MONALEESA-2 Subgroup Analysis Reveals Survival Effect of Ribociclib/Letrozole in HR+ Breast Cancer

Dr. Joyce O’Shaughnessy

The frontline combination of ribociclib (quiscali) and letrozole has been shown to improve the efficacy of letrozole in select patients with hormone receptor-positive, HER2-negative advanced breast cancer with new metastatic disease or late recurrence on neoadjuvant therapy. It significantly prolonged overall survival (OS) compared to monotherapy. Data from an exploratory analysis of the Phase 3 MONALEESA-2 trial (NCT01958021).1

Findings published in 2023 ESMO Breast Cancer Annual Meeting With a median follow-up of 79.8 months, this subgroup had a median OS of 69.2 months with doublet therapy (n = 275) compared with a median OS of 54.3-54.3 months with letrozole monotherapy (n = 270). month, which corresponds to a relative 25% reduction in OS. Mortality risk (HR, 0.75; 95% CI, 0.60-0.93; P. = .005). This hazard ratio was found to be consistent with that observed across the study population.

“Median survival for patients with new metastatic disease or late recurrence exceeded that of the overall population in both groups, reaching almost six years in the ribociclib group,” said lead study author Joyce of Baylor University Medical Center. Dr. O’Shaughnessy said. The American Oncology Research Network in Dallas, Texas, and colleagues wrote a poster about the data. “Ann [approximate] First-line ribociclib demonstrated 15-month improvement over placebo. ”

In this subgroup, the combination of ribociclib and letrozole improved progression-free survival (PFS) over letrozole alone, with a median PFS of 30.3 months vs. 16.7 months, respectively, which was associated with increased risk of disease progression or death. This means that it has decreased by 43%. This population (HR, 0.57; 95% CI, 0.46-0.70; P. < .001).

The phase 3 MONALEESA-2 trial includes postmenopausal women with locally confirmed hormone receptor-positive/HER2-negative recurrent or metastatic breast cancer who have not received prior systemic therapy with advanced therapies has been registered2. Has an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1 criteria, and acceptable bone marrow and organ function.

Patients were allowed to have previously received neoadjuvant endocrine therapy if they had a treatment-free interval (TFI) greater than 12 months. TFI was defined as the time from the end of preoperative endocrine therapy to disease recurrence. 1,2

Study participants received 600 mg oral ribociclib daily and 2.5 mg continuous letrozole daily, or placebo and letrozole as part of a 3-week on/1-week off schedule were randomly assigned to groups that Same dose and schedule.1

The primary endpoint of the trial was investigator-assessed PFS, with OS serving as a key secondary endpoint.

Final OS data from the MONALEESA-2 trial were previously published. New England Journal of MedicineIn addition, median OS for the entire patient population was 63.9 months (95% CI, 52.4–71.0) with ribociclib plus letrozole (n = 334) compared to 51.4 months (95 %CI, 47.2–59.7) (n = 334). = 334; HR, 0.76; 95% CI, 0.63–0.93; bilateral P. = .008).2

Patients with early recurrence, or TFI >12 months, are known to respond poorly to first-line therapy and have outcomes similar to those of previously treated patients with advanced breast cancer.1 At the 2023 ESMO Breast Cancer Annual Meeting, investigators reported survival and safety data from a subgroup analysis of MONALEESA-2 patients with de novo metastatic disease or late recurrence. 1

Patients with de novo metastatic disease had not received any prior therapy for their disease. This group included those who had not experienced a first recurrence/progression or first recurrence within 90 days of diagnosis and had not previously received antineoplastic agents. In late recurrence patients, he had her TFI >12 months from completion of neoadjuvant therapy. They could not have been treated for advanced or metastatic disease.

In subgroup analyses, investigators assessed OS, PFS, time to chemotherapy or death (TTC), chemotherapy-free survival (CFS), and safety. All endpoints were assessed using the Kaplan-Meier method and hazard ratios were estimated using the stratified Cox proportional hazards mode.

Of the 688 patients enrolled in MONALEESA-2, 18.4% exhibited early disease recurrence and were not enrolled in subgroup analyses. Of the remaining 545 patients, 275 were in the ribociclib group and 270 were in the placebo group. In the research department, 41.5% of his patients had de novo metastatic disease and 58.5% had late recurrence. In the placebo group, these rates were 41.9% and 58.1%, respectively.

It was noted that the baseline characteristics of patients with new metastatic disease or late recurrence were generally balanced between groups. The median age of patients in both groups was 64 years. The proportion of patients aged 65 years or older was 50.9% in the ribociclib group and 51.5% in the placebo group. The proportion of patients aged ≤65 years was 49.1% and 48.5%, respectively. Across the arm, most patients were Caucasian (79.3% vs. 84.1%) and had an ECOG performance status of 0 (61.5% vs. 58.9%).

