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 (HRþ/HER2À) 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 HRþ/HER2À 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 (w60%) 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 drugedrug interaction between ribociclib and fulvestrant or new safety signals were observed. Conclusions: This analysis reported extended OS follow-up in MONALEESA-3. mOS was w12 months longer in patients with HRþ/HER2À ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

“…Patients remained on either treatment for one year. The overall survival (OS) for the group treated with ribociclib/fulvestrant was 51.8 months, compared to 39.7 months for the fulvestrant-only group [30]. These data suggested that ribociclib and fulvestrant could help to extend survival in both men and women with HR+ breast cancer.…”

Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials

“…In metastatic disease, the CDK4/6 inhibitors associated with endocrine therapy radically changed clinical practice due to a remarkable improvement in terms of PFS compared to hormone therapy alone of 9-13 months in first line [9,10,15,16,24,25], of 8-11 months in both first second line [26][27][28][29]), and of 5-7 months in second line [11][12][13]22,23]. Those results have never been seen before and so this class of drugs entered quickly into clinical practice.…”

“…In particular, tucatinib showed a significant advantage of 4.5 months [40], atezolizumab demonstrated a non-statistically improvement of 3.7 months in the ITT population and an interesting clinical advantage of 9.5 months in PD-L1-positive patients [34,35], and talazoparib did not demonstrate a statistically significant benefit in OS [32,33]. The trials with an available OS update were those that evaluated CDK4/6 inhibitors in both the first and second line and second line, showing an improvement of 11-12 and 7-9 months, respectively [11][12][13]22,23,[26][27][28][29]. The other trials were SOLAR-1, in which alpelisib showed a non-statistically significant benefit in OS (8 months) [37,38], and the trials with PARP-inhibitors, where an advantage in OS was not demonstrated [32,33].…”

“…In the first-line setting, median OS was not reached for the ribociclib arm with about 60% of patients alive at the median follow-up, while median OS was 51.8 months in the placebo arm (HR 0.64). In the second-line setting, median OS was 39.7 and 33.7 months, respectively (HR 0.78) [27].…”

Endocrine Treatment for Breast Cancer Patients Revisited—History, Standard of Care, and Possibilities of Improvement

“…Besides, in both the study program trials, namely the MONARCH-3 for abemaciclib and PALOMA-2 for palbociclib, any data on OS have not been reported yet and further results are expected. For ribociclib, however, a total of three trials have reported data on OS and show a consistent significant benefit that is independent from its use in the first or second treatment line, pre- or postmenopausal women, or with an AI or fulvestrant as ET partner [ 78 , 79 , 80 ]. In the MONALEESA-2 study, postmenopausal patients under first-line ribociclib and letrozole achieved a median OS of 63.9 months, the longest OS data reported for aBC to date [ 78 ].…”