Date: 2016-12-09
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the San Antonio Breast Cancer Symposium (SABCS)
Company: Novartis (Switzerland)
Product: LEE011 (ribociclib)
Action
mechanism: kinase inhibitor/cyclin dependent kinase inhibitor. 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. In August 2016, 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.
Disease: postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer
Therapeutic area: Cancer - Oncology
Country: Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Republic of Korea, Lebanon, The Netherlands, Norway, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, UK, USA, Japan, Mexico
Trial
details: 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. The MONALEESA-3 trial is evaluating LEE011 in combination with fulvestrant compared to fulvestrant alone in men and post-menopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy.
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. The trial randomized 668 patients in a 1:1 ratio stratified by the presence of liver and/or lung metastases at 223 clinical trial sites globally. Patients received LEE011 600 mg/daily (three weeks on and one week off), or placebo, in combination with letrozole 2.5 mg/daily. MONALEESA-2 is the only Phase III trial of a CDK4/6 inhibitor in the first-line setting to be stopped early due to superior PFS results, as LEE011 plus letrozole met the primary endpoint at the first efficacy analysis. (NCT01958021)
The MONALEESA-7 trial is investigating LEE011 in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in pre-menopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. Both Phase III trials, MONALEESA-3 and MONALEESA-7 are fully enrolled.
Latest
news: * On December 9, 2016, Novartis announced additional analyses from the Phase III MONALEESA-2 study that show LEE011 (ribociclib) plus letrozole significantly prolonged progression-free survival (PFS) across pre-planned patient subgroups with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer, including post-menopausal women diagnosed de novo, those with visceral liver and lung metastases, and those with bone-only disease. * On October 8, 2016, Novartis announced results from the pivotal Phase III MONALEESA-2 study show LEE011 (ribociclib) plus letrozole significantly extended progression-free survival (PFS) compared to a standard of care, letrozole, as a first-line treatment in postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer (median PFS, 95% CI (19.3 months - not reached) vs. 14.7 months (13.0 - 16.5 months); HR=0.556; p=0.00000329). The data have been presented at the European Society for Medical Oncology (ESMO) 2016 Congress . The results will also be published simultaneously online in The New England Journal of Medicine.
These findings demonstrate the strength of LEE011 plus letrozole in the first-line setting, showing that treatment benefit was evident across all patient subgroups regardless of their disease burden or tumor location, including those patients with aggressive disease. Data have been presented at the San Antonio Breast Cancer Symposium (SABCS) (Abstracts P4-22-05 and P4-22-16).
First-line ribociclib + letrozole in patients with de novo HR+, HER2- advanced breast cancer: A subgroup analysis of the MONALEESA-2 trial (Abstract P4-22-05)
A predefined subgroup analysis of the MONALEESA-2 trial evaluated the safety and efficacy of LEE011 plus letrozole versus letrozole alone in 227 patients with de novo advanced breast cancer, defined as disease found to be metastatic at the time of first diagnosis. Because de novo disease has not been previously treated with systemic treatment for early-stage breast cancer, tumors may exhibit a different disease biology, which could result in varied responses compared to patients who experienced recurrence. In patients with de novo advanced breast cancer, LEE011 plus letrozole reduced the risk of disease progression or death by 55% over letrozole alone (HR=0.448 [95% CI: 0.267-0.750]). The 12-month PFS rate was 82% in the LEE011 plus letrozole arm compared to 66% with letrozole alone.
Consistent with the overall study population, most adverse events were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and reduction. The most common grade 3/4 adverse events (>=15% of patients with de novo advanced breast cancer; LEE011 plus letrozole vs. letrozole alone) were neutropenia (55.3% vs. 0.9%) and leukopenia (21.1% vs. 0%)[1].
First-line ribociclib + letrozole in patients with HR+, HER2- advanced breast cancer presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial (Abstract P4-22-16)
In separate predefined subgroups, 393 patients with advanced breast cancer with visceral metastases and 147 patients with bone-only disease were evaluated as part of the MONALEESA-2 trial. Those with visceral metastases have metastatic growth at the site of the lung or liver, and typically have a poorer prognosis than patients with non-visceral disease. Results of these analyses show that first-line LEE011 plus letrozole was well tolerated and reduced the risk of disease progression or death by 47% (patients with visceral disease: HR=0.535 [95% CI: 0.385-0.742]) and by 31% (patients with bone-only disease: HR=0.690 [95% CI: 0.381-1.249]) respectively. Treatment benefit with LEE011 in combination with letrozole was observed regardless of the number of metastatic sites and (HR=0.607 (95% CI: 0.437-0.845) among patients with less than 3 metastases; HR=0.456 (95% CI: 0.298-0.700) among patients with 3 or more metastases).
Among patients with visceral metastases the most frequent grade 3/4 adverse events (>=20% of patients; LEE011 plus letrozole vs. letrozole alone) were neutropenia (64.0% vs 1%) and leukopenia (20.8% vs 0.5%). Among patients with bone-only disease the most frequent grade 3/4 adverse events (>=20% of patients; LEE011 plus letrozole vs. letrozole alone) were neutropenia (53.6% vs 1.3%) and leukopenia (23.2% vs 1.3%).
The MONALEESA-2 study is ongoing to evaluate secondary endpoints, including overall survival.
The results demonstrate that LEE011 plus letrozole reduced the risk of death or progression by 44% over letrozole alone. The combination significantly improved PFS across all patient subgroups, regardless of disease characteristics or demographics. More than half of women with measurable disease taking LEE011 plus letrozole saw their tumor size shrink by at least 30% (overall response rate (ORR) in patients with measurable disease = 53% vs 37%, p=0.00028).
Most adverse events in the MONALEESA-2 trial were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and reduction. The discontinuation rate due to adverse events in the MONALEESA-2 trial was 7.5% for LEE011 plus letrozole and 2.1% for letrozole alone.
The most common grade 3/4 (most severe) adverse events were as follows for LEE011 plus letrozole compared to letrozole alone: neutropenia (60% vs 1%), leukopenia (21% vs 1%), elevated alanine aminotransferase (9% vs 1%), lymphopenia (7% vs 1%) and elevated aspartate aminotransferase (6% vs 1%). The most common all-grade adverse events (>=35% of patients in either arm, regardless of relationship to study treatment) were as follows for LEE011 plus letrozole compared to letrozole alone: neutropenia (74% vs 5%), nausea (52% vs 29%), infections (50% vs 42%), fatigue (37% vs 30%), and diarrhea (35% vs 22%)[1]. Nausea, infections, fatigue, and diarrhea were mostly grade 1 or 2.
The MONALEESA-2 findings validate the use of a selective CDK4/6 inhibitor in combination with hormonal therapy as initial treatment for HR+/HER2- advanced breast cancer. Due to the significant extension of PFS and clinical benefit seen with LEE011, analysis of the primary endpoint (PFS) in MONALEESA-2 was stopped early in May 2016 as recommended by the Independent Data Monitoring Committee.