No patients in the ribociclib group received prior preoperative endocrine therapy, compared with 0.7% of patients in the placebo group. 43.6% of patients in the ribociclib group and 40% of patients in the placebo group had received prior adjuvant endocrine therapy.

Among patients with late recurrence (n = 318), the median TFI was 52.8 months. Composite disease-free interval (DFI), defined as the time from initial diagnosis to disease recurrence, was ≥5 years in 85.2% of patients and ≥10 years in 46.5% of patients.

In patients with new metastatic disease or late recurrence, the median TFI for ribociclib plus letrozole was 52.6 months, with 56.5% of patients having a TFI of at least 36 months. Median TFI for letrozole alone in this population was 54.4 months, with 51% of patients having TFI of at least 36 months. The proportions of patients in the ribociclib group who experienced DFI >5 and 10 years were 83.2% and 48.4%, respectively. In the placebo group, 87.3% of patients had DFI greater than 5 years and 44.6% of patients had DFI greater than 10 years.

The study authors reported that similar proportions of patients in the trial and control groups (89.8% and 93.7%, respectively) discontinued treatment. In addition, 86.2% of patients and 90.6% of her, respectively, received subsequent antitumor therapy.

Chemotherapy alone (14.6% vs. 16.8%), chemotherapy plus hormone therapy/other (10.5% vs. 9.4%), and hormone therapy alone (34.0% vs. 31.6%) in the ribociclib and placebo groups %) received. , hormone therapy plus other (24.7% vs. 30.9%), targeted therapy only (1.6% vs. 0.8%), targeted therapy plus other (0.4% vs. 0%), immunotherapy alone (0.4% vs. 0.4%), other (0 % vs 0.8%).

Of those subsequently treated with CDK4/6 inhibitors, 16.2% in the study group and 34.4% in the placebo group received palbociclib (Ibrance). 5.3% and 2.0% of patients, respectively, received ribociclib. 2.4% and 3.9% of patients, respectively, received abemaciclib (Qiscali).

In this patient population, the addition of ribociclib to letrozole and the addition of letrozole alone prolonged both CFS and TTC. His median TTC in the ribociclib group was 54.1 months and 40.9 months in the placebo group (HR, 0.74, 95% CI, 0.59-0.93, 95% CI, 0.59-0.93; P. = .004). Median CFS was 42.5 months in the ribociclib/letrozole group and 36.1 months in the letrozole alone group (HR, 0.75; 95% CI, 0.61-0.92; P. = .002). According to the study authors, these findings were comparable to the TTC and CFS data reported in the MONALEESA-2 intent-to-treat population.

From a safety perspective, the incidence of adverse reactions (AEs) in this subgroup was found to be consistent with AEs previously observed in this study. No new safety signals were observed.

The most common grade ≥3 AEs occurring in this subgroup included neutropenia (ribociclib, 53.5%; placebo, 0.7%), neutropenia (19.3%, 0.4%), hypertension (16%, 17.2%) included white blood cell counts. decreased (13.5%, 0%), anemia (4.4%, 2.2%), increased alanine aminotransferase (11.6%, 6.7%), increased aspartate aminotransferase (6.5%, 0.7%), vomiting (4.4%, 1.1%) ), back pain (4%, 1.5%), fatigue (3.3%, 1.1%), nausea (2.9%, 1.1%), diarrhea (2.5%, 1.1%), joint pain (1.5%, 1.9%), appetite decreased (1.5%, 0.4%), rash (1.1%, 0.4%), constipation (1.1%, 0%), headache (0.7%, 0.7%), hot flashes (0.4%, 0%), pain in extremities ( 0%), 0.4%).

Disclosure: Dr. O’Shaughnessy has made financial and He reports that he has a personal interest and serves on an advisory board. , Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma, Prime, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre, Samsung, Sanofi.


  1. O’Shaughnessy J, Beck T, Chia S, et al. First-Line (1L) Ribociclib (RIB) in Patients (pts) with New Metastatic Disease and Late Relapse with (neo)adjuvant Therapy (tx) in MONALEESA (ML)-2 + Efficacy and safety of letrozole (LET). Presented at: 2023 ESMO Breast Cancer Annual Meeting. May 11-13, 2023. Berlin, Germany. Abstract 196P.
  2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib and letrozole in advanced breast cancer. N English J Medicine. 2022;386(10):942-950. Doi: 10.1056/NEJMoa2114663

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