According to results from the phase III MONALEESA-7 trial presented at the 2018 Miami Breast Cancer Conference, the progression-free survival benefit for ribociclib in pre- or perimenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer had been sustained across patient subgroups.
Debu Tripathy, MD
According to results from the phase III MONALEESA-7 trial presented at the 2018 Miami Breast Cancer Conference, the progression-free survival (PFS) benefit for ribociclib (Kisqali) in pre- or perimenopausal women with hormone receptorpositive, HER2-negative advanced or metastatic breast cancer had been sustained across patient subgroups.
Patients were randomized to either the CDK4/6 inhibitor ribociclib in combination with tamoxifen or a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) plus goserelin (n = 335), or to endocrine treatment plus goserelin (n = 337). The median PFS across the study population was 23.8 months for the ribociclib arm compared with 13.0 months for the control arm (HR, 0.553; 95% CI, 0.441-0.694;P<.0001).
“The MONALEESA-7 trial is the first large randomized trial in advanced breast cancer in nearly 20 years focusing specifically on premenopausal women. While the use of ovarian suppression has been used with endocrine therapy, this trial was dedicated to assessing the CDK 4/6 inhibitor ribociclib compared to placebo in combination with ovarian suppression using goserelin along with either AI or tamoxifen,” said Debu Tripathy, MD, professor and chair, Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center.
Tripathy also said, “It confirmed a significant benefit in progression free-survival and response rate, and also showed comparable efficacy with either AI or tamoxifenboth findings representing important advances in the treatment of this population of patients."
There was little difference in patient characteristics between the 2 arms. The median patient age in the ribociclib arm was 43 (range, 25-58); 55.8% of patients were white, 29.6% were Asian, 8.7% were black, Native American, or other, and 6.0% were reported as unknown race.
The ECOG performance status was 0 for 73.1% of patients, 1 for 26.0%, and unknown for the remaining 0.9%. Visceral metastases was detected in 57.6% of patients, with 24.2% having bone-only metastases.
The experimental regimen included daily oral administration of ribociclib at 600 mg; tamoxifen at 20 mg, or letrozole at 2.5 mg, or anastrozole at 1 mg; and a subcutaneous injection of goserelin at 3.6 mg once every 28 days. Patients were given ribociclib treatment for 3 weeks and followed this with 1 week off.
Ribociclib had similarPFS benefit when the CDK4/6 inhibitor was combined with either tamoxifen or an NSAI. The 87 patients receiving ribociclib/tamoxifen had a median PFS of 22.1 months (95% CI, 16.6-24.7) compared to 11.0 months (95% CI, 9.1-16.4) in the 90 patients treated with tamoxifen plus placebo (HR, 0.585; 95% CI, 0.387-0.884). The 248 patients treated with ribociclib plus an NSAI had a median PFS of 27.5 months (95% CI, 19.1 to not reached) compared with 13.8 months (95% CI, 12.6-17.4) for patients given an NSAI plus placebo (HR, 0.569; 95% CI, 0.436-0.743).
The ribociclib PFS benefit was consistent across other prespecified subgroups, including age (<40 years: HR, 0.443; ≥40 years: HR, 0.590), race (Asian: HR, 0.401; non-Asian: HR, 0.657), ECOG performance status (0: HR, 0.549; 1: HR, 0.495), ER/PgR status (ER+/PgR+: HR, 0.574; other: 0.444), liver and/or lung involvement (no: HR, 0.642; yes: HR, 0.503), bone-only disease (no: HR, 0.533; yes: HR, 0.703), prior chemotherapy for advanced disease (no: HR, 0.566; yes: HR, 0.547) and disease-free interval (≤12 months: HR, 0.560; >12 months: HR, 0.615;de novo: HR, 0.428).
The overall response rate (ORR) was 40.9% among the patients in the ribociclib arm compared with 29.7% for the placebo arm (P = .00098). For patients with measurable disease, the ORRs were 50.9% versus 36.4%, respectively (P= .000317). These patients with measurable disease also demonstrated a clinical benefit rate of 79.9% versus 67.3%, respectively (P= .000340).
In the ribociclib arm, the median duration of exposure was 15.1 months compared with 11.4 months in the control arm. Patient-reported outcomes demonstrated that ribociclib was associated with statistically significant improvement in time to deterioration, as well as a durable, clinically meaningful reduction in pain score as early as 8 weeks after initiation.
The most frequently reported adverse event (AE) for both the experimental arm (76%) and the placebo arm (8%)was neutropenia in updated safety results. 6 in 10 patients from the ribociclib arm had experienced grade 3/4 neutropenia compared with 4% in the placebo arm, but the condition was asymptomatic for most of the patients. Neutropenia associated with fever and infection was experienced by 2% of patients in the experimental arm and 1% in the placebo arm.
Hot flashes, nausea, leukopenia, and joint pain/stiffness were among other AEs reported. The most common (≥5%) grade 3/4 AEs in patients receiving ribociclib combination therapy compared to endocrine therapy alone were neutropenia (60.6% vs 3.6%) and leukopenia (14.3% vs 1.2%)
Treatment was discontinued in 48.1% (n = 161) of the ribociclib arm and 64.1% (n = 216) of the placebo group. The cause of discontinuation was disease progression and AEs for 36.4% (n = 22) versus 51.6% (n = 174) and 3.6% (n = 12) versus 3.0% (n = 10) of the ribociclib versus control arms, respectively.
The FDA granted ribociclib a breakthrough therapy designation for use in combination with tamoxifen or an AI as frontline treatment for pre- or perimenopausal women with hormone receptorpositive, HER2-negative advanced or metastatic breast cancer in January 2018.
UPDATE:The FDA granted expanded approval for ribociclib in breast cancerbased on these results.
Tripathy D, Im S-A, Colleoni M, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a nonsteroidal aromatase inhibitor in premenopausal women with hormone receptorpositive, HER2-negative advanced breast cancer: results from the randomized phase 3 MONALEESA-7 trial. Presented at: 35th Annual Miami Breast Cancer Conference; March 8-11, 2018; Miami, FL. Abstract 626.
37.9% of patients reported prior neoadjuvant or adjuvant endocrine therapy. 14% of patients reported prior chemotherapy for advanced disease, 41.2% of patients had prior neoadjuvant or adjuvant chemotherapy, and 44.8% reported no prior chemotherapy. The disease-free interval at baseline was ≤12 months for 6.9% of patients and >12 months for 52.5% of patients.