FDA Approves Kisqali for Breast Cancer Subset

Kisqali (ribociclib), a CDK 4/6 inhibitor, gained approval from the Food and Drug Administration (FDA) for the frontline treatment of postmenopausal women with hormone-receptor (HR)—positive, HER2-negative advanced breast cancer.

The approval is based on findings from the phase 3 MONALEESA-2 trial, in which combining Kisqali 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.

"In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53 percent) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30 percent. This is a significant result for women with this serious form of breast cancer," MONALEESA-2 principal investigator Gabriel N. Hortobagyi, M.D., Professor of Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, said in a statement. "These results affirm that combination therapy with a CDK4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer."

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 Kisqali 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 Kisqali arm. The analysis occurred after 243 qualifying events, including progression or death. Ninety-three (27.8 percent of randomized patients) events occurred in the Kisqali arm compared with 150 (44.7 percent) in the placebo arm.

After a median follow-up of 15.3 months, the Kisqali 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 Kisqali arm.

The 18-month PFS was 63 percent with Kisqali versus 42.2 percent for the placebo group. Among patients with measurable disease, the overall response rate was 52.7 percent with letrozole plus Kisqali and 37.1 percent with letrozole and placebo.

Kisqali 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 Kisqali 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 Kisqali 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). The events were grade 1/2 severity in most cases. Rates of discontinuation were 7.5 percent with Kisqali and 2.1 percent 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.

"Kisqali is emblematic of the innovation that Novartis continues to bring forward for people with HR+/HER2- metastatic breast cancer," Bruno Strigini, CEO, Novartis Oncology, said in a statement. "We at Novartis are proud of the comprehensive clinical program for Kisqali that has led to today`s approval and the new hope this medicine represents for patients and their families."