Type of information: Granting of a Market Authorisation in the EU
Product name: Kisqali® in combination with letrozole
Compound: ribociclib in combination with letrozole
Therapeutic area: Cancer - Oncology
- 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)
- HR+/HER2- advanced breast cancer
- • On August 24, 2017, Novartis announced that the European Commission approved Kisqali® (ribociclib) in combination with an aromatase inhibitor for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer as initial endocrine-based therapy. Kisqali® is the first CDK4/6 inhibitor approved in Europe based on a first-line Phase III trial that met its primary endpoint of progression-free survival (PFS) at interim analysis.
- EU approval was based on superior efficacy and demonstrated safety of Kisqali® plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The opinion included a recommendation that allows oncologists the flexibility to prescribe Kisqali® with any aromatase inhibitor (i.e., letrozole, anastrozole or exemestane) they deem most appropriate for their patient.
MONALEESA-2 enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer and showed that Kisqali plus letrozole, an aromatase inhibitor, reduced the risk of progression or death by 43% over letrozole alone (median PFS=25.3 months (95% CI: 23.0-30.3) vs. 16.0 months (95% CI: 13.4-18.2); HR=0.568 (95% CI: 0.457-0.704). More than half of patients (55%) with measurable disease taking Kisqali plus letrozole experienced a tumor reduction of at least 30 percent.
- The MONALEESA clinical trial program includes MONALEESA-2, MONALEESA-3, and MONALEESA-7. These trials are evaluating LEE011 in multiple endocrine therapy combinations across a broad range of patients, including men and premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin. These trials are fully enrolled.
Novartis is initiating two multi-center, randomized, double-blind Phase III clinical trials, EarLEE-1 and EarLEE-2, to evaluate the safety and efficacy of Kisqali with endocrine therapy as adjuvant therapy in pre- and postmenopausal women who have not previously received treatment with CDK4/6 or aromatase inhibitors. EarLEE-1 aims to assess Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- high-risk early breast cancer. EarLEE-2 will investigate Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- intermediate-risk early breast cancer.
The CompLEEment-1 study is evaluating the safety and efficacy of Kisqali plus letrozole in men and pre- or postmenopausal women with HR+/HER2- advanced breast cancer with no prior hormonal therapy for advanced disease. The open-label, multicenter, Phase IIIb CompLEEment-1 trial is currently enrolling participants.
- Kisqali® can be taken orally once-daily with or without food at a suggested starting dose of 600 mg (three 200 mg tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with continuous use of any aromatase inhibitor.
- • On June 22, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Kisqali® for the treatment of locally advanced or metastatic breast cancer. The drug will be available as 200-mg film-coated tablets. The full indication is: "Kisqali® in combination with an aromatase inhibitor is indicated for the treatment of postmenopausal women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer as initial endocrine based therapy".
- • 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). 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: 0.429-0.72) 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
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
UE authorization: 2017-08-24
Favourable opinion UE: 2017-06-22
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: