June 5, 2021—Longer overall survival (OS) was maintained with the addition of ribociclib to fulvestrant in follow-up lasting nearly 5 years in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer, according to updated results of MONALEESA-3, presented at the annual meeting of the American Society of Clinical Oncology, which took place online from June 4 to 8.
The MONALEESA-3 trial demonstrated a significant progression-free survival (PFS) and OS benefit of ribociclib, a CDK4/6 inhibitor, when added to fulvestrant in men and postmenopausal women with advanced breast cancer. “The HR-positive, HER2-negative subgroup of breast cancer [patients] appear to be particularly sensitive to inhibition by specific CDK4/6 inhibitors,” said Dennis J. Slamon, MD, PhD, of the University of California at Los Angeles, during his presentation of the data. Dr. Slamon presented an exploratory update of the OS in MONALEESA-3, with longer follow-up of 56.3 months.
For the international, phase III MONALEESA-3 trial, 726 men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer were randomized 2:1 to 600 mg ribociclib once daily for 3 weeks on and 1 week off (n = 484) or placebo (n = 242). Both arms also received fulvestrant at a dose of 500 mg every 28 days, with one additional dose on day 15 of cycle 1. Half of the patients were enrolled in the first-line setting, defined as patients with a relapse more than 12 months after completion of neoadjuvant endocrine therapy and patients with de novo advanced breast cancer.
At data cut-off on October 30, 2020, 99.7% of all randomized patients were treated. Treatment was ongoing for 14.0% of patients taking ribociclib and 8.7% taking placebo. The major reason for ending treatment was progressive disease, in 61.8% and 79.8%, respectively. Other reasons for discontinuation included adverse events, patient/guardian decision, physical decision, and death. Of all randomized patients, 87.4% entered survival follow-up.
Consistent with the previously reported final protocol-specified OS analysis, ribociclib continued to demonstrate a clinically relevant OS benefit. At 4 years, the median OS was 53.6% with ribociclib versus 44.5% placebo. At 5 years, it was 46.0% versus 31.1% (hazard ratio 0.726, 95% confidence interval 0.588–0.897).
Looking exclusively at patients who were treated in the first-line setting, median OS was not reached in the ribociclib arm and was 51.6 months in the placebo arm, reflecting a 36% reduction in risk of death (95% confidence interval 0.464–0.883). This was slightly higher than the 30% reduction reported at the previous data cut-off.
For patients treated in the second-line setting, OS was 39.7 months with ribociclib, compared with 33.7 months with placebo (hazard ratio 0.78, 95% confidence interval 0.587–1.037).
In subgroup analyses, OS benefit was observed across most relevant subgroups, including harder-to-treat patients, such as those with liver/lung metastases, three or more metastatic sites, and resistance to endocrine therapy.
Patients taking ribociclib plus fulvestrant experienced a nearly 20-month delay in first subsequent chemotherapy use over fulvestrant alone (48.1 months vs 28.8 months, hazard ratio 0.704, 95% confidence interval 0.566–0.876). Chemotherapy-free survival, defined as time from randomization to the beginning of first chemotherapy treatment or death after discontinuation of the trial regimen, was 32.3 months with ribociclib versus 22.4 months with placebo (hazard ratio 0.688, 95% confidence interval 0.570–0.830).
The PFS 2, defined as the time from randomization to the first documented disease progression while patients were receiving subsequent antineoplastic therapy, or death from any cause, was also longer for patients receiving ribociclib versus placebo (37.4 months vs 28.1 months, hazard ratio 0.693, 95% confidence interval 0.570–0.844). This benefit was observed regardless of treatment setting but was more apparent in the first-line setting (hazard ratio 0.63, 95% confidence interval 0.47–0.84).
The safety profile of ribociclib was consistent with previous analyses. The most frequent any-grade hematologic adverse events of special interest were neutropenia (72%), leukopenia (33%), anemia (20%), and thrombocytopenia (9%). Grade 3 neutropenia occurred in half of the patients taking ribociclib, and grade 4 neutropenia in 8%. Anemia was the most frequent adverse event for patients receiving placebo, which occurred in 9%. Any-grade nonhematologic adverse events of special interest with ribociclib included infections (59%), pulmonary toxicity (38%), hepatobiliary toxicity (24%), and renal toxicity (13%).
“[In] this exploratory analysis with an extended follow-up of just under 5 years, we saw that the ribociclib-fulvestrant arm maintained its OS benefit in this postmenopausal population,” concluded Dr. Slamon. “MONALEESA-3 remains the only randomized trial that evaluated a CDK inhibitor and demonstrated a significant OS benefit in patients in the first-line setting.”
The MONALEESA-3 trial was funded by Novartis Pharmaceuticals Corporation.