Novartis LEE011 (ribociclib) plus letrozole analyses show superior PFS across broad spectrum of patients in first-line HR+/HER2- advanced breast cancer versus letrozolev

• LEE011 plus letrozole reduced risk of progression or death by 55% over letrozole alone in de novopatients, and by 54% in patients with three or more metastases – the most aggressive form of the disease
   
• Consistent with overall study population, most adverse events were mild to moderate, identified early through routine monitoring, and generally managed through dose interruption and reduction
   
• FDA granted LEE011 Breakthrough Therapy designation and Priority Review, which may lead to faster access for US patients

By: Novartis News

December 10, 2016

Novartis announced today 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[1],[2].

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 will be presented today at the San Antonio Breast Cancer Symposium (SABCS) (Abstracts P4-22-05 and P4-22-16).

“Results from the de novo subgroup of women in the MONALEESA-2 trial establish ribociclib in combination with letrozole as a meaningful treatment option in the first-line setting for this patient population,” said Joyce O’Shaughnessy, MD, Co-Chair, Breast Cancer Research, Texas Oncology-Baylor Charles A. Sammons Cancer Center. “These de novo patients are often diagnosed initially with advanced breast cancer that has already metastasized, so it is critical to start them with treatments that extend time until disease progression.”

“Breast cancer that has metastasized to areas such as the liver or lungs can often be more challenging to effectively treat with current standards of care,” said Howard A. Burris, MD, President, Clinical Operations and Chief Medical Officer, Sarah Cannon. “We have been encouraged by the MONALEESA-2 results because treatment benefit was observed regardless of the number of metastatic sites and was maintained across all subgroups taking ribociclib plus letrozole. Our observations indicate that this novel therapy may be a promising treatment option for many patients living with advanced forms of breast cancer.”

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[1]. 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[1]. 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])[1]. 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[1]. 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[2]. 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[2]. 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)[2].

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%)[2]. 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%)[2].

“These additional results from the MONALEESA-2 study are very promising for women with HR+ advanced breast cancer,” said Bruno Strigini, CEO, Novartis Oncology. “We believe LEE011 could significantly benefit a broad range of women as an initial treatment for metastatic breast cancer and look forward to working with global health authorities to bring this new treatment to patients.”

The MONALEESA-2 study is ongoing to evaluate secondary endpoints, including overall survival. LEE011 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA) in August 2016 and Priority Review in October 2016.

About LEE011 (ribociclib)
LEE011 (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 in a cell, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring cancer cells do not grow uncontrollably.

LEE011 is not approved for any indication in any market at this time. LEE011 was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the MONALEESA Clinical Trial Program
Novartis is continuing to assess LEE011 through the robust MONALEESA (Mammary ONcology Assessment of LEE011’s Efficacy and SAfety) clinical trial program, which 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-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[3].

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[3]. Patients received LEE011 600 mg/daily (three weeks on and one week off), or placebo, in combination with letrozole 2.5 mg/daily.

The primary endpoint of the trial was PFS[3]. Secondary endpoints included: overall survival, overall response rate, clinical benefit rate, health-related quality of life, safety and tolerability[3].

In MONALEESA-2, 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%)[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[1].

The MONALEESA-3 trial is a phase III trial 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-7, the largest phase III trial of a CDK4/6 inhibitor in this patient population, 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 MONALEESA-3 and MONALEESA-7 are fully enrolled.

References
[1] O’Shaughnessy J. First-line ribociclib + letrozole in patients with de novo HR+, HER2- advanced breast cancer: A subgroup analysis of the MONALEESA-2 trial. Presented at San Antonio Breast Cancer Symposium (SABCS), December 9, 2016, San Antonio, Texas (abstract # P4-22-05)
[2] Burris H. 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. Presented at San Antonio Breast Cancer Symposium (SABCS), December 9, 2016, San Antonio, Texas (abstract # P4-22-16)
[3] Hortobagyi G, Stemmer S, Burris H, et al. First-line ribociclib plus letrozole for postmenopausal women with HR+, HER2-, advanced breast cancer: First results from the Phase III MONALEESA-2 study. Presented at the European Society for Medical Oncology (ESMO) Congress, October 8, 2016, Copenhagen, Denmark (abstract # LBA1_PR)
[4] O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. The Oncologist. 2005;10(Suppl 3):20-29.
[5] American Cancer Society. How do you determine the stage of breast cancer? Available at http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-staging(link is external). Accessed May 10, 2016.
[6] American Cancer Society. Breast cancer survival rates, by stage. Available at http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-survival-by-stage(link is external). Accessed July 7, 2016.
[7] Novartis Data on File

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