Ribociclib in combination with fulvestrant showed an improvement in progression-free survival in postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced breast cancer; the benefit was seen both in treatment-naive patients, and in patients who had received 1 prior line of therapy, according to the results from the phase III MONALEESA-3 trial presented at the ASCO Annual Meeting.
Dennis J. Slamon, MD, PhD
Ribociclib in combination with fulvestrant showed an improvement in progression-free survival in postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced breast cancer; the benefit was seen both in treatment-naive patients, and in patients who had received 1 prior line of therapy, according to the results from the phase III MONALEESA-3 trial presented at the ASCO Annual Meeting.1
Median PFS at the time of data cut-off was 20.5 months in patients randomized to ribociclib compared with 12.8 months in those randomized to placebo, representing a 41% reduction in the risk of disease progression (P= .00000041), reported Dennis J. Slamon, MD, PhD, at the 2018 ASCO Annual Meeting.
MONALEESA-3 “is the first study that shows the benefit of a CDK4/6 inhibitor plus fulvestrant combination in patients in the setting of de novo advanced breast cancer and patients with disease that relapsed over 12 months after completion of neoadjuvant endocrine therapy,” said Slamon, who is director of clinical/translational research and director of the Revlon/UCLA Women's Cancer Research Program in Santa Monica, California. “Ribociclib combined with fulvestrant represents a new first- or second-line treatment option for postmenopausal women with HR-positive, HER2-negative advanced breast cancer.”
The improvement in PFS with the CDK4/6 inhibitor was realized both in the first-line and second-line setting, and was consistent across patient subgroups, Slamon added.
The ribociclib/fulvestrant combination previously demonstrated efficacy in clinical trials of patients with HR-positive breast cancer who had progressed on prior endocrine therapy.2,3MONALEESA-3 was the first to test this combination in the de novo setting and in patients who relapsed >12 months after prior endocrine therapy with no subsequent treatment for advanced disease.
A total of 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer 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 primary objective was investigator-assessed PFS.
Baseline patient characteristics were balanced between arms. The median patient age was 63 years. Approximately 60% of patients had visceral disease and 21% had bone-only metastasis. 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.
The median duration from randomization to data cut-off was 20.4 months. At the time of the analysis, treatment was ongoing in 42.1% of those randomized to ribociclib and 31.4% of those in the placebo arm. Treatment was discontinued in 57.6% and 68.2% of patients, respectively. The primary reason for treatment discontinuation was disease progression in 39.9% of patients in the ribociclib arm and 58.7% of patients in the placebo arm.
In addition to investigator assessment, PFS by a blinded Independent Review Committee was assessed in 290 patients as a supportive analysis, which demonstrated that median PFS was not reached in the ribociclib arm and was 10.9 months in the placebo arm. Corresponding to a 51% reduction in the risk of progression with ribociclib (HR, 0.492; 95% CI, 0.345-0.703).
The PFS benefit with ribociclib was equally apparent in all subgroups, including those defined by prior line of endocrine therapy, metastatic site and number of metastatic sites, prior tamoxifen therapy, prior aromatase inhibitor therapy, age, race, and performance status. When ribociclib was given as first-line therapy, the median PFS was not reached in the ribociclib arm and was 18.3 months in the placebo arm (HR, 0.577; 95% CI, 0.415-0802). When used in the second-line setting, median PFS was 14.8 months in the ribociclib arm and 9.1 months in the placebo arm (HR, 0.565; 95% CI, 0.428-0.744).
In all patients, the overall response rate (ORR) was 32.4% in the ribociclib arm versus 21.5% in the placebo arm (P = 0.000912) and in those with measurable disease, ORR was 40.9% and 28.7%, (P= .003), respectively. The clinical benefit rate was 70.2% for ribociclib versus 62.8% for placebo (P= 0.020) in the overall cohort, and 69.4% versus 59.7% (P= .015), respectively, in patients with measurable disease.
Overall survival data were not mature at data cut-off. At the time of data analysis, 14.5% of patients in the combination ribociclib/fulvestrant arm and 20.7% in the placebo/fulvestrant arm died.
Median relative dose intensity (ribociclib or placebo) was 92.1% in the ribociclib arm and 100% in the placebo arm. Dose interruption due to adverse events was required in 68.5% of the ribociclib arm and 18.7% of the placebo arm.
Grade 3 neutropenia occurred in 46.6% of the ribociclib recipients versus 0% of the placebo recipients, and the corresponding rates of grade 4 neutropenia were 6.8% and 0%, respectively. Febrile neutropenia was observed in 5 (1.0%) patients 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.