Overall survival with ribociclib plus fulvestrant in advanced breast cancer
Open accessAbstract
BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).
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CDK4/6 inhibitors plus endocrine therapy are standard of care for ER-positive/HER2-negative ABC.
“The last 2 years have seen the establishment of cyclin-dependent kinase (CDK)4/6 inhibitors combined with endocrine therapy (ET) as the standard of care for ER-positive/HER2-negative ABC”
From 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020) · cites this paper as [37]
The paper’s Abstract (page not supplied) says CDK4/6 inhibitors have improved outcomes in advanced breast cancer and that three are approved for hormone-receptor-positive, HER2-negative disease. The Discussion (page not supplied) says its findings may support considering ribociclib plus fulvestrant as initial therapy. These passages support the clinical role of the combination, but do not establish that CDK4/6 inhibitors plus endocrine therapy became the standard of care in the stated two-year period. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCDK4/6 inhibitors plus endocrine therapy provide substantial PFS benefit and a favorable toxicity profile.
“substantial PFS benefit and good toxicity profile.36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57”
From 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020) · cites this paper as [37]
The Progression-free Survival section reports a substantial benefit for ribociclib plus fulvestrant over placebo plus fulvestrant in patients with advanced breast cancer. The Adverse Events section reports no new safety signals, but adverse events were more frequent with ribociclib, including grade 3 or 4 neutropenia in 57.1% versus 0.8%; it does not establish the claimed good toxicity profile. The trial also addresses this specific combination, not CDK4/6 inhibitors as a class. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCDK4/6 inhibitors can be combined with an aromatase inhibitor or fulvestrant and are effective across de novo or recurrent ABC, first or second line, primary or secondary resistance, postmenopausal and premenopausal women (with ovarian suppression/ablation), and men.
“These agents can be combined with an aromatase inhibitor (AI) or fulvestrant, and are effective in de novo or recurrent ABC, in first or second line, in cases of primary or secondary resistance, in postmenopausal and premenopausal women (the latter with ovarian function suppression/ablation), and in men (preferably with a luteinising hormone-releasing hormone agonist).”
From 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020) · cites this paper as [37]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredTwo ribociclib trials that enrolled some patients receiving first-line therapy demonstrated a significant overall survival benefit.
“To date, two trials evaluating ribociclib that included some patients receiving firstline therapy showed a significant overall survival benefit. 14-16”
From Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. (2022) · cites this paper as [15]
The Discussion (page unavailable) says that MONALEESA-3 and MONALEESA-7 both showed significant overall-survival benefits. The Overall Survival section documents patients receiving first-line treatment in MONALEESA-3, but our copy does not establish that MONALEESA-7 also enrolled first-line patients. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCDK4/6 inhibitors plus endocrine therapy confer OS benefit in first- and second-line settings for ER-positive/HER2-negative ABC.
“in view of the OS benefit seen in several trials,36, 37, 38, 39, 40, 41, 42 both in the first- and second-line settings”
From 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020) · cites this paper as [37]
MONALEESA-3 showed significantly longer overall survival among postmenopausal patients receiving first- or second-line ribociclib plus fulvestrant compared with fulvestrant alone.
“In addition, the MONALEESA-3 trial showed significantly longer overall survival among postmenopausal patients with first- and second-line ribociclib plus fulvestrant than with fulvestrant alone. 15”
From Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. (2022) · cites this paper as [15]
Earlier, three trials-MONALEESA-7, MONALEESA-3, and MONARCH 2-reported significant overall survival gains from adding a CDK4/6 inhibitor (ribociclib or abemaciclib) in broad HR-positive, HER2-negative advanced breast cancer populations.
“Previously, the MONALEESA-7, MONALEESA-3, and MONARCH 2 trials have shown a significant overall survival benefit with the addition of a CDK4/6 inhibitor (either ribociclib or abemaciclib) in broad groups of patients with HR-positive, HER2-negative advanced breast cancer. 14-16”
From Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. (2022) · cites this paper as [15]
Those trials reported reductions in death risk of 29%, 28%, and 24%, respectively.
“These trials showed a 29%, 28%, and 24% lower risk of death, respectively.”
From Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. (2022) · cites this paper as [15]
In the final prespecified analysis, a significant overall survival benefit was observed with ribociclib + fulvestrant over fulvestrant alone; median overall survival was not reached in the intent-to-treat population (NR vs 40.0 months; HR 0.72; 95% CI 0.57-0.92) nor in the first-line subgroup (NR vs 45.1 months; HR 0.70; 95% CI 0.48-1.02).
“In the final prespecified analysis, a significant OS benefit was observed with ribociclib + fulvestrant over fulvestrant alone; however, at the time of this analysis, the mOS was not reached in the ribociclib arm in the intent-to-treat (ITT) population (mOS, NR vs. 40.0 months [HR 0.72; 95% CI 0.57–0.92; P = 0.00455]) nor was it reached in the first-line (de novo or late relapse) subgroup (mOS, NR”
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5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)
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“The last 2 years have seen the establishment of cyclindependent kinase (CDK)4/6 inhibitors combined with endocrine therapy (ET) as the standard of care for ER-positive/HER2-negative ABC in view of the OS benefit seen in several trials,(36-42) both in the first- and second-line settings, substantial PFS benefit and goo…”
BackgroundOverall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.
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“3 months) analysis of MONALEESA-3, have been reported previously [8, 17].”
BackgroundMethodResultInfluentialSelf-citation
- Authors
- Slamon, D. J., Neven, P., Chia, S., Fasching, P. A., De Laurentiis, M., Im, S.-A., Petrakova, K., Bianchi, G. V., Esteva, F. J., Martín, M., Nusch, A., Sonke, G. S., De la Cruz-Merino, L., Beck, J. T., Pivot, X., Sondhi, M., Wang, Y., Chakravartty, A., Rodriguez-Lorenc, K., Taran, T., & Jerusalem, G.
- Affiliations
- BC Cancer Agency (CA)
- From the David Geffen School of Medicine at UCLA, Los Angeles (D.J.S.); Multidisciplinary Breast Center, Universitair Ziekenhuis Leuven, Leuven (P.N.), and Centre Hospitalier Universitaire Liège and Liege University, Liege (G.J.) — all in Belgium; the British Columbia Cancer Agency, Vancouver, Canada (S.C.); University Hospital Erlangen, Comprehensive Cancer Center Erlangen–European Metropolitan Region of Nuremberg, and Department of Gynecology and Obstetrics, Friedrich-Alexander University...
- Universidad Complutense de Madrid (ES)
- Novartis (Switzerland) (CH)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-02-06
- Volume
- 382
- Issue
- 6
- Pages
- 514-524
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3133509869
- Cited by
- 865
- References
- 20
- Citations by year
- 2026: 94 · 2025: 142 · 2024: 104 · 2023: 129 · 2022: 131 · 2021: 163 · 2020: 101
- FWCI
- 72.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- ORBi (University of Liège) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Funders
- Novartis
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- ribociclib, fulvestrant, advanced breast cancer, hormone receptor-positive breast cancer, HER2-negative breast cancer, overall survival, progression-free survival, CDK4/6 inhibitors, first-line therapy, second-line therapy, postmenopausal women
- MeSH terms
- Fulvestrant, Progression-Free Survival, Aged, Aminopyridines, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Drug Administration Schedule, Female, Humans, Middle Aged, Purines, Receptors, Estrogen, Receptors, Progesterone, Postmenopause, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Kaplan-Meier Estimate
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