Ribociclib Receives EU Approval as First-Line Treatment for HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer

The approval concerns combination therapy with any aromatase inhibitor

On 24 August, 2017, Novartis announced that the European Commission (EC) approved ribociclib (Kisqali®) in combination with an aromatase inhibitor for 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. It 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 follows a positive opinion granted in June by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), which was based on superior efficacy and demonstrated safety of ribociclib 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 ribociclib 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-positive, HER2-negative advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer and showed that ribociclib 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; p<0.0001). More than half of patients (55%) with measurable disease taking ribociclib plus letrozole experienced a tumour reduction of at least 30%.

Ribociclib 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. Ribociclib is taken in combination with continuous use of any aromatase inhibitor.

This decision is applicable to all 28 European Union member states plus Iceland, Norway and Liechtenstein. Additional regulatory filings are underway with other health authorities worldwide.

In March 2017, the US Food and Drug Administration (FDA) approved ribociclib, in combination with any aromatase inhibitor, as a treatment for metastatic breast cancer. Ribociclib in combination with letrozole was added to the National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a category 1 option for HR-positive, HER2-negative postmenopausal metastatic breast cancer patients.

Ribociclib is a selective cyclin-dependent kinase inhibitor, a 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, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Ribociclib was developed by the Novartis Institutes for BioMedical Research under a research collaboration with Astex Pharmaceuticals.

Novartis is continuing to assess ribociclib through the robust MONALEESA clinical trial programme, which includes two additional phase III trials, MONALEESA-3 and MONALEESA-7 that are evaluating ribociclib in combination with multiple endocrine therapy partners across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating ribociclib in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating ribociclib in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR-positive, HER2-negative advanced breast cancer who have not previously received endocrine therapy. These trials are fully enrolled.

Novartis is initiating two multicentre, randomised, double-blind phase III clinical trials, EarLEE-1 and EarLEE-2, to evaluate the safety and efficacy of ribociclib 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 ribociclib with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR-positive, HER2-negative high-risk early breast cancer. EarLEE-2 will investigate ribociclib with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR-positive, HER2-negative intermediate-risk early breast cancer.

The CompLEEment-1 study is evaluating the safety and efficacy of ribociclib plus letrozole in men and pre- or postmenopausal women with HR-positive, HER2-negative advanced breast cancer with no prior hormonal therapy for advanced disease. The open-label, multicentre, phase IIIb CompLEEment-1 trial is currently enrolling participants.

Important safety information from the summary of product characteristics

The most common adverse reactions and the most common grade 3/4 adverse reactions (reported at a frequency ≥20% and ≥2% respectively) for which the frequency for ribociclib plus letrozole exceeds the frequency for placebo plus letrozole were blood and lymphatic system disorders, headache, back pain, nausea, fatigue, diarrhoea, vomiting, constipation, hair loss and rash and abnormally low levels of neutrophils or white blood cells, abnormal liver function tests (increased alanine and aspartate aminotransferase), abnormally low lymphocyte count, low levels of phosphate, vomiting, nausea, fatigue and back pain, respectively. Low levels of neutrophils was the most commonly seen severe adverse event; fever in addition to a low neutrophil count was reported in 1.5% of patients.

Ribociclib can cause serious side effects such as a significant decrease in neutrophil count, abnormal liver function tests and may have an effect on QT/QTc interval prolongation, which could lead to disturbances in heart rhythm. As a precaution, patients should have complete blood counts, liver function, and serum electrolyte levels measured prior to starting treatment as well as during treatment with ribociclib. Patients should also have their heart activity checked before and monitored during treatment.

The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.

The use of ribociclib with medicinal products known to prolong QTc interval or strong CYP3A4 inhibitors should be avoided as this may lead to prolongation of the QT/QTc interval. If treatment with a strong CYP3A4 inhibitor cannot be avoided, the ribociclib dose should be reduced. Concomitant administration with other medicines that could affect cardiac repolarization or prolong the QT/QTc interval should be taken into account prior to and during treatment with ribociclib. Patients taking sensitive CYP3A4 substrates with narrow therapeutic index should use caution because of the increased risk of adverse events that may occur if these medications are co-administered with ribociclib.

Ribociclib contains soya lecithin and therefore it should not be taken by patients who are allergic to peanut or soya.

Animal studies suggest that ribociclib may cause foetal harm in pregnant women. Therefore, as a precaution, women of childbearing potential should use effective contraception while receiving ribociclib during treatment and up to 21 days after stopping treatment. Women should not breast feed for at least 21 days after the last dose of ribociclib. It may affect fertility in males.

The Novartis press release contains forward-looking statements.