Patients With Postmenopausal HR+/HER2– Advanced Breast Cancer Experience Notable OS Benefit With Ribociclib/Letrozole Combo


Data from the phase 3 MONALEESA-2 trial demonstrate significant benefit of frontline ribociclib (Kisqali) added to letrozole for hormone receptor–positive, HER2-negative advanced breast cancer

A statistically significant and clinically meaningful overall survival (OS) boost was noted in postmenopausal patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer who were treated with the combination of ribociclib (Kisqali) and letrozole in the phase 3 MONALEESA-2 trial (NCT01958021), according to data presented during the 2021 European Society for Medical Oncology Congress.1

Results showed that the addition of ribociclib prolonged the median OS by more than 12 months, at 63.9 months for the combination vs 51.4 months for letrozole alone (HR, 0.76; 95% CI, 0.63-0.93; P = .004).

“Ribociclib combined with endocrine therapy is the only first-line treatment with OS benefit and should therefore be considered the preferred treatment option for HR-positive, HER2-negative breast cancer,” Gabriel Hortobagyi, MD, a professor of medicine, Nellie B. Connally Chair in Breast Cancer, and program director for the Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, said during a presentation of the data. “The MONALEESA trials with ribociclib demonstrate a consistent OS benefit regardless of endocrine therapy partner, line of therapy, or menopausal status.”

The first primary end point analysis of the MONALEESA-2 trial, which examined the combination of ribociclib plus letrozole in the first-line setting for patients with HR-positive, HER2-negative advanced breast cancer, was presented in 2016. At the time, the duration of progression-free survival (PFS) was significantly longer with the combination vs with letrozole plus placebo.2 At the time of the second interim analysis in 2018, the combination showed a statistically significant PFS benefit compared with placebo plus letrozole, with a median PFS of 25.3 months vs 16.0 months, respectively (HR, 0.568, P = 9.63 x 10-8).3

Additionally, the phase 3 MONALEESA-7 (NCT02278120) and MONALEESA-3 (NCT02422615) trials both demonstrated statistically significant OS benefit with the addition of ribociclib to endocrine therapy compared with endocrine therapy alone in pre- and postmenopausal patients with HR-positive, HER2-negative advanced breast cancer.4,5

Here, investigators report the final OS analysis from the MONALEESA-2 study.

The study enrolled a total of 668 postmenopausal patients with HR-positive, HER2-negative advanced breast cancer who had received no prior therapy for advanced disease. Prior adjuvant or neoadjuvant endocrine therapy was permitted, and patients were stratified by the presence or absence of liver and/or lung metastases.

Patients were randomized 1:1 to receive either 600 mg of ribociclib daily on a 3-weeks-on, 1-week-off schedule plus 2.5 mg of letrozole daily (n = 334), or placebo plus 2.5 mg/day of letrozole (n = 334).

The primary end point was PFS, which was locally assessed per RECIST v1.1 criteria, and the key secondary end point was OS. Select secondary end points included overall response rate, clinical benefit rate, safety, and quality of life.

The statistical design required approximately 400 deaths for the final protocol-specified OS analysis, according to Hortobagyi. A hierarchical testing strategy was used, and OS was to be tested under a 5-look group sequential design only if the PFS results were positive. The prespecified Lan-DeMets (O’Brien-Fleming) stopping boundary for claiming superior efficacy was defined as a 1-sided P value of .0219 or less, and the study had approximately 90% power to detect a difference in OS. Additionally, an exploratory analysis of time to first subsequent chemotherapy was performed.

At data cutoff on June 2021, the median duration of follow-up was 80 months, which is the longest reported for a CDK4/6 inhibitor to date, Hortobagyi noted. At that time 92.4% of patients had discontinued treatment, although notably, nearly twice as many patients on the ribociclib arm were still on treatment vs the placebo arm (9.0% vs 5.1%, respectively). The most common reason for treatment discontinuation was disease progression (69.9%).

Additional data showed that the addition of ribociclib led to an increased OS benefit over time. The difference in the 4-year OS rate was 5.7%, favoring the combination vs letrozole alone (60.9% vs 55.2%, respectively). The difference in the 5-year OS rate was 8.4% (52.3% vs 43.9%, respectively), and the difference in the 6-year OS rate was 12.2% (44.2% vs 32.0%, respectively).

“Prespecified subgroup analysis showed consistent OS benefit across key subgroups by performance status, age, ethnicity, location, prior neoadjuvant or adjuvant therapy, as well as the number and location of metastatic sites,” Hortobagyi said. “Of note, the small number of patients in some subgroups resulted in wide confidence intervals.”

Regarding subsequent therapy after discontinuation of the study regimen, more patients on the placebo arm received subsequent treatment with a CDK4/6 inhibitor (34.4%) vs on the combination arm (21.7%).

Moreover, the addition of ribociclib was found to delay the time to first chemotherapy by approximately 1 year. Results from an exploratory analysis showed that the median time to first chemotherapy for the combination arm was 50.6 months vs 38.9 months in the placebo arm (HR, 0.74; 95% CI, 0.61-0.91).

In terms of safety, the median treatment duration for the combination was approximately 2 years vs 1 year for letrozole alone. After 80 months of follow-up, no new safety signals were identified, and the majority of adverse effects (AEs) occurred within the first year of treatment. The most common grade 3/4 AEs of special interest were neutropenia (63.8% for the combination vs 1.2% for letrozole alone), hepatobiliary toxicity (14.4% vs 4.8%, respectively), prolonged QT interval (4.5% vs 2.1%, respectively), and interstitial lung disease/pneumonitis (0.6% vs 0%, respectively).

“This is the longest median survival reported to date in any phase 3 advanced breast cancer trial,” Hortobagyi concluded.


  1. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival results from the phase III MONALEESA-2 trial of postmenopausal patients with HR+/HER2– advanced breast cancer treated with endocrine therapy ± ribociclib. Presented at: 2021 ESMO Congress. September 16-21, 2021; virtual. Abstract LBA17_PR.
  2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi:10.1056/NEJMoa1609709
  3. 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. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155
  4. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi:10.1056/NEJMoa1903765
  5. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi:10.1056/NEJMoa1911149

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