Howard A. “Skip” Burris, MD
A subgroup analysis of the randomized MONALEESA-2 trial showed that patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer, and visceral metastases obtained a significant benefit from treatment with the CDK4/6 inhibitor ribociclib (LEE011) combined with letrozole.
Patients with visceral metastases had a 45% reduction in the hazard for progression or death with ribociclib and letrozole versus letrozole and placebo. An identical benefit was observed in the more favorable prognostic subgroup with bone-only metastases. The improvement in those 2 groups mirrored the 44% reduction in the progression-free survival (PFS) hazard observed in the overall population of 668 patients in the MONALEESA-2 trial.
Other prespecified subgroups had reductions in the PFS hazard ranging from 39% to 61%, as reported at the 2016 San Antonio Breast Cancer Symposium.
“The MONALEESA-2 trial showed that ribociclib plus letrozole significantly prolonged PFS compared with placebo plus letrozole in postmenopausal women with HR-positive, HER2
-negative advanced breast cancer,” Howard A. Burris, III, MD, a medical oncologist at the Sarah Cannon Research Institute in Nashville, and colleagues concluded in a poster presentation. “Ribociclib plus letrozole was generally well tolerated in most patient subgroups, with a safety profile similar to that observed in the full population.”
Endocrine therapy remains the cornerstone of treatment for patients with advanced HR-positive, HER2
-negative breast cancer. The MONALEESA-2 trial was designed to determine whether adding the CDK inhibitor ribociclib to standard endocrine therapy could improve PFS. The primary results, reported at the European Society for Medical Oncology meeting, showed a 44% reduction in the PFS hazard for patients who received ribociclib in addition to letrozole.
Patients with advanced breast cancer and visceral metastases have a poorer prognosis, compared with patients who have only bone metastases. Yet, treatment guidelines for the 2 types of patients are the same.
Burris and colleagues performed an analysis of the MONALEESA-2 data to determine how the addition of ribociclib to endocrine therapy affected in various prespecified subgroups of patients, including those with visceral versus bone-only metastases. They also examined the safety of the combination therapy in the same subgroups.
The trial had a primary objective of PFS, and key secondary objectives included overall survival and safety.
The MONALEESA-2 study population included 393 patients with visceral metastases and 147 patients with bone-only metastases. In the subgroup with visceral metastases, 30% to 35% had liver involvement, and about 77% had lung involvement. More than 50% of patients with visceral metastases had 3 or more metastatic sites. In contrast, only 1 patient with bone-only disease had more than 1 metastatic site.
The analysis failed to identify any subgroup that did not benefit from the addition of ribociclib to letrozole. Beyond patients with and without visceral metastases, the analysis showed a beneficial effect by age (<65 vs ³65), ECOG performance status (0 vs 1), race (Asian vs non-Asian), number of metastatic sites (<3 vs ³3), de novo disease (yes or no), prior endocrine therapy, and chemotherapy history.
Among patients with visceral metastases, the median PFS was 13.0 months with letrozole alone versus not yet reached with ribociclib and letrozole (HR 0.535; 95% CI, 0.385-0.742).
Burris and colleagues found that the safety and tolerability of ribociclib combined with letrozole were similar in patients with visceral or bone-only metastases, and consistent with the safety and tolerability observe in the overall trial.
Among patients with visceral metastases, the most frequent adverse events (AEs) (³30% of patients, all grades, regardless of association with treatment) were neutropenia, nausea, fatigue, leukopenia, diarrhea, and alopecia. The most frequent grade 3/4 AEs (³20% of patients) were neutropenia and leukopenia. The most common AEs leading to discontinuation were elevated liver enzymes (ALT, 4.6%; AST, 2.5%), vomiting (4.1%), and nausea (1.5%).
Dose interruptions and reductions were required in 77% and 55.3% of ribociclib-treated patients with visceral metastases, compared with rates of 40.3% and 6.1% among patients who received letrozole and placebo. The median duration of treatment exposure was 12 to 13 months in both arms of the study.
In the patients with bone-only metastases, types, rates, and severity of AEs were similar to those seen among patients with visceral metastases. Additionally, the duration of treatment ranged from 12 to 13 months in the ribociclib and placebo groups.
Burris HA, Chan A, Campone M, et al. First-line ribociclib + letrozole in patients with HR+, HER2advanced breast cancer (ABC) presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P4-22-16.