Ribociclib in combination with fulvestrant demonstrated a statistically significant improvement in overall survival in postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer, according to interim results from the phase III MONALEESA-3 trial.
Susanne Schaffert, PhD
Ribociclib (Kisqali) in combination with fulvestrant demonstrated a statistically significant improvement in overall survival (OS) in postmenopausal women with hormone receptor (HR)positive, HER2-negative advanced or metastatic breast cancer, according to interim results from the phase III MONALEESA-3 trial.1
This is the second phase III clinical trial that has demonstrated, as of the planned interim analysis, that ribociclib combination therapy prolongs life for patients with breast cancer.
“We are thrilled that Kisqali combination therapy again has demonstrated improved overall survival for patients with HR+/HER2- advanced breast cancerfirst in pre-menopausal and peri-menopausal women in MONALEESA-7, and now in post-menopausal women in MONALEESA-3,” Susanne Schaffert, PhD, president, Novartis Oncology, the company developing the CDK4/6 inhibitor, said in a statement. “We will continue to reimagine cancer to help patients live longer, and also improve quality of life as we work towards finding a cure for this incurable disease.”
The phase III MONALEESA-3 trial investigated the combination of ribociclib and fulvestrant in the de novo setting and in patients who relapsed more than 12 months after prior endocrine therapy with no subsequent treatment for advanced disease. The trial enrolled 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who were randomized 2:1 to ribociclib, 600 mg/day in a 3-weeks-on/1-week-off schedule plus fulvestrant, 500 mg/day, or placebo.
The median patient age was 63 years. Half of the patients received treatment in the first-line setting and half in the second-line setting. About 60% of patients received prior endocrine therapy in the neoadjuvant setting and 16.5% (placebo arm) and 22.7% (ribociclib arm) in the adjuvant setting.
Progression-free survival (PFS) was the primary endpoint of the trial and the key secondary endpoint was OS.
Prior reports of the MONALEESA-3 trial showed that the median PFS was 20.5 months with ribociclib and fulvestrant compared with 12.8 months in the placebo arm (P= .00000041).2
The PFS benefit with ribociclib and fulvestrant was seen in both the first-line (HR, 0.577; 95% CI, 0.415-0802) and second-line settings (HR, 0.565; 95% CI, 0.428-0.744), and across patient subgroups.
The overall response rate (ORR) was 32.4% in the ribociclib arm versus 21.5% in the placebo arm (P= .000912), and in those with measurable disease, the ORRs were 40.9% and 28.7%, (P= .003), respectively. The clinical benefit rate was 70.2% for ribociclib versus 62.8% for placebo (P= .020) in the overall cohort, and 69.4% versus 59.7% (P= .015), respectively, in patients with measurable disease.
Grade 3 neutropenia occurred in 46.6% of the patients receiving ribociclib versus 0% of the patients receiving placebo, and the corresponding rates of grade 4 neutropenia were 6.8% and 0%, respectively. Febrile neutropenia was observed in 5 patients (1.0%) in the ribociclib arm and none in the placebo arm. Post-baseline QTcF >480 ms occurred in 5.6% of patients in the ribociclib arm and 2.5% in the placebo arm. Grade 3 and 4 elevation in alanine transaminase and aspartate transaminase occurred in 6.6% of patients and 1.9% of the ribociclib arm, respectively, and in 4.8% and 1.2% of the placebo arm.Results of the phase III MONALEESA-7 trial recently published in theNew England Journal of Medicineconfirmed the OS benefit of ribociclib in patients with HR-positive, HER2-negative breast cancer.3
The MONALEESA-7 trial investigated the combination of ribociclib plus endocrine therapy in pre- or perimenopausal women with advanced breast cancer, enrolling 672 patients.
Patients were allowed to have received prior endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting, and up to 1 prior line of chemotherapy for advanced disease.
The patients were randomized 1:1 to either ribociclib and endocrine therapy (n = 335) or endocrine therapy and 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 (n = 495) or tamoxifen (n = 177), based on the patient's previous adjuvant or neoadjuvant therapy or preference.
At 42 months, the estimated OS rate was 70.2% (95% CI, 63.5%-76.0%) in the ribociclib arm and 46.0% (95% CI, 32.0%-58.9%) in the placebo group (HR, 0.71; 95% CI, 0.54-0.95;P= .00973). The median OS was not reached in the ribociclib group compared with 40.9 months in the placebo arm.
Previous reports demonstrated that the PFS with the combination of ribociclib and endocrine therapy was 23.8 months (95% CI, 19.2-not reached) compared with 13.0 months (95% CI, 11.0-16.4) in the placebo group (HR, 0.55; 95% CI, 0.44-0.69;P<.0001).4
The most frequent grade 3/4 adverse events (AEs; >10%) included neutropenia (61% with ribociclib vs 4% with placebo) and leucopenia (14% vs 1%). Serious AEs attributed to treatment were observed in 4% of patients in the ribociclib group and 2% in the placebo arm.
Treatment discontinuation due to AEs occurred in 4% of patients in the ribociclib arm and in 3% in the placebo arm. Eleven deaths occurred, 5 in the ribociclib group and 6 in the placebo group, although none were considered treatment related.
The FDA has granted ribociclib an expanded approval in breast cancer based on both of these trials. The CDK4/6 inhibitor is approved in combination with an aromatase inhibitor in the frontline setting for pre- or perimenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, and in combination with fulvestrant for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy.