Ribociclib Granted Approval for HR+/HER2-Negative Breast Cancer


The FDA has granted approval to ribociclib (Kisqali) for firstline treatment of HR+/HER2- breast cancer.

Ribociclib Granted Approval for HR positive HER2 negative Breast Cancer

The FDA has approved the CDK 4/6 inhibitor ribociclib (Kisqali) for use in combination with an aromatase inhibitor 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 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 <.0001).1,2

"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%) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30%. This is a significant result for women with this serious form of breast cancer," MONALEESA-2 principal investigator Gabriel N. Hortobagyi, MD, 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 CDK 4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer," Hortobagyi added.

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.

At 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 = .002).

After an additional 11 months of follow-up, a subsequent analysis showed that the median PFS was 25.3 months with the ribociclib combination versus 16 months with letrozole alone. Overall survival data are still not mature.

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. CDK 4/6 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."


  1. 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.
  2. 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.

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