Debu Tripathy, MD
The progression-free survival (PFS) benefit for ribociclib (Kisqali) in pre- or perimenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer was sustained across patient subgroups, according to findings from the phase III MONALEESA-7 trial presented at the 2018 Miami Breast Cancer Conference.
MONALEESA-7 randomized patients 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). Across the overall study population, the median PFS 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
“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,” Debu Tripathy, MD, professor and chair, Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, said in an interview with OncLive.
“It confirmed a significant benefit in progression free-survival and response rate, and also showed comparable efficacy with either AI or tamoxifen—both findings representing important advances in the treatment of this population of patients,” added Tripathy.
Patient characteristics were balanced 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, and other; and the race of 6.0% of patients was unknown.
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.
Prior neoadjuvant or adjuvant endocrine therapy was reported for 37.9% of patients. Fourteen percent of patients had prior chemotherapy for advanced disease, 41.2% had prior neoadjuvant or adjuvant chemotherapy, and 44.8% of patients had no prior chemotherapy. At baseline, the disease-free interval was ≤12 months for 6.9% of patients and >12 months for 52.5% of patients.
The experimental regimen consisted of 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. Ribociclib treatment was administered for 3 weeks followed by 1 week off.
The PFS benefit with ribociclib was similar when the CDK4/6 inhibitor was combined with either tamoxifen or an NSAI. For the 87 patients receiving ribociclib/tamoxifen, the median PFS was 22.1 months (95% CI, 16.6-24.7) compared with 11.0 months (95% CI, 9.1-16.4) for the 90 patients treated with tamoxifen plus placebo (HR, 0.585; 95% CI, 0.387-0.884). Among the 248 patients treated with ribociclib plus an NSAI, the median PFS was 27.5 months (95% CI, 19.1 to not reached) compared with 13.8 months (95% CI, 12.6-17.4) for patients receiving an NSAI plus placebo (HR, 0.569; 95% CI, 0.436-0.743).
The ribociclib PFS benefit was also 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).
Among all patients, the overall response rate (ORR) was 40.9% for the ribociclib arm compared with 29.7% for the placebo arm (P = .00098). In patients with measurable disease, the ORRs were 50.9% versus 36.4%, respectively (P
= .000317). Also among patients with measurable disease, the clinical benefit rate was 79.9% versus 67.3%, respectively (P
The median duration of exposure was 15.1 months for the ribociclib arm compared with 11.4 months for the control arm. Patient-reported outcomes showed that ribociclib was associated with a 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.
Neutropenia was the most frequently reported adverse event (AE) for both the experimental arm (76%) and the placebo arm (8%) in updated safety results. Six in 10 patients in the ribociclib arm experienced grade 3/4 neutropenia compared with 4% in the placebo arm, but the condition was asymptomatic in most patients. Two percent of patients in the experimental arm and 1% in the placebo arm experienced neutropenia associated with fever and infection.
Other AEs included hot flashes, nausea, leukopenia, and joint pain/stiffness. 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. Disease progression and AEs were the cause of discontinuation 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.
In January 2018, 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 receptor–positive, HER2-negative advanced or metastatic breast cancer.
Ribociclib is currently approved by the FDA for use in combination with an aromatase inhibitor for the frontline treatment of postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer.
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 receptor–positive, 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.