Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival

Abstract

Background: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months).

Patients and methods: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling).

Results: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed.

Conclusions: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.

Keywords: CDK4/6 inhibitor; advanced breast cancer; overall survival; ribociclib.

Conflict of interest statement

Disclosure DJS reports board of directors (stock) and travel expenses from BioMarin; stock ownership, research funding, and travel expenses from Pfizer; advisory board, consulting, research funding, and travel expenses from Novartis; consulting from Eli Lilly; and stock ownership from Amgen and Seattle Genetics. SC reports that his institution received grants and personal fees for advisory boards from Novartis, Pfizer, Hoffmann-La Roche, and Eli Lilly, outside the submitted work. GJ reports personal fees from Novartis, during the conduct of the study; grants, personal fees, and non-financial support from Novartis, Roche, and Pfizer; personal fees and non-financial support from Lilly, Amgen, BMS, and AstraZeneca; personal fees from AbbVie and Daiichi-Sankyo; and non-financial support from Med-immune and Merck KGaA, outside the submitted work. MDL reports personal fees for speaker honoraria and advisory board honoraria from Novartis, AstraZeneca, Eli Lilly, and Pierre Fabre, outside the submitted work. SI reports grants from AstraZeneca, Pfizer, Eisai, and Daewoong; advisory and personal fees from AstraZeneca, Novartis, Hanmi, Pfizer, Eisai, Amgen, MediPacto, Roche, Eli Lilly, MSD, and GlaxoSmithKline; and non-financial support from Novartis. KP reports personal fees for advisory board from Novartis, AstraZeneca, Roche, Pfizer, and BMS, outside the submitted work. GVB reports personal fees for advisory board from Novartis and Eli Lilly, outside the submitted work. MM reports personal fees for speaker honoraria and honoraria for participation in advisory boards from Lilly and Pfizer; honoraria for participation in advisory boards from AstraZeneca, GlaxoSmithKline, Pharmamar, and Taiho Oncology; and research grants and honoraria for participation in advisory boards from Novartis and Roche-Genentech, outside the submitted work. AN reports consulting/advisory role, travel/accommodation/expenses, and research funding from Novartis and consulting/advisory role from Amgen during the conduct of the study. GSS reports institutional reimbursement for patient accrual and education and steering committee activities from Novartis and institutional research support from Merck, AstraZeneca, and Roche, outside the submitted work. LDLC-M reports personal fees for consultant/advisory role, research funding, and speaking engagements from MSD-Merck; consultant/advisory role, research funding, speaking engagements, and grant support from Roche Farma; consultant/advisory role, speaking engagements, and grant support from Bristol Myers Squibb; consultant/advisory role from Novartis and Pierre Fabre; consultant/advisory role and speaking engagements from Amgen; and research funding from Celgene, outside the submitted work. JTB reports grants for institutional funding for doing research from AbbVie, Alliance, Amgen, Ascentage Pharma Group, AstraZeneca, Bayer, Boston Biomedial, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech-Roche, Hutchison, Immunomedics, Janssen, MT Group, Nektar, Pfizer, Polynoma, Seattle Genetics, Serono-EMD, Tesaro, TG Therapeutics, Biodesix, Exact Sciences, Boehringer Ingleheim, Laekna, Novocure, Daiichi-Sankyo, Mirati Therapeutics, and Tarveda Therapeutics, during the conduct of the study. YJ, CW, UD, AC, JPZ, and TT report employment and stock ownership from Novartis. PAF reports personal fees for advisory board from Celgene, Merck Sharp & Dohme, Macrogenics, Eisai, Puma, Lilly, and AstraZeneca; lectures from Daiichi-Sankyo, Merck Sharp & Dohme, and Lilly; and research support from Cepheid and Novartis, outside the submitted work. PN has declared no conflicts of interest. Data sharing Novartis made the study protocols available for MONALEESA-3 at the time of primary publications. Individual participant data will not be made available.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.