New research demonstrates that a CDK4/6 inhibitor, used in combination with standard endocrine therapy with temporary ovarian suppression significantly improves progression-free survival in younger patients who currently have few treatment options.
Adding Kisqali® (ribociclib), a CDK4/6 inhibitor, 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. These results, from the clinical trial called MONALEESA-7, were recently reported at the 2017 San Antonio Breast Cancer Symposium.
The phase 3 findings demonstrate for the first time that a CDK4/6 inhibitor is effective in younger patients who currently have few treatment options, experts said.
For women who received Kisqali in combination with either tamoxifen or a nonsteroidal aromatase inhibitor (AI) and Zoladex® (goserelin), a luteinizing hormone-releasing hormone analog, the median PFS was 23.8 months compared with 13 months for those who received the standard endocrine therapy plus placebo.
For patients who received the regimen containing Kisqali and tamoxifen, the median PFS was 22.1 months compared with 11 months for the placebo arm. Combining Kisqali with an AI resulted in 14-month improvement in median PFS compared with an AI alone.
The overall response rate was 51 percent versus 36 percent in favor of the experimental arm. Patient-reported outcomes showed that Kisqali 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 Kisqali 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 Zoladex, according to lead investigator Debu Tripathy, M.D., who discussed the findings during a press briefing. Tripathy is 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 CURE®. “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 percent 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.
Kisqali 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 Ibrance (palbociclib) and Verzenio (abemaciclib), both CDK4/6 inhibitors. Novartis, the company developing Kisqali, 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 Kisqali 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 Kisqali plus Femara® (letrozole) improved PFS by 9.3 months compared with Femara plus placebo.
Overall, the MONALEESA-7 trial randomized 672 patients to Kisqali in combination with tamoxifen or an AI (Femara or anastrozole) plus Zoladex 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 Kisqali at 600 mg, tamoxifen at 20 mg, and either Femara at 2.5 mg anastrozole at 1 mg plus a subcutaneous injection of Zoladex at 3.6 mg once every 28 days. Kisqali 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 percent) and the placebo arm (8 percent) in updated safety results. Six in 10 patients in the Kisqali arm experienced grade 3/4 neutropenia compared with 4 percent in the placebo arm, but the condition was asymptomatic in most patients. Two percent of patients in the experimental arm and 1 percent 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 percent compared with 3.0 percent in patients who received endocrine therapy alone. The most common (≥5 percent) grade 3/4 AEs in patients receiving Kisqali combination therapy compared to endocrine therapy alone were neutropenia (60.6 percent vs 3.6 percent) and leukopenia (14.3 percent vs 1.2 percent)
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 percent of those in the Kisqali arm versus 2.4 percent of those in the placebo group.