Ribociclib Granted Breakthrough Therapy Designation by FDA for HR+/HER2- Premenopausal Breast Cancer

Based on results of the phase III MONALEESA-7 trial, ribociclib (Kisqali) has been granted a breakthrough therapy designation by the FDA for use in combination with tamoxifen or an aromatase inhibitor as frontline treatment for pre- or perimenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.

Samit Hirawat

Based on results of the phase III MONALEESA-7 trial, ribociclib (Kisqali) has been granted a breakthrough therapy designation by the FDA for use in combination with tamoxifen or an aromatase inhibitor (AI) as frontline treatment for pre- or perimenopausal women with hormone receptor—positive, HER2-negative advanced or metastatic breast cancer.

In the study, the median progression-free survival (PFS) was 23.8 months for women treated with ribociclib in combination with either tamoxifen or a nonsteroidal AI and goserelin, compared with 13.0 months for those who received the standard endocrine therapy plus placebo and goserelin (hazard ratio [HR], 0.553; 95% CI, 0.441-0.694;P<.0001).

The phase III findings demonstrate for the first time that a CDK4/6 inhibitor is effective in younger patients who currently have few treatment options. The breakthrough designation will expedite the development and review of ribociclib in this setting.

"This breakthrough therapy designation reflects the significance and promise of the MONALEESA-7 data presented at SABCS last month," Samit Hirawat, MD, head, Novartis Oncology Global Drug Development, said in a statement. "Younger women often have distinct treatment goals and needs, and it is important for oncologists to offer effective and well-studied treatment options for their specific disease. We look forward to working with the FDA to make this combination therapy available to premenopausal women living with HR+/HER2- advanced breast cancer in the United States as soon as possible."

The MONALEESA-7 trial randomized 672 premenopausal or perimenopausal women with HR-positive/HER2-negative advanced breast cancer to ribociclib in combination with tamoxifen or an AI (letrozole or anastrozole) plus goserelin (n = 335) versus endocrine treatment plus goserelin (n = 337). The patients ranged from 25 to 58 years in age and had not previously received endocrine therapy for advanced disease.

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.

For patients who received the regimen containing ribociclib and tamoxifen, the median PFS was 22.1 months compared with 11.0 months for the placebo arm (HR, 0.585; 95% CI, 0.387-0.884). Combining ribociclib with an AI resulted in 14-month improvement in median PFS compared with an AI alone (27.5 vs 13.8 months; HR, 0.569; 95% CI, 0.436-0.743).

The overall response rate was 51% versus 36% in favor of the experimental 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. AEs leading to discontinuation of treatment occurred in 3.6% of the ribociclib arm compared with 3.0% in patients who received endocrine therapy alone. 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%)

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, Sohn J, Im SA, et al. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized phase III MONALEESA-7 trial. Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract GS2-05.