The FDA granted ribociclib a priority review to a new drug application for certain patients with breast cancer.
Ribociclib (LEE011) was granted a priority review to a new drug application (NDA) by the U.S. Food and Drug Administration (FDA) for use in combination with letrozole as a frontline therapy for patients with hormone-receptor (HR)—positive, HER2-negative advanced breast cancer.
The NDA for the CDK 4/6 inhibitor is primarily based on findings from the phase 3 MONALEESA-2 trial, in which combining ribociclib with letrozole reduced the risk of progression or death by 44 percent compared with letrozole alone in the first-line setting for HR+/HER2- advanced breast cancer. Under the priority designation, the NDA will be reviewed within six months, compared with the standard 10-month review.
“These regulatory milestones, along with the FDA breakthrough therapy designation granted in August, underscore the need for new treatment options for women living with HR+/HER2- advanced breast cancer," Bruno Strigini, CEO of Novartis Oncology, the developer of ribociclib, said in a statement.
“Priority review allows a shorter review period compared with FDA standard review in the United States, helping us to potentially bring LEE011 plus letrozole to patients more quickly. We also are working diligently with the EMA and other health authorities to bring this treatment to patients around the world as fast as possible,” added Strigini.
The phase 3 MONALEESA-2 trial enrolled 668 postmenopausal women with advanced breast cancer who had not yet received prior therapy for advanced disease. Letrozole was administered at 2.5 mg per day along with placebo or ribociclib at 600 mg per day for three weeks followed by one week off. The primary endpoint of the study was progression-free survival (PFS). Secondary outcome measures focused on overall survival, overall response rates, and safety.
The trial ended prematurely after an initial interim data analysis demonstrated a significant benefit in favor of the ribociclib arm. The analysis occurred after 243 qualifying events, including progression or death. Ninety-three (27.8 percent of randomized patients) events occurred in the ribociclib arm compared with 150 (44.7 percent) in the placebo arm.
After a median follow-up of 15.3 months, the ribociclib group’s median PFS had yet to be reached, whereas the placebo group had an estimated median PFS of 14.7 months. Blinded PFS assessment by an independent review committee resulted in a hazard ratio of 0.59 in favor of the ribociclib arm.
The 18-month PFS was 63 percent with ribociclib versus 42.2 percent for the placebo group. Among patients with measurable disease, the overall response rate was 52.7 percent with letrozole plus ribociclib and 37.1 percent with letrozole and placebo.
Ribociclib did add to treatment-associated toxicity, as 59.3 percent of patients who received the CDK 4/6 inhibitor developed grade 3/4 neutropenia, as compared with 0.9 percent of patients who received placebo. Grade 3/4 leukopenia occurred in 21 percent of the ribociclib arm and 0.6 percent of the placebo group. Hematologic adverse events were uncomplicated and resolved without incident in most cases.
The most common nonhematologic adverse events (all grades) were nausea (51.5 percent with ribociclib vs 28.5 percent with placebo), infections (50.3 percent vs 42.4 percent), fatigue (36.5 percent vs 30.0 percent) and diarrhea (35 percent vs 22.1 percent).
Inhibition of CDK 4/6 offers an attractive therapeutic strategy for hormone-receptor breast cancer. CDK 4 and 6, along with their protein regulator, cyclin D1, regulate cell-cycle progression. CDK4/6 overexpression and amplification of cyclin D1 gene occur frequently in HR-positive breast cancer, and increased CDK 4/6 activity, in particular, is associated with resistance to endocrine therapy.