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INDIANAPOLIS, Dec. 9, 2020 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced additional data from a pre-planned primary outcome analysis from the Phase 3 monarchE trial that showed Verzenio® (abemaciclib) in combination with standard adjuvant endocrine therapy (ET) decreased the risk of breast cancer recurrence by 28.7 percent compared to standard adjuvant ET alone for people with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high risk early breast cancer (HR: 0.713; 95% CI: 0.583, 0.871; p = 0.0009). This statistically significant improvement corresponds to a three percent difference in the two-year rate of invasive disease-free survival (IDFS) between arms (92.3 percent in the Verzenio arm and 89.3 percent in the control arm). The data presented today during the 2020 Virtual San Antonio Breast Cancer Symposium (SABCS) included an additional 3.6 months of follow-up since the pre-planned interim analysis results announced in September 2020, and more than 1,400 patients have completed two years of treatment since the start of the study.
The timing of the primary outcome analysis was driven by the number of IDFS events observed in the intent-to-treat population across both arms as prespecified in the study's statistical analysis plan. The statistically significant benefit observed was consistent across all pre-specified subgroups. The median follow up was approximately 19.1 months.
The addition of Verzenio to ET also resulted in an improvement in distant relapse-free survival (DRFS), or time to developing breast cancer that has spread to other parts of the body. The combination reduced the risk of developing metastatic disease by 31.3 percent compared to 28.3 percent at interim analysis (HR: 0.687; 95% CI: 0.551, 0.858). Safety data from monarchE were consistent with the known safety profile of Verzenio and no new safety signals were observed. Compared to the interim analysis results, there were minimal increases in adverse events.
"As the monarchE data have matured, we have seen an improvement in the reduction of risk of recurrence for people with HR+, HER2- high risk early breast cancer," said Priya Rastogi, M.D., associate professor at the University of Pittsburgh School of Medicine, medical oncologist at UPMC Hillman Cancer Center and medical director of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation. "With more than 1,400 patients completing two years of treatment, we are pleased to see the curves continue to separate, as reflected by the numerically greater hazard ratio estimates for both invasive disease-free survival and distant relapse-free survival in the primary outcome analysis."
monarchE randomized 5,637 patients with HR+, HER2- high risk early breast cancer from more than 600 sites in 38 countries. High risk was defined by cancer that spread to the lymph nodes, a large tumor size, or high cellular proliferation (as determined by tumor grade or Ki-67 index). Patients were treated for two years (treatment period) or until meeting criteria for discontinuation. After the treatment period, all patients will continue ET for five to 10 years, as clinically indicated.
"The monarchE primary outcome data builds on the significance of the results of the interim analysis with a 28.7 percent reduction in the risk of recurrence for patients with HR+, HER2-, high risk early breast cancer," said Maura Dickler, M.D., vice president, late phase development, Lilly Oncology. "We are extremely pleased that these results continue to be strong and reinforce Verzenio as the only CDK4 & 6 inhibitor with positive results in the early breast cancer setting. We thank all those who participated in the trial and we are committed to making Verzenio available for these patients as quickly as possible."
A key secondary analysis evaluated the IDFS treatment benefit of patients enrolled in monarchE based on Ki-67 index. In patients whose tumors had high Ki-67 (≥20%), Verzenio with ET also significantly decreased the risk of breast cancer recurrence by 30.9 percent, compared to those who received ET alone (HR: 0.691; 95% CI: 0.519, 0.920). Ki-67 is a biomarker of high cell proliferation and increased risk of recurrence. This is the first time a prespecified threshold of ≥20% for Ki-67 has been used to prospectively evaluate the utility of central Ki-67 using a standardized assay in a phase III registration trial. These results suggest that Ki-67 ≥20% could be used together with clinicopathological features of nodal involvement, tumor size, and grade, to identify patients with HR+, HER2-, early breast cancer at high risk of recurrence.
All patients on monarchE will continue to be followed to assess overall survival and other endpoints. Lilly will submit the monarchE data to regulatory authorities before the end of 2020.
About the monarchE Study monarchE is a Phase 3, multicenter, randomized, open-label trial that enrolled 5,637 patients with HR+, HER2- node-positive, high risk early breast cancer. Patients were randomized 1:1 to Verzenio (150 mg twice daily) plus standard adjuvant endocrine therapy or standard adjuvant endocrine therapy alone. Patients were treated for two years (treatment period) or until meeting criteria for discontinuation. After the treatment period, all patients will continue on endocrine therapy for five to 10 years, as clinically indicated. The primary objective is invasive disease-free survival (IDFS) defined according to the Standard Definitions for Efficacy Endpoints (STEEP) criteria. In adjuvant breast cancer trials, this includes the length of time before any cancer comes back, a new cancer develops or death. Secondary objectives include distant relapse-free survival, overall survival, safety, pharmacokinetics and health outcomes.
High risk was specifically defined as women (any menopausal status) and men with resected HR+, HER2- invasive early breast cancer with either ≥4 pathologically positive axillary lymph nodes (ALNs) or 1 to 3 positive ALNs and at least one of the following high-risk features: primary invasive tumor size ≥5 cm, histological grade 3 tumor, or central Ki-67 index ≥20%. If applicable, patients must have also completed adjuvant chemotherapy and radiotherapy prior to enrolling and have recovered from all acute side effects.
About Early Breast Cancer Breast cancer is the most common cancer among women worldwide.1 An estimated 90% of all breast cancer is diagnosed at an early stage.2 Approximately 70% of all breast cancers are HR+, HER2-, the most common subtype.3 Even within this subtype, HR+, HER2- breast cancer is a complex disease, and many factors – such as if the cancer has spread to the lymph nodes and the biology of the tumor – can impact the risk of recurrence. Approximately 30% of people diagnosed with HR+ early breast cancer are at risk of their cancer returning, potentially to incurable metastatic disease.4
About Verzenio® (abemaciclib) Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.
In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.
Verzenio is Lilly's first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.
INDICATION Verzenio is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:
IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib)
Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.
Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.
Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.
Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.
Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
Febrile neutropenia has been reported in
