Breast cancer is the most common cancer among women worldwide. Approximately 90% of patients diagnosed with breast cancer are diagnosed with early breast cancer and 70% of these patients have hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−) early breast cancer.
HR+, HER2- breast cancer, the most common subtype, is a complex disease, and many factors – such as if cancer has metastasized to the lymph nodes and the biology of the tumor – can impact the risk of recurrence.
Most of these patients may not experience recurrence or have a distant recurrence which can be treated with currently available standard therapies. However, in contrast, a minority of approximately 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence. 
To meet the unmet medical needs of these patients, and to prevent early recurrence and development of metastases for this group of patients, new superior treatment options are needed.
The open-label, randomized phase III monarchE trial, sponsored by Eli Lilly and Co., investigated the addition of abemaciclib (Verzenio®; Eli Lilly and Co.), a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with standard-of-care adjuvant endocrine therapy for the treatment of HR+, HER2− advanced breast cancer.
Participating patients were randomized 1:1 to abemaciclib (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 the criteria for discontinuation. After the treatment period, all patients will continue on endocrine therapy for five to 10 years, as clinically indicated.
The results of the monarchE study demonstrated that abemaciclib added to standard adjuvant standard-of-care adjuvant endocrine therapy significantly improved the primary end point was invasive disease-free survival (IDFS), the primary end point of the study, in women and men with HR+, HER2−, node-positive early breast cancer at high risk of early recurrence.
Updated data of the monarchE trial, presented at the 2020 San Antonio Breast Cancer Symposium (SABCS), held December 8-11, 2020, shows that abemaciclib continues to improve invasive disease-free survival among patients with high-risk, HR+, HER2-, early-stage breast cancer.
“While many patients with HR-positive early breast cancer will not experience recurrence on endocrine therapy alone, approximately 20% may experience disease recurrence in the first 10 years, often in the form of incurable metastatic breast cancer,” noted 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.
“The risk of recurrence is higher among patients whose cancer has certain clinical and/or pathological risk factors such as a high number of positive lymph nodes, large tumor size, or a high cellular proliferation as measured by tumor grade or biomarkers,” Rastogi continued.
“There is a significant unmet need for this patient population, and research must be done to find new treatment options to help prevent early breast cancer from returning for these patients,” she added.
Earlier results from an interim analysis of the monarchE trial, which is comparing abemaciclib plus adjuvant endocrine therapy with endocrine therapy alone in 5,637 patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer, have been previously reported.
After a median follow-up of 15.5 months and 323 invasive disease-free events, it was found that the addition of abemaciclib to endocrine therapy reduced the risk of invasive disease by 25%. The two-year IDFS rates in the combination arm and the endocrine therapy alone arm were 92.2% and 88.7%, respectively.
The current study describes an extended follow-up of this trial, capturing results from 395 invasive disease-free events with a median follow-up time of 19 months.
Following surgery, and radiotherapy and/or chemotherapy as indicated, patients were randomly assigned to receive standard of care adjuvant endocrine therapy with or without abemaciclib (150 mg twice per day for two years).
Patients were eligible to be included if they had at least four positive nodes, or had one to three positive nodes in combination with either grade 3 disease, a tumor of at least 5 cm, or centrally assessed high Ki-67 status (where “high” is defined as at least 20% positivity in tumor cells). Higher levels of Ki-67 protein are indicative of a fast-growing, aggressive tumor with an increased probability of recurrence.
At the time of this analysis, 1,437 patients (25.5%) had completed the two-year treatment period and 3,281 patients (58.2%) were in the two-year treatment period. Compared with patients who received endocrine therapy alone, those who also received abemaciclib had a 28.7 percent reduced risk of invasive disease (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% in the abemaciclib arm and 89.3% in the control arm).
In addition, the researchers observed an improvement in the two-year distant relapse-free survival (DRFS) rate among patients who received the combinatorial treatment compared with those who received endocrine therapy alone (93.8% versus 90.8%, respectively).
“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,” explained 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,” she added.
The researchers also evaluated outcomes among 2,498 patients with centrally assessed high Ki-67 status. Among patients in this cohort and whose tumors had high Ki-67 (≥20%), abemaciclib in combination with endocrine therapy, also significantly decreased the risk of breast cancer. These patients had a 30.9% decreased risk of invasive disease compared with those who received endocrine therapy alone (HR: 0.691; 95% CI: 0.519, 0.920). The two-year IDFS rates in the combination arm and the endocrine therapy alone arm were 91.6% and 87.1%, respectively.
According to the investigators, 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.
“Across the spectrum of data for abemaciclib, we have observed a consistent benefit, in all subgroups,” said Rastogi.
Safety data from this trial were consistent with the known safety profile of abemaciclib and no new safety signals were observed.
“These results may mark a notable treatment advance in the last two decades for people living with high-risk, node-positive, HR-positive, HER2-negative early breast cancer,” Priya Rastogi continued.
“These clinically meaningful results have the potential to change how high-risk, HR-positive, HER2-negative early breast cancer is treated,” she concluded.
Rastogi noted that overall survival data are immature at this time, and additional follow-up is warranted.
Endocrine Therapy With or Without Abemaciclib (LY2835219) Following Surgery in Participants With Breast Cancer (monarchE) – NCT03155997
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Featured image: 42nd San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo Courtesy: © 2019 AACR/Todd Buchanan. used with permission.