and what percentage of patients remain free of progression at this point," Gomez-Abuin commented.

A consistent OS benefit was seen across key subgroups stratified according to performance status, age, race, geographic location, and prior adjuvant or neoadjuvant therapy, as well as number or location of metastatic sites.

However, the HR 0.91 for patients with non de novo disease is "intriguing" as it differs from HR 0.60 previously reported for PFS, Gomez-Abuin noted.

"It is important to mention that according to the PFS analysis, these two subgroups -- de novo and non de novo -- have the same intrinsic sensitivity to ribociclib/letrozole," he said. "But how can we explain the apparent lack of benefit is overall survival for the non de novo subgroup? We need more data, but it will be interesting to know whether OS is different according to different levels of endocrine sensitivity."

The investigators also assessed the time to the first chemotherapy regimen in each arm and found that patients treated with ribociclib had an extra year of delay before chemotherapy was utilized (50.8 months vs 38.9 months, HR 0.74, 95% CI 0.61-0.91).

Median treatment duration was approximately 2 years for the ribociclib arm and 1 year for the placebo arm. "However, after 80 months of follow-up, no new safety signals were identified," Hortobagyi reported. "And the majority of events occurred in the first 12 months of treatment."

The most common adverse events were neutropenia and liver function abnormalities.

Twice as many patients treated with ribociclib had prolonged QT interval compared with patients who received placebo (4.5% vs 2.1%). However, no clinical consequences of this EKG finding were observed. Just 0.6% of patients treated with ribociclib developed interstitial lung disease.

The the ribociclib-AI combo in 2018 as initial endocrine-based therapy for pre/perimenopausal or postmenopausal women with HR+/HER- advanced or metastatic breast cancer.

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