Type of information: Submission of a Market Application in the EU
Product name: Kisqali® in combination with letrozole
Compound: ribociclib in combination with letrozole
Therapeutic area: Cancer - Oncology
Action mechanism: kinase inhibitor/cyclin dependent kinase inhibitor. Kisqali® (LEE011 - ribociclib) is a selective cyclin dependent kinase inhibitor, a new class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated in a cell, can enable cancer cells to grow and divide too quickly. LEE011 has been studied in non-clinical models and is currently being evaluated in combination with additional endocrine agents as part of the MONALEESA (Mammary ONcology Assessment of LEE011's Efficacy and SAfety) clinical trial program.
LEE011 was developed by Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.
Company: Novartis (Switzerland)
Disease: HR+/HER2- advanced breast cancer
- • On March 13, 2017, the FDA approved ribociclib (Kisqali®), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
Approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2), in post-menopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who received no prior therapy for advanced disease. A total of 668 patients were randomized to receive either ribociclib plus letrozole (n=334) or placebo plus letrozole (n=334). Ribociclib 600 mg or placebo was administered orally once daily for 21 consecutive days, followed by 7 days off, with letrozole 2.5 mg administered orally once daily for 28 days. Treatment continued until disease progression or unacceptable toxicity.
- A pre-planned interim efficacy analysis demonstrated an improvement in PFS (investigator-assessed) with hazard ratio of 0.556 (95% CI: 0.429, 0.720; p<0.0001). The estimated median PFS had not been reached in the ribociclib-containing arm and was 14.7 months in the placebo-containing arm. Objective response rate (ORR) in patients with measurable disease was 52.7% (95% CI: 46.6, 58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI: 31.1, 43.2) in the placebo plus letrozole arm. Overall survival data are immature.
- The recommended starting dose of ribociclib is 600 mg orally (three 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment.
- FDA granted this application a priority review and breakthrough therapy designation.
- • On November 1, 2016, Novartis announced that the FDA accepted the company's New Drug Application (NDA) for filing and granted Priority Review for LEE011 (ribociclib) as first-line treatment of postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer in combination with letrozole. The NDA is based on a comprehensive clinical package, including results of the Phase III MONALEESA -2 trial. The trial, which was presented at the European Society for Medical Oncology (ESMO) 2016 Congress and published simultaneously in the New England Journal of Medicine, showed LEE011 plus letrozole reduced the risk of progression or death by 44% (HR = 0.556, 95% CI: 0.429-0.720; P = 0.00000329) over letrozole alone, significantly extending progression-free survival (PFS) across all patient subgroups.
- Novartis also announced that the EMA has accepted for review the marketing authorization application for LEE011 plus letrozole in the same patient population.
- • On August 3, 2016, Novartis announced that the FDA has granted Breakthrough Therapy designation to LEE011 (ribociclib), in combination with letrozole, for the treatment of hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer. The Breakthrough Therapy designation is based primarily on positive results of the Phase III MONALEESA-2 trial of LEE011 in combination with letrozole in postmenopausal women who had received no prior therapy for their advanced disease. The MONALEESA-2 trial met the primary endpoint of clinically meaningful improvement in progression free survival (PFS) at a pre-planned interim analysis. Results of this study will be presented at an upcoming medical congress and will form the basis of regulatory discussions in the US, Europe and other countries for use in this indication.
- MONALEESA-2 is a Phase III randomized, double blind, placebo controlled, multicenter global registration trial to evaluate the safety and efficacy of LEE011 in combination with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- advanced breast cancer who received no prior therapy for their advanced breast cancer. MONALEESA-2 met the primary endpoint of clinically meaningful improvement in PFS at the pre-planned interim analysis and is continuing to assess overall survival data.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-03-13
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: