The FDA granted ribociclib a breakthrough therapy designation for some patients with breast cancer.
Ribociclib (LEE011) was recently granted a breakthrough therapy designation 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 designation of the CDK4/6 inhibitor, which is meant to expedite the development of promising new therapies, was based on findings from the phase 3 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, global head, Oncology Development and Medical Affairs, Novartis Oncology, which is the company developing ribociclib.
The phase 3 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 three weeks followed by one 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 3 study, a phase 1b study looked at the combination of letrozole with ribociclib (13 patients) or the PI3K alpha inhibitor alpelisib. The median age of patients enrolled in the letrozole/ribociclib arm was 58 years, and 31 percent had received five or more prior regimens, which included prior endocrine therapy (85 percent). The median number of prior therapies was three.
One patient experienced a partial response (7.7 percent) and three had stable disease, for a disease control rate of 31 percent. An additional five patients were without measurable disease or progression and three had progressed.
The most common all grade AEs were neutropenia (85 percent), nausea (39 percent), leukopenia (39 percent), fatigue (23 percent), anemia (23 percent), lymphopenia (23 percent),and increased creatinine (15 percent). The most common grade 3/4 AEs were neutropenia (46 percent), lymphopenia (23 percent) and leukopenia (15 percent), 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 3 MONALEESA-3 trial is exploring ribociclib with Faslodex (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 3 MONALEESA-7 trial is currently exploring ribociclib with tamoxifen and Zoladex (goserelin) or a non-steroidal aromatase inhibitor and Zoladex 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 Ibrance (palbociclib), which is FDA-approved as a frontline therapy in combination with letrozole and as a second-line therapy with Faslodex for patients with HR+, HER- advanced breast cancer.