Debu Tripathy, MD
Newly released results from the MONALEESA-7 trial showed that adding ribociclib (Kisqali) to standard endocrine therapy with temporary ovarian suppression significantly improved progression-free survival (PFS) as a first-line treatment for pre- and perimenopausal women with advanced HR-positive/HER2-negative breast cancer. 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, experts said in discussing the results at the 2017 San Antonio Breast Cancer Symposium.
The median PFS was 23.8 months for women who received ribociclib in combination with either tamoxifen or a nonsteroidal aromatase inhibitor (AI) and goserelin, a luteinizing hormone-releasing hormone analog, compared with 13.0 months for those who received the standard endocrine therapy plus placebo (hazard ratio [HR], 0.553; 95% CI, 0.441-0.694; P <.0001).1
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.
MONALEESA-7 is the first clinical trial to have the statistical power to show that ribociclib is associated with clinical benefit specifically for pre- and perimenopausal women with HR-positive/HER2-negative advanced breast cancer, and the first to show that the CDK4/6 inhibitor is effective in combination with either tamoxifen or a nonsteroidal AI together with ovarian suppression using goserelin, according to lead investigator Debu Tripathy, MD, who discussed the findings during a press briefing. Tripathy is a professor of medicine and chair of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center.
“Over the last few years, several trials have shown that the addition of a class of drugs known as CDK4/6 inhibitors to standard hormonal therapies can double the average time until breast cancer progresses in patients with advanced (metastatic) breast cancer that is positive for hormonal receptors and negative for HER2,” he said in an email interview with OncLive. “MONALEESA-7 results now confirm that the same benefits in times to progression do in fact also apply to premenopausal patients. The side effect profile was similar to those seen with prior trials of this type. In addition, this is the first study to test tamoxifen as well as aromatase inhibitors as the hormonal therapy combined with CDK4/6 inhibition.”
Tripathy noted that premenopausal patients tend to have more aggressive cancers and represent 20% of all patients diagnosed in the United States. Premenopausal breast cancer is a biologically distinct form of the disease and the leading cause of cancer death in women 20 to 59 years old worldwide. Treatment guidelines for this group of patients have by default been the same as postmenopausal patients with either medical blockade of ovarian function or surgical removal of the ovaries.
Ribociclib gained the FDA’s approval in March 2017 in combination with an AI as initial endocrine therapy for postmenopausal women with advanced or metastatic HR-positive, HER2-negative breast cancer. Additionally, the agency has approved palbociclib (Ibrance) and abemaciclib (Verzenio), both CDK4/6 inhibitors. Novartis, the company developing ribociclib, said the results of the MONALEESA-7 trial would be used to support an application for the drug as a standard-of-care medication for premenopausal women.
In August, the European Commission approved ribociclib for use in combination with an AI for the frontline treatment of postmenopausal women with HR-positive/HER2-negative locally advanced or metastatic breast cancer based on previously published results from the MONALEESA-2 trial that showed ribociclib plus letrozole (Femara) improved PFS by 9.3 months compared with letrozole plus placebo.2
Another CDK4/6 inhibitor, palbociclib (Ibrance), is also approved as firstline treatment for postmenopausal women with HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor. The drug is also indicated in combination with fulvestrant for the second-line treatment of HR+/HER2- metastatic breast cancer following progression on endocrine therapy.
In September, the FDA approved a third CDK4/6 inhibitor, abemaciclib (Verzenio), as monotherapy and in combination with fulvestrant for women with HR+/HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy.
Favorable Adverse Event Profile
Overall, the MONALEESA-7 trial randomized 672 patients to ribociclib in combination with tamoxifen or an AI (letrozole or anastrozole) plus goserelin (n = 335) versus endocrine treatment alone in premenopausal or perimenopausal women with HR-positive/HER2-negative advanced breast cancer who 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, and either letrozole at 2.5 mg anastrozole at 1 mg plus 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.
Neutropenia remained 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% 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%)
Safety results were generally consistent with those observed in MONALEESA-2, which were identified early and mostly managed through dose interruptions or reductions. AEs resulted in discontinuation for 8.1% of those in the ribociclib arm versus 2.4% of those in the placebo group.
- Tripathy D, Sohn J, Im SA, et al. . GS2-05. 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. www.abstracts2view.com/sabcs/view.php?nu=SABCS17L_828&terms=
- Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC). J Clin Oncol. 2017;35(suppl; abstr 1038). meetinglibrary.asco.org/record/153081/abstract