Ribociclib plus hormonal therapy in the first-line setting boosted overall survival by more than 1 year, vs hormone therapy alone, in postmenopausal women with hormone receptor–positive HER2-negative advanced breast cancer, according to the latest findings from the MONALEESA-2 trial, reported at the European Society for Medical Oncology (ESMO) Congress 2021 by Gabriel N. Hortobagyi, MD, MACP, FASCO.1 Ribociclib plus an aromatase inhibitor was approved by the U.S. Food and Drug Administration in 2018 as initial endocrine-based therapy for pre/perimenopausal or postmenopausal women with hormone receptor–positive HER2-negative advanced or metastatic breast cancer.
Gabriel N. Hortobagyi, MD, MACP, FASCO
“This is the longest median survival reported to date in any advanced breast cancer phase III clinical trial,” said Dr. Hortobagyi, who is Professor of Medicine at The University of Texas MD Anderson Cancer Center, Houston. “Ribociclib and letrozole should be considered the preferred treatment option for hormone receptor–positive HER2-negative advanced breast cancer.”
Invited discussant of the MONALEESA-2 trial, Gonzalo Gomez-Abuin, MD, of the Hospital Alemán in Buenos Aires, expanded on this -distinction: “MONALEESA-2 is the first study to break the 5-year median overall survival barrier in hormone receptor–positive HER2-negative postmenopausal metastatic breast cancer.”
The final overall survival results showed that patients treated with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib plus the aromatase inhibitor letrozole achieved a median overall survival of 63.9 months, compared with 51.4 months with letrozole alone (hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.63–0.93; P = .004).
“This represents a clinically meaningful overall survival benefit of ribociclib over placebo and a 24% reduction in the relative risk of death. The overall survival benefit began to emerge around 20 months and continued to increase with longer follow-up,” Dr. Hortobagyi observed.
Previous analyses of MONALEESA-2 showed a statistically significant improvement in median progression-free survival with ribociclib/letrozole: median 25.3 months vs 16.0 months (HR = 0.568; P = 9.63 x 10-8).2
What Previous Studies Have Shown
This is not the first time a survival benefit has been observed with a CDK4/6 inhibitor in advanced breast cancer; however, populations and treatment settings have varied. In MONALEESA-7, ribociclib plus endocrine therapy in the first-line setting significantly improved overall survival vs endocrine therapy alone in premenopausal or perimenopausal patients (HR = 0.71; P = .00973).3 In MONALEESA-3, ribociclib plus fulvestrant significantly improved survival in postmenopausal patients (HR = 0.70; P = .00455) in the first- and second-line settings.4
“Taken together, the MONALEESA trials with ribociclib demonstrate a consistent overall survival benefit regardless of the endocrine therapy partner, line of therapy, or menopausal status,” Dr. Hortobagyi said.
Abemaciclib plus fulvestrant also produced an overall survival benefit in postmenopausal and peri/premenopausal patients in the second-line setting in MONARCH 2 (HR = 0.76; P = 0.137).5 And, in the PALOMA-3 trial, among patients with sensitivity to previous endocrine therapy, palbociclib plus fulvestrant resulted in longer overall survival than treatment with fulvestrant alone (HR = 0.72, 95% CI = 0.55–0.94).6
The trial randomly allocated 668 patients to receive ribociclib at 600 mg/d plus letrozole at 2.5 mg/d or placebo plus letrozole. Patients were excluded if they had previously received a CDK4/6 inhibitor, chemotherapy, or endocrine therapy in the advanced setting. The primary endpoint was -progression-free survival, which, as previously reported, was 25.3 months with ribociclib plus letrozole and 16.0 months with placebo plus letrozole.2 Overall survival was the key secondary endpoint and was to be tested if the primary endpoint was met.
In the study, the median treatment duration was approximately 2 years for the ribociclib arm and 1 year for the placebo arm. The current analysis was based on a median follow-up of 80 months—the longest follow-up reported for a CDK4/6 inhibitor to date, according to Dr. Hortobagyi.
More About Benefit in Overall Survival
The overall survival benefit began to emerge after 20 months and continued to increase over time. At 4 years, the absolute improvement was 5.7% favoring ribociclib; this rate increased to 8.4% at 5 years and to 12.2% at 6 years. At 6 years, 44.2% of the ribociclib arm was alive, compared with 32.0% of those given endocrine therapy alone.
A consistent benefit was seen across key subgroups stratified according to performance status, age, ethnicity, geographic location, and prior adjuvant or neoadjuvant therapy, as well as the number and location of metastatic sites.
More patients in the placebo arm received subsequent therapy (90.2% vs 87.8%), especially with a CDK4/6 inhibitor (34.4% vs 21.7%). Despite this imbalance favoring the placebo arm, the benefit in the experimental arm was clear, Dr. Hortobagyi added.
Furthermore, an exploratory analysis showed that ribociclib delayed the need for chemotherapy by more than 1 year vs letrozole alone. The time to first chemotherapy was 50.8 months vs 38.9 months, respectively (HR = 0.74, 95% CI = 0.61–0.91).
No new safety signals emerged with extended follow-up, and most events occurred in the first year of treatment. The most common adverse events with ribociclib were neutropenia and liver function abnormalities (mostly reversible). Twice as many patients treated with ribociclib had prolonged QT interval compared with patients who received placebo (4.5% vs 2.1%), but no clinical consequences were observed. Interstitial lung disease was recorded in 0.6% of patients receiving ribociclib.
DISCLOSURE: Dr. Hortobagyi has received research funding and personal fees from Novartis for the MONALEESA trials.
1. Hortobagyi GN, Stemmer SM, Burris III HA, et al: Overall survival results from the phase III MONALEESA-2 trial of postmenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer treated with endocrine therapy ± ribociclib. ESMO Congress 2021. Abstract LBA17_PR. Presented September 19, 2021.
2. Hortobagyi GN, Stemmer SM, Burris HA, et al: Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor–positive, HER2-negative advanced breast cancer. Ann Oncol 29:1541-1547, 2018.
3. 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.
4. Slamon DJ, Neven P, Chia S, et al: Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med 382:514-524, 2020.
5. Sledge Jr GW, Toi M, Neven P, et al: The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: A randomized clinical trial. JAMA Oncol 6:116-124, 2020.
6. Turner NC, Slamon DJ, Ro J, et al: Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 379:1926-1936, 2018.
Gonzalo Gomez-Abuin, MD
The invited discussant of the MONALESSA-2 trial was Gonzalo Gomez-Abuin, MD, a medical oncologist who is Head of the Clinical Research Unit at Hospital Alemán in Buenos Aires. According to Dr. Gomez-Abuin, phase III trials of three different CDK4/6...