Sara A. Hurvitz, MD
Treatment with the combination of ribociclib (Kisqali) and endocrine therapy demonstrated an estimated overall survival (OS) rate of 70.2% at 42 months compared with 46.0% for placebo and endocrine therapy in peri or premenopausal women with hormone receptor (HR)-positive, HER2-negative advanced breast cancer, according to updated findings from the phase III MONALEESA-7 trial that were simultaneously published in the New England Journal of Medicine
and presented at the 2019 ASCO Annual Meeting.1,2
The improvement in OS rate represented a 29% reduction in the risk of death with the addition of the CDK4/6 inhibitor to endocrine therapy (HR, 0.71; 95% CI, 0.54-0.95; P
= .00973). The 42-month progression-free survival (PFS) rate was 54.6% with ribociclib compared with 37.8% with placebo, representing a 31% reduction in the risk of progression or death with the combination (HR, 0.69; 95% CI, 0.55-0.87).
“This is the first time a statistically significant improvement in overall survival has been observed with a CDK4/6 inhibitor in combination with endocrine therapy in patients with HR+/HER2- advanced breast cancer,” lead study author Sara A. Hurvitz, MD, director of the Breast Cancer Clinical Research Program at UCLA Jonsson Comprehensive Cancer Center, said during an early presentation of the findings. “It’s important to note that it is very difficult in metastatic breast cancer studies to demonstrate a significant improvement in overall survival, because patients have the opportunity to receive subsequent treatments after coming off trial.”
Ribociclib was initially approved by the FDA in 2017 in combination with an aromatase inhibitor for postmenopausal women with HR+/HER2- advanced breast cancer. In July 2018, the FDA expanded this indication to include pre and perimenopausal women with the disease, based on an earlier assessment of PFS from the MONALEESA-7 study. The median PFS was 27.5 months with ribociclib compared with 13.8 months for placebo (HR, 0.569; 95% CI, 0.436-0.743).
The MONALEESA-7 trial enrolled 672 pre or perimenopausal women with advanced breast cancer to receive endocrine therapy with ribociclib (n = 335) or placebo (n = 337). Ribociclib was administered at a dose of 600 mg once daily for 21 days followed by 7 days without the CDK4/6 inhibitor. Endocrine therapy consisted of a nonsteroidal aromatase inhibitor (NSAI; n = 495) or tamoxifen (n = 177), based on the patient's previous adjuvant or neoadjuvant therapy or preference. The use of these therapies was evenly balanced across each arm. Subcutaneous goserelin was administered to patients in both groups at a dose of 3.6 mg on day 1 of each cycle.
Overall, 68.9% and 73.2% of patients went on to receive subsequent therapy in the ribociclib and placebo groups, respectively. The subsequent therapies received were similar between arms, and consisted of chemotherapy alone (22.4% and 28.6%, for ribociclib and placebo, respectively), hormone therapy alone (22.4% and 20.4%, respectively), hormone therapy plus other therapy (14.2% and 14.6%), chemotherapy plus hormone therapy or other therapy (8.2% and 7.9%), and other therapies (1.8% each). Overall, 10.0% of patients in the ribociclib arm and 18.6% of patients in the placebo group received a subsequent CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib, if they were in the placebo group).
At the 42-month analysis, median OS could not be estimated in the ribociclib arm compared with 40.9 months in the placebo group. The median PFS was 23.8 months with ribociclib compared with 13.0 months with placebo (HR, 0.55; 95% CI, 0.44-0.69; P
The 42-month OS analysis reached a predefined efficacy stopping boundary, making these data the final OS analysis for the study. Prior OS analyses from the study showed an OS advantage for ribociclib beginning to emerge at 24 months. The 24-month OS rate was 82.7% in the ribociclib arm compared with 81.8% for placebo; however, by month 36 the Kaplan–Meier curves began to separate, with an OS rate of 71.9% in the ribociclib arm compared with 64.9% with placebo.
When analyzing subgroups by type of endocrine therapy, the greatest benefit was observed for patients receiving an NSAI. In this group, 248 patients received ribociclib and 247 were administered placebo. There was a statistically significant 30% reduction in the risk of death observed with the addition of ribociclib (HR, 0.70; 95% CI, 0.50-0.98). The estimated OS rate at 42 months was 69.7% with ribociclib compared with 43.0% for placebo.
In the tamoxifen subgroup, there was not a non-statistically significant 21% reduction in the risk of death with ribociclib (HR, 0.79; 95% CI, 0.45-1.38). Patient numbers were small in this cohort, with 87 patients in the ribociclib arm and 90 in the placebo group. The 42-month OS rate was 71.2% with ribociclib compared with 54.5% with placebo.
“This is a smaller subgroup. We actually do not give tamoxifen with ribociclib. Subsequent to this study closing, it was determined that tamoxifen is associated with prolongation of the QT interval, so it could put patients at risk for arrhythmia. [Ribociclib] is not approved in combination with tamoxifen,” said Hurvitz.
Commenting on the findings in a statement released by ASCO prior to the presentation of the data, expert Harold J. Burstein, MD, PhD, said that “advanced breast cancer in premenopausal women can be very aggressive. It is important and encouraging to see a targeted therapy that significantly increases survival for younger women with this disease.”
“In an era when we are thinking about value in oncology care, the demonstration of a robust survival benefit adds to the value proposition for products like ribociclib,” said Burstein. “So, hopefully, these data will enable access to this product to more women around the world, particularly in healthcare systems that assess value more rigorously as part of their decisions for national access to their drugs.”
Ribociclib continues to be explored in earlier settings for patients with HR+/HER- breast cancer. The phase III NATALEE trial is currently examining the CDK 4/6 inhibitor as an adjuvant therapy in combination with endocrine therapy for patients with early breast cancer. The primary endpoint of the study is invasive disease-free survival, and the estimated primary completion date is December 2025 (NCT03701334).
- Hurvitz SA, Im S-A, Lu Y-S, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: Overall survival (OS) results. J Clin Oncol. 2019;37 (suppl; abstr LBA1008).
- Im S-A, Lu Y-S, Bardia A, et al. Overall survival with riboiclib plus endocrine therapy in breast cancer. N Engl J Med. 2019.