The FDA granted a priority review to a new drug application (NDA) for ribociclib (LEE011) 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 III MONALEESA-2 trial, in which combining ribociclib with letrozole reduced the risk of progression or death by 44% compared with letrozole alone in the first-line setting for HR+/HER2- advanced breast cancer (HR, 0.556; 95% CI, 0.43-0.72; P
Under the priority designation, the NDA will be reviewed within 6 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 III 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 3 weeks followed by 1 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% of randomized patients) events occurred in the ribociclib arm compared with 150 (44.7%) 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 (P
The 18-month PFS was 63% with ribociclib versus 42.2% for the placebo group. Among patients with measurable disease, the overall response rate was 52.7% with letrozole plus ribociclib and 37.1% with letrozole and placebo.
Ribociclib did add to treatment-associated toxicity, as 59.3% of patients who received the CDK 4/6 inhibitor developed grade 3/4 neutropenia, as compared with 0.9% of patients who received placebo. Grade 3/4 leukopenia occurred in 21% of the ribociclib arm and 0.6% 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% with ribociclib vs 28.5% with placebo), infections (50.3% vs 42.4%), fatigue (36.5% vs 30.0%), and diarrhea (35% vs 22.1%). The events were grade 1/2 severity in most cases. Rates of discontinuation were 7.5% with ribociclib and 2.1% with placebo.
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.
- Hortobagyi GN, Stemmer SM, Burris HA, et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA1.
- Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer [published online October 8, 2016]. N Engl J Med. doi:10.1056/NEJMoa1609709.