Updated MONALEESA-3 Data Underscore Frontline Efficacy of Ribociclib/Fulvestrant in HR+ Advanced Breast Cancer

Updated overall survival data from the phase 3 MONALEESA-3 trial demonstrated a sustained benefit with the addition of ribociclib to fulvestrant in patients with hormone receptor–positive, HER2-negative advanced breast cancer, and provide further evidence that this is a feasible approach for frontline therapy in this population.

Updated overall survival (OS) data from the phase 3 MONALEESA-3 trial (NCT02422615) demonstrated a sustained benefit with the addition of ribociclib (Kisqali) to fulvestrant (Faslodex) in patients with hormone receptor–positive, HER2-negative advanced breast cancer, and provide further evidence that this is a feasible approach for frontline therapy in this population, according to Dennis J. Slamon, MD.

The data, which were presented during the 2021 ASCO Annual Meeting, showed that at a median follow-up of 56.3 months, the median OS in the subgroup of patients who received treatment in the first-line setting had not yet been reached with ribociclib/fulvestrant vs 51.8 months with fulvestrant alone (HR, 0.640; 95% CI, 0.464-0.883).

In the subgroup of patients who were receiving treatment in the second line or who had early relapse, the median OS was 39.7 months with ribociclib/fulvestrant vs 33.7 months with fulvestrant alone (HR, 0.780; 95% CI, 0.587-1.037). In the overall study population, the median OS was 53.7 months vs 41.5 months, respectively (HR, 0.726; 95% CI, 0.588-0.897).

“The debate about whether [CDK4/6 inhibitors] should be used in the first-line setting should finally be settled,” Slamon said. “These are large data set, with a lot of patients treated. Essentially half of the experimental population [received treatment] in the first-line setting. Moreover, we have not yet even reached the median OS [with ribociclib in that population], whereas the median in the control population was 51 months.”

In an interview with Onclive®, Slamon, director of Clinical/ Translational Research, director of Revlon/UCLA Women’s Cancer Research Program, professor of medicine and chief of the Division of Hematology/ Oncology, and executive vice chair for research in the UCLA Department of Medicine, discussed updated results from the MONALEESA-3 trial examining ribociclib plus fulvestrant in patients with HR-positive/HER2-negative breast cancer.

Onclive®: Could you start by spotlighting the initial data reported from the pivotal phase 3 MONALEESA-3 trial?

Slamon: The initial trial results showed a statistically significant improvement in progression-free survival [PFS], as well as in overall survival [OS]. We also [saw] improvements in time to first chemotherapy and PFS2, [defined as] time to any subsequent therapy. [In those who responded,] the effect appeared to continue even after the patient went off the study. All of that was very positive, but the main takeaway from MONALEESA-3 was that it was the only trial that had a large first-line patient population. A debate had been going on, [with the argument] that many of these patients should not receive treatment with a CDK4/6 inhibitor until after they had [received] endocrine therapy. We had been [accustomed] to using that approach for decades, until the CDK4/6 inhibitors [became available].

Our laboratory [at UCLA Health] was involved in showing that [CDK4/6 inhibitors] are effective in these ER-positive, HER2-negative cells. However, the question was, how big would the impact be? In several trials, including the phase 3 PALOMA-3 [NCT01942135] and monarchE [NCT03155997] trials, and now the MONALEESA-3 trial, there was a significant impact on PFS. Both monarchE and MONALEESA-3, at their initial [read out] with shorter follow-up, showed an OS advantage.

The difference with MONALEESA-3 was that it showed this advantage in the first-line population; this settles the argument about whether this [approach] should be used up front. Patients should receive this treatment based on the data [that have been] observed.

With the current analysis, the follow-up is just under 5 years, or 56.3 months. It turns out that the OS advantage is holding; [we are seeing] a difference in OS of just over 1 year in the patients who received the CDK4/6 inhibitor vs those who did not. These are very compelling data.

What did the updated results from the trial presented during the 2021 ASCO Annual Meeting show in terms of survival benefit?

A total of 726 patients were randomized 2:1, and they received placebo plus fulvestrant [Faslodex] or ribociclib [Kisqali] plus fulvestrant. We saw an improvement [of more than 1 year] with regard to median OS, at a follow-up of 56.3 months. The landmark analysis shows the predicted difference at 4 years for this population would be 44% in the control arm vs 53% in the experimental arm. At 5 years, [the difference] was even greater, at about 15%; [these rates were] 31% in the control arm vs 46% in the experimental arm. It is exciting to see that these data have held up with longer follow-up, and patients are benefiting in a significant way with this therapy.

What was revealed regarding the subgroup analysis that was conducted?

When conducting a subgroup analysis, it was seen that almost all groups benefited with ribociclib, whether patients had the treatment in the first- or the second-line [setting], or whether they had liver or lung involvement or not. [Notably,] patients with involvement generally have a worse outcome, but these patients still had a significant benefit [with this approach]. Patients with bone-only disease also had significant benefit, [as well as those with] more or less than 3 metastatic sites, and those who were older or younger than 65 years. [Benefit was also seen in patients irrespective of whether they received] their therapy in the adjuvant or the neoadjuvant setting.

Essentially, all groups benefited [from this regimen], and this speaks to the importance of using these drugs in this patient population when the disease is first diagnosed—even in the first-line setting.

The other thing that the MONALEESA studies have [collectively] shown is that even [when this is given] as adjuvant therapy in premenopausal patients, as seen in the phase 3 MONALEESA-7 trial [NCT02278120], we are seeing the same benefit in terms of PFS and OS.

Were any new safety signals revealed with longer follow-up? What should be known about this approach in terms of toxicity?

No new safety signals were reported. [We saw] the anticipated class effect of neutropenia, and leukopenia that is often seen with all CDK4/6 inhibitors, in particular palbociclib [Ibrance] and ribociclib; [these effects are observed a] little less often with abemaciclib [Verzenio]. Although, abemaciclib has more gastrointestinal toxicity that is not seen with ribociclib or palbociclib.

The QTc prolongation was also seen with ribociclib, and that is not seen with palbociclib or abemaciclib. However, no significant increases in [measure was reported] and no torsades de pointes or any problems [of that nature occurred]. The [rates of] QTc prolongation for all grades were 8.5 [in the experimental arm] vs 2.1 [in the control arm]; for grade 3/4, it was 2.9 vs 1.2, respectively. A big difference was not observed between the study arms, but there was a difference that should be noted. [Otherwise], everything looked exactly [as it had] in the initial analysis of the study.

Are any other analyses planned for MONALEESA-3 trial?

There may be some further follow-up, but this is about the longest a study has been designed for follow-up. The number of patients who remain on study treatment in the experimental arm and control arm are 14% and 7%, respectively.

What should be taken away from this research?

All these data are compelling, and should give us comfort in treating patients with ribociclib and fulvestrant, as was done in this study. [This is an] appropriate first-line treatment for the patients with ER-positive, HER2-negative disease.


  1. Slamon DJ, Neven P, Chia SKL, et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) +/- ribociclib (RIB). J Clin Oncol. 2021;39(suppl 15):1001. doi:10.1200/JCO.2021.39.15_suppl.1001