Ribociclib (Kisqali) has been approved by the US Food and Drug Administration (FDA) for use in combination therapy with an aromatase inhibitor for first-line treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer.1
Last August, the FDA had granted ribociclib, then, still known as LEE011, breakthrough therapy designation in combination with letrozole. Ribociclib combined with letrozole reduces the risk of breast cancer progression and death, compared with letrozole alone.
The drug approval was based on the results of the first-line phase III MONALEESA-2 trial, which was published in The New England Journal of Medicine in October 2016.2 The randomized, placebo-controlled trial ended prematurely as it demonstrated significant benefit. It included 668 postmenopausal women with HR-positive/HER2-negative, advanced or metastatic breast cancer who had not undergone previous systemic treatment for their breast cancer.
Patients received ribociclib (600 mg per day, 3-weeks on, 1-week off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, overall response rate, and safety. The median duration of follow-up was 15.3 months.
Results showed that PFS was significantly longer in the women who took ribociclib than those in the placebo group. After 18 months, the PFS rate was 63% in the ribociclib group and 42.2% in the placebo group. Among those who had measurable disease when the study began, the women in the ribociclib group showed an overall response rate of 52.7%, compared with 37.1% in the placebo group.
"In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44% 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," said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center and MONALEESA-2 Principal Investigator, in a release. "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-positive advanced breast cancer."3
Treatment toxicity remains an issue with ribociclib as with other breast cancer treatments; however, the benefits did outweigh the concerns. Of the patients who received ribociclib, 59.3% developed grade 3/4 neutropenia, compared with 0.9% of patients in the placebo group; 21% of patients in the ribociclib group experienced grade 3/4 leukopenia compared with 0.6% of the placebo group. The most common nonhematologic adverse events were:
- Nausea (51.5% with ribociclib vs 28.5% with placebo);
- Infections (50.3% with ribociclib vs 42.4% with placebo);
- Fatigue (36.5% with ribociclib vs 30% with placebo); and
- Diarrhea (35% with ribociclib vs 22.1% with placebo).
Speaking at the European Society of Medical Oncology this past October, Hortobagyi said, “The results of this trial represent a compelling proof of principle, and suggest a paradigm shift in metastatic, HR-positive breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signaling pathways might lead to additional progress in the management of several subtypes of breast cancer.”4
- US Food and Drug Administration. Ribociclib (Kisqali). 2017 Mar 13.
- Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748.
- Novartis. Novartis Kisqali (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor. 2017 Mar 13.
- European Society for Medical Oncology. ESMO 2016 Press Release: Ribociclib Improves Progression-free Survival in Advanced Breast Cancer. 2016 Oct 8.