Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors interrupt signaling that leads to cell-cycle progression and cancer growth. These agents are used in the management of advanced hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer (BC). Recently, the role of one of these drugs, ribociclib (in conjunction with the use of endocrine therapy [ET]), was evaluated in a protocol-specified interim analysis of the MONALEESA-7 (Mammary Oncology Assessment of LEE011’s [ribociclib] Efficacy and Safety-7) trial, which focused on overall survival (OS) as a key secondary endpoint.
MONALEESA-7 is an international, randomized, double-blind, placebo-controlled, phase III trial that compared ribociclib or placebo plus ET in premenopausal or perimenopausal women with HR+, HER-advanced BC (ABC). Ribociclib was administered at a dosage of 600 mg orally once daily for 21 days of a 28-day cycle. Goserelin 3.6 mg was administered subcutaneously on Day 1 of the 28-day cycle in each group. The ribociclib and placebo groups also both received either a nonsteroidal aromatase inhibitor (AI)—i.e., letrozole 2.5 mg, anastrozole 1 mg—or tamoxifen 20 mg once daily.
In order to participate in this trial, women had to be aged 18 to 59 years, be pre- or perimenopausal, and have histologically or cytologically confirmed HR+, HER- ABC that was noncurative and involved locoregionally recurrent or metastatic disease.
OS was defined as the time from randomization to death from any cause. Another endpoint was progression-free survival (PFS), which referred to the time from randomization to the first documented disease progression in patients receiving second-line therapy.
A total of 672 patients (335 randomized to ribociclib and 337 randomized to placebo) were enrolled between December 2014 and August 2016. A prespecified analysis was performed after 192 deaths occurred that revealed an OS rate of 24.8% (83/335) in the ribociclib group compared with 32.3% (109/337) in the placebo group. A Kaplan-Meier–estimated OS at 42 months was 70.2% in the ribociclib group and 46% in the placebo group (hazard ratio [HR] for death = 0.71; CI, 0.54-0.95). Treatment with ribociclib resulted in a 29% lower risk of death, demonstrating superiority over placebo for OS.
Subgroup analyses revealed that of the 495 patients who received an AI, 24.6% in the ribociclib group and 32.4% in the placebo group had died. The estimated OS at 42 months for the AI group was 69.7% in the ribociclib group and 43% in the placebo group. This amounted to a 30% lower risk of death in the ribociclib group compared with placebo (HR for death = 0.7, CI, 0.50-0.98). Of the 177 patients who received tamoxifen, 25.3% of the CDK 4/6 inhibitor group and 32.2% of the placebo group died. Further analysis of the tamoxifen group showed that 71.2% of the ribociclib group and 54.5% of the placebo group reported an estimated OS at 42 months. Although this resulted in a 21% lower risk of death in the ribociclib group versus placebo, this difference was not statistically significant (HR for death = 0.79, CI, 0.45-1.38). Other subgroup analyses demonstrated similar survival benefits; however, they lacked sufficient sample sizes.
Discontinuation rates were high at 65.4% for the ribociclib group and 83.1% for the placebo group. In the ribociclib group, 68.9% received subsequent antineoplastic therapies compared with 73.2% in the placebo group. These therapies included chemotherapy and/or ET. Disease progression or death occurred in 37.6% of the CDK 4/6-inhibitor group compared with 47.8% in placebo patients who received subsequent therapies. At 42 months, 54.6% of the ribociclib group and 37.8% of the placebo group were alive and without disease progression following administration of second-line therapy, resulting in a significant 31% decrease in these negative outcomes in the CDK 4/6-inhibitor group (HR for disease progression or death = 0.69, CI, 0.55-0.87).
Grade 3 or 4 neutropenia was observed in 63.5% of the ribociclib group compared with 4.5% of the placebo group. Other adverse events included hepatobiliary toxicity and prolongation of the QTc interval without the development of torsades de pointes.
This trial demonstrated that the addition of ribociclib to ET significantly prolonged OS compared with ET alone in women with HR+, HER2- ABC. Similar benefits were seen in PFS.
This study provides information on treatment options that pharmacists can recommend when managing the HR+, HER2- BC patient with advanced disease.
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