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MONALEESA-3: Ribociblib Plus Fulvestrant Improves Overall Survival Over Fulvestrant Alone in the First-Line Setting


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In an updated analysis of the phase III MONALEESA-3 trial, which included postmenopausal patients with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer, first-line treatment with ribociclib plus fulvestrant added nearly 16 months of overall survival time vs fulvestrant alone. These findings are from an exploratory analysis of MONALEESA-3 data, including untreated patients who were previously negative for stage IV estrogen receptor–positive, HER2-negative breast cancer, presented at the European Society for Medical Oncology (ESMO) Breast Cancer Congress 2022 by Patrick Neven, MD, PhD, of the Universitaire Ziekenhuizen Leuven, Belgium.1


“I think, as do most of you, that CDK4/6 inhibitors are the greatest therapeutic achievement in breast cancer of the past 20 years.”
— Patrick Neven, MD, PhD

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After 70.8 months of follow-up of first-line patients, including those with “de novo metastatic” or “late-relapse” disease, median overall survival was 67.6 months with ribociclib plus fulvestrant vs 51.8 months with fulvestrant alone (hazard ratio [HR] = 0.67; 95% confidence interval [CI] = 0.50–0.90). “We have an impressive benefit…. Ribociclib combined with fulvestrant demonstrated the longest median overall survival observed for a first-line population in the phase III setting of advanced breast cancer,” Dr. Neven said.

“Not only is survival improved, but also secondary endpoints, including progression-free survival-2, chemotherapy-free survival, and time to chemotherapy,” he said. “These results stress the importance of combining these agents [inhibitors of cyclin-dependent kinases (CDK) 4 and 6] with endocrine treatment in advanced breast cancer…. I think, as do most of you, that CDK4/6 inhibitors are the greatest therapeutic achievement in breast cancer of the past 20 years.”

MONALEESA-2, -3, and -7 have all shown a statistically significant overall survival benefit for ribociclib plus endocrine therapy in pre-, peri-, and postmenopausal patients. MONALEESA-3 evaluated ribociclib plus fulvestrant in 726 patients with advanced or metastatic hormone receptor–positive/HER2-negative breast cancer, either previously untreated or treated with no more than one prior line of therapy.

Dr. Neven presented an updated analysis that focused on the 365 patients treated in the first-line setting. The study found that ribociclib plus fulvestrant achieved a median overall survival of 67.6 months compared with 51.8 months for fulvestrant alone, resulting in a 33% reduction in death (HR = 0.673; 95% CI = 0.504–0.899). With extended follow-up, the estimated survival rate at 5 years was 56.5% vs 42.1%. Additionally, 16.5% of patients receiving the doublet compared with 8.6% receiving fulvestrant alone were still undergoing treatment at this longer follow-up.

Previous Analyses

The current analysis builds upon previous findings for MONALEESA-3. In the final protocol-specified overall survival analysis, after 39.4 months of follow-up, ribociclib was associated with a statistically significant overall survival benefit over placebo (HR = 0.72; P = .00455).2

KEY POINTS

  • With further follow-up of MONALEESA-3, ribociclib plus fulvestrant achieved a median overall survival of more than 5.5 years (67.6 months) in the first-line setting for postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer.
  • The combination reduced the relative risk of death by 33%, adding nearly 16 months of survival.
  • This is the only CDK4/6 inhibitor/fulvestrant combination to demonstrate an overall survival benefit in previously untreated patients.

A further exploratory analysis at 56.3 months of follow-up confirmed the overall survival benefit, showing a median overall survival of 53.7 months with ribociclib vs 41.5 months with placebo (HR = 0.73; 95% CI = 0.59–0.90) in the intent-to-treat population.3 However, median overall survival was not reached in the subset receiving treatment in the first-line setting, which accounted for about half the population. This subset was the focus of the current analysis, which was performed after a median of 70.8 months, offering an additional 2.5 years of -follow-up.

Secondary Endpoints Improved

Patients treated with first-line ribociclib plus fulvestrant compared with fulvestrant alone experienced more than 1.5 years’ additional delay to the subsequent use of chemotherapy: 49.2 months vs 29.0 months (HR = 0.62; 95% CI = 0.481–0.810). The time to second disease progression (the time from randomization to first disease progression after discontinuing treatment) was also notably prolonged, from 34.6 months with fulvestrant to 50.7 months with ribociclib plus fulvestrant (HR = 0.64; 95% CI = 0.49–0.84). The time to chemotherapy was also delayed (HR = 0.57; 95% CI = 0.42–0.79), he reported.

No new safety signals were observed. The frequency of adverse events remained generally consistent with prior analyses of the study. 

DISCLOSURE: Dr. Neven is employed by Universitaire Ziekenhuizen (UZ) and
Katholieke Universiteit (KU) Leuven; is a member of the oncology drugs working group of CTG RIZIV/INAMI; and has received honoraria (paid to UZ Leuven) for travel, lectures, serving on advisory boards, steering committees, or data monitoring safety boards from Amgen, Astra Zeneca, Eli Lilly, Gilead, Novartis, Pfizer, and Roche.

REFERENCES

1. Neven P, Fasching PA, Chia S, et al: Updated overall survival results from the first-line population in the phase III MONALEESA-3 trial of postmenopausal patients with HR+/HER2– advanced breast cancer treated with ribociclib + fulvestrant. ESMO Breast Cancer Congress 2022. Abstract LBA4. Presented May 4, 2022.

2. Slamon DJ, Neven P, Chia S, et al: Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36:2465-2472, 2018.

3. Slamon DJ, Neven P, Chia SKL, et al: Updated overall survival results from the phase III MONALEESA-3 trial of postmenopausal patients with HR+/HER2– advanced breast cancer treated with fulvestrant ± ribociclib. 2021 ASCO Annual Meeting. Abstract 1001. Presented June 4, 2021.


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