In an extended analysis of the phase 3 monarchE study, adding the cyclin-dependent kinase (CDK) inhibitor abemaciclib to standard adjuvant endocrine therapy continued to improve invasive disease-free survival (IDFS) among patients with high-risk, node-positive, early-stage, hormone receptor (HR)-positive, HER2-negative breast cancer. Physician’s Weekly interviews lead study author Priya Rastogi, MD, a medical oncologist at the University of Pittsburgh, Pennsylvania, and medical director of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, who presented these results during the 2020 San Antonio Breast Cancer Symposium [1].

At the pre-planned interim analysis, 19 month follow-up data from the phase 3, open-label study evaluating abemaciclib combined with endocrine therapy compared to endocrine therapy alone in 5,637 patients with node-positive, HR+, HER2-, high risk early breast cancer (EBC) confirmed and improved the statistically significant benefit in invasive disease-free survival.

Earlier results from the monarchE trial (NCT03155997), with a median follow-up of 15.5 months, were presented at ESMO 2020. After 323 invasive disease-free events at that time, 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 where indicated, patients were randomly assigned to receive standard of care adjuvant endocrine therapy with or without abemaciclib (150 mg twice per day for 2 years). Eligibility criteria included having at least 4 positive nodes, or having 1-3 positive nodes in combination with either grade 3 disease, a tumor of at least 5 cm, or centrally assessed high Ki-67 status (the researchers defined “high” as at least 20% positivity in tumor cells). At the time of this analysis, 1,437 patients (25.5%) had completed the 2-year treatment period and 3,281 patients (58.2%) were in the 2-year treatment period. Compared with patients who received endocrine therapy alone, those who also received abemaciclib had a 28.7% reduced risk of developing invasive disease (HR 0.713; 95% CI 0.583-0.871; P=0.0009;).

There was also 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). Of the 2,498 patients with centrally assessed high Ki-67 status, those who received the combination treatment 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; P=0.0111). The 2-year IDFS rates in the combination arm and the endocrine therapy alone arm were 91.6% and 87.1%, respectively. Safety data from this trial were consistent with the known safety profile of abemaciclib and no new safety signals were observed. additional follow-up is warranted. Overall survival was immature at the current time of analysis.

Physician’s Weekly asked Dr. Rastogi for her perspectives:

What were the key take-home messages from the updated monarchE results? What were the most important safety signals?

“The monarchE trial was for patients with hormone receptor positive, HER2-negative, node-positive, early breast cancer. This was a high risk patient population, so patients had to have 4 or more positive nodes or at least 3 nodes and histological grade 3 disease, or tumor size of at least 5 centimeters. We also included patients with 1 to 3 positive nodes who also had a tumor of at least 20% cells positive for proliferation marker Ki-67. So following surgery, chemotherapy, radiotherapy, if indicated, patients were then randomized to abemaciclib with endocrine therapy or endocrine therapy alone.

What was really striking with this study, is that patients who received abemaciclib with endocrine therapy had a 28.7% reduction in the risk of developing invasive disease. There was also a 31.3% reduction in developing metastatic disease. Furthermore, in the patients whose tumors stained at least 20% for Ki-67, there also was a reduction in the IDFS of 30.9%. These results may mark a notable treatment advance in the last 2 decades for people living with high-risk, node-positive, HR-positive, HER2-negativeearly breast cancer. These clinically meaningful results have the potential to change how high-risk, HR-positive, HER2-negativeearly breast cancer is treated. In terms of safety, the safety profile was consistent with what is known with abemaciclib, so that includes diarrhea, leukopenia, and neutropenia, mostly at grade 1-2. It is very well tolerated, overall.”

Will the improved DFS translate into improved overall survival do you think?

“I think is really interesting that the hazard ratios continue to improve for IDFS. So from 0.74 which we reported at ESMO last September, to 0.713 now at SABCS. This equates to roughly 25% benefit at ESMO to a 28.7% reduction for IDFS now. The study will be ongoing and we are following patients for up to 10 years, continuing to look at both efficacy and overall survival.”

What is the context with the PALLAS (NCT02513394) and Penelope-B (NCT01864746) trials?

“It is very difficult to answer that question because all three trials were different, with different duration, different patient populations, as well as the different properties of each drug. We are just excited about the monarchE positive results for IDFS. The other trials did not show positive data, but comparing across trials is complex.”

What will be the optimal duration of therapy?

‘’In monarchE, we based the choice of a 2 year duration on the historical data from the ATAC trial (NCT00849030). At the time that monarchE was being developed, we had seen from ATAC that there was a high risk of recurrence about 2 years after starting endocrine therapy, similar to what we had seen from NSABP data. We can deduct from these data collectively that the patients are at the highest risk for recurrence in those first few years after initiating therapy. Our hypothesis was, when we were developing monarchE, that we wanted to treat through the first peak of recurrence. Also, there was a pragmatic aspect, that we are adding a drug to endocrine therapy after patients have finished chemotherapy, radiation therapy, and surgery, and thus 2 years seemed to be a decent amount of time for a patient to take a new drug on top of 5 to 10 years of endocrine therapy. We will continue to follow these patients, and we will see what occurs. ”

Tumors positive for cellular proliferation markers were predictive?

“The patient population that we looked at was the node-positive, the histological grade 3 disease, large tumor size, as well as the centrally tested tumors at least 20% positive for Ki-67 staining. So it is very interesting data and with the Ki-67 of at least 20% for cohort 1 and 2, there was that 30.9% reduction in IDFS. We are really excited about that outcome; we wanted to look at both high risk features from a clinical and pathological standpoint, for example for cellular proliferation in tumors stratified by a Ki-67 positive count of at least 20%.”

Next steps?

“It is exciting to see that in early stage breast cancer, where there is a significant unmet need, that these results were very notable and promising in the adjuvant setting. We will continue to follow these patients for at least 10 years.”

1. O’Shaughnessy J et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Abstract GS1-01.