N Engl J Med
Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.
Abstract
Background
In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.
Methods
Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.
Results
After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed.
Conclusions
First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).
Related Questions
How does your treatment approach vary in patients with HR+/HER2- breast cancer presenting with CNS metastases?
There are preclinical studies published about ribociclib entering the CNS (Patel et al., PMID 31079218), as well as some clinical studies in non-breast tumors such as meningiomas (Sanai et al., ESMO 2019). However, I am not aware of any published studies in ribociclib analogous to the Phase 2 trial ...
Would you consider AI alone over CDK4/6 inhibitor combinations in older patients with breast cancer considering the subgroup analyses from MONALEESA-2 suggest less benefit in patients over 65?
In MONALEESA-2, 295 patients (44%) were ≥ 65 years of age, 150 were randomized to ribociclib + letrozole; and 145 received placebo + letrozole. 370 patients were <65 years of age, 184 were randomized to the ribociclib group, and 186 to the placebo group. The baseline characteristics were balanced be...
How do you select your first-line endocrine therapy to accompany CDK4/6 inhibitor in metastatic HR+ breast cancer?
If this is a denovo metastatic patient, my choice of endocrine therapy backbone will be an aromatase inhibitor. If the patient develops metastatic disease while on an AI, or within 6-12 months after completing or discontinuing an AI, I will consider fulvestrant. If there is evidence of an ESR1 mutat...
How do you decide among approved CDK4/6 inhibitors for first line treatment of patients with metastatic HR+ breast cancer now that OS analyses are available in MONALEESA-2, MONARCH-3 and PALOMA-2?
Updated Answer 1/23/24: I was asked to update my prior answer in light of final OS results from the MONARCH 3 trial, which read out at SABCS, and comment on whether this would impact my treatment selection. While MONARCH-3 did not show a statistically significant OS benefit, the difference in OS b...
Do you think about CDK4/6 inhibitor selection differently in a patient with de novo rather than recurrent metastatic disease?
No. The selection of first line CDK4/6 inhibitors is dependent on different things including overall survival data, patient characteristics, and other factors elaborated in the answer to the next question. Exploratory subgroup analysis of MONALEESA-2 showed OS benefit in various subgroups consistent...
In patients with metastatic hormone receptor-positive, HER2-low breast cancer, how many and which lines of therapy would you recommend prior to using trastuzumab deruxtecan?
In spite of the exciting results observed with trastuzumab deruxtecan in DESTINY-Breast04, endocrine based therapy continues to be the most appropriate first line choice for the majority of patients with hormone receptor-positive, HER2-negative disease, particularly as we are now seeing median overa...
What are your top takeaways in Breast Cancer from ASCO 2022?
DESTINY-Breast04: it is phase III study of Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice in HER2-low metastatic breast cancer (MBC). This study showed improved progression-free survival (PFS) and overall survival (OS) with T-DXd vs standard therapy in this patient population. T-...
What is the preferred sequence of systemic therapy in a patient with endocrine resistant HR+ metastatic breast cancer?
Several factors can affect the next line of therapy in my view like disease free interval (DFI) before the patient developed metastatic disease, duration of response (if any) to prior endocrine with/without CDK4/6i, disease burden, patient's performance status and competing comorbidity. If the patie...
How would you manage subsequent treatment for a patient with metastatic ER+HER2- breast cancer that develops pneumonitis on a CDK4/6 inhibitor but had an excellent response to therapy?
One of our fellows and I conducted a lit search on this topic several months ago, and then again (briefly) today. There is not much literature to support evidence-based decision making, as the 3 available CDK4/6 inhibitors (palbociclib, abemacicilib, and ribociclib) all have pneumonitis as a reporte...
Would you use sequential CDK 4/6 inhibitors in HR-positive metastatic breast CA in successive lines of therapy?
There is no preclinical or clinical data to support this approach at this time. I would not use sequential therapy in the absence of data. Several studies are ongoing to evaluate whether continued suppression of this pathway in the face of disease progression benefits patients. Until those studies h...