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Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial.

ABSTRACT: Endocrine therapy is recommended for patients with hormone receptor-positive (HR+) advanced and metastatic breast cancer without visceral crisis (symptomatic visceral disease). However, many patients experience disease progression during treatment, and most patients eventually develop endocrine resistance. Therefore, it is important to identify treatment options that prolong the effectiveness of first-line endocrine therapies. Ribociclib is an orally bioavailable cyclin-dependent kinase (CDK) 4/6 inhibitor that has been approved for use in combination with an aromatase inhibitor for the treatment of HR+, human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This approval is based on findings from the MONALEESA-2 study, a double-blind, placebo-controlled, randomized phase 3 trial (NCT01958021) in which first-line therapy with ribociclib + letrozole significantly improved progression-free survival (PFS) compared with placebo + letrozole in patients with HR+/HER2- advanced breast cancer. This review will discuss the overall findings from the MONALEESA-2 study and will provide a summarized analysis of results from the available subgroups in the study by age, visceral metastases, bone-only disease, de novo disease, and prior therapy. On the basis of these data, ribociclib has established itself as a beneficial treatment option for these different populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01958021 . Registered on 8 October 2013.

SUBMITTER: Hortobagyi GN

PROVIDER: S-EPMC6194611 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial.

Hortobagyi Gabriel N GN

Breast cancer research : BCR 20181019 1

Endocrine therapy is recommended for patients with hormone receptor-positive (HR<sup>+</sup>) advanced and metastatic breast cancer without visceral crisis (symptomatic visceral disease). However, many patients experience disease progression during treatment, and most patients eventually develop endocrine resistance. Therefore, it is important to identify treatment options that prolong the effectiveness of first-line endocrine therapies. Ribociclib is an orally bioavailable cyclin-dependent kina ...[more]

PMID: 30340505

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Project description:BackgroundThe phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2- ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population.MethodsPostmenopausal patients with HR+/HER2- ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615).ResultsAt data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50-0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed.ConclusionsThis analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2- ABC.

Project description:BackgroundThe CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2- advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2- ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1.Patients and methodsMen and women of any menopausal status with HR+/HER2- ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured.ResultsSafety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events.ConclusionsThese findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2- ABC more representative of patients in real-world clinical practice.

Project description:Among pre- and postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), combinations of an aromatase inhibitor (AI) or fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to standard single-agent hormone therapy alone as first-line therapy for de novo metastatic disease or relapse during or after adjuvant therapy and no previous therapies in an advanced setting. We here reviewed clinical data about ribociclib in advanced and early BC. Also, we shed light on patient selection and special settings in which medical oncologists urgently await an advance in treatment. Ribociclib was FDA-approved in combination with letrozole based on a Phase III study in which 668 postmenopausal women with HR+, HER2-negative recurrent or metastatic BC were treated with first-line letrozole with or without ribociclib. For patients with metastatic disease at presentation or after a course of AIs, the results of the MONALEESA-3 trial suggest ribociclib's efficacy in combination with fulvestrant, and this combination is FDA-approved for initial- and subsequent-line endocrine therapy for postmenopausal women with metastatic hormone receptor-positive, HER2-negative BC. In adjuvant and neoadjuvant settings, the use of CDK 4/6 inhibitors may be useful to boost outcomes in high-risk patients with HR+ BC, but data contrast with those of a phase III study, which produced positive results. New combinations are being explored in upfront disease (neoadjuvant) or in association with other targeted agents in metastatic disease. Compared to other CDK 4/6 available, ribociclib has a higher incidence of liver function test abnormalities than the other agents and can cause QTc prolongation, and therefore may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation (drugs, interactions). In these cases, different agents (palbociclib or abemaciclib) may be used. In conclusion, ribociclib with letrozole or with fulvestrant is effective for the entire spectrum of patients with HR+ BC in the advanced setting. Ribociclib has all the characteristics of an innovative drug able to change the clinical practice and most BC patients' prognoses.

Dataset Information

Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial.

Publications

Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial.

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