FDA Grants Ribociclib Breakthrough Designation for Breast Cancer

Alessandro Riva, MD

The FDA has granted a breakthrough therapy designation to the CDK4/6 inhibitor ribociclib (LEE011) in combination with letrozole for its potential as a frontline therapy for patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer.

The designation, which is meant to expedite the development of promising new therapies, was based on findings from the phase III MONALEESA-2 trial, in which ribociclib and letrozole significantly improved progression-free survival (PFS) compared with letrozole alone. Based on this improvement, the study was halted in May. Data have not yet been released from the study and are being prepared for presentation at an upcoming medical meeting and for regulatory submissions.

"This designation shows the potential of LEE011, and we look forward to close collaboration with the FDA and the advanced breast cancer community to provide a new treatment option for women living with HR+/HER2- advanced breast cancer as quickly as possible," Alessandro Riva, MD, global head, Oncology Development and Medical Affairs, Novartis Oncology, which is the company developing ribociclib.

The phase III trial that was the basis for the designation 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 PFS. Secondary outcome measures focused on overall survival (OS), overall response rates, and safety.

Adverse events (AEs) observed in the study were consistent with previous reports for ribociclib, according to a statement from Novartis. Although the trial was stopped, data will continue to be assessed for OS. Approval discussions with the FDA and other global regulatory agencies were initiated in May, following the positive PFS analysis.

Prior to the phase III study, a phase Ib study looked at the combination of letrozole with ribociclib (n = 13) or the PI3K alpha inhibitor alpelisib. The median age of patients enrolled in the letrozole/ribociclib arm was 58 years, and 31% had received >5 prior regimens, which included prior endocrine therapy (85%). The median number of prior therapies was 3.

One patient experienced a partial response (7.7%) and 3 had stable disease, for a disease control rate of 31%. An additional 5 patients were without measurable disease or progression and 3 had progressed.

The most common all grade AEs were neutropenia (85%), nausea (39%), leukopenia (39%), fatigue (23%), anemia (23%), lymphopenia (23%), and increased creatinine (15%). The most common grade 3/4 AEs were neutropenia (46%), lymphopenia (23%), and leukopenia (15%), which were all suspected to be study treatment-related.

"Despite advancements in treatment, an estimated 40,000 individuals in the United States die each year from advanced breast cancer," Riva noted.

A number of clinical trials continue to assess ribociclib as a treatment for patients with breast cancer. The phase III MONALEESA-3 trial is exploring ribociclib with fulvestrant for patients with advanced breast cancer following one prior line of endocrine therapy. The primary endpoint of the study is PFS. The trial plans to enroll 660 participants (NCT02422615).

The ongoing phase III MONALEESA-7 trial is currently exploring ribociclib with tamoxifen and goserelin or a non-steroidal aromatase inhibitor and goserelin for patients with HR+/HER2- advanced breast cancer. The primary endpoint of the study, which plans to enroll 660 patients, is also PFS (NCT02278120).

There are currently several CDK4/6 inhibitors in development, including abemaciclib and palbociclib (Ibrance), which is FDA-approved as a frontline therapy in combination with letrozole and as a second-line therapy with fulvestrant for patients with HR+, HER- advanced breast cancer.

Munster PN, Hamilton EP, Estevez LG, et al. Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2- breast cancer. J Clin Oncol. 2014;32 (suppl 26; abstr 143).