Abemaciclib, Standard Endocrine Therapy Show Continued Lower Risk in iDFS in High-Risk Early HR+ Breast Cancer


Treatment with abemaciclib and standard endocrine therapy reduced the risk of invasive disease recurrence or death in patients with high-risk, early hormone receptor–positive, HER2-negative breast cancer.

Treatment with abemaciclib (Verzenio) and standard endocrine therapy reduced the risk of invasive disease recurrence or death by 28.7%, compared with endocrine therapy alone, in patients with high-risk, early hormone receptor–positive, HER2-negative breast cancer, according to findings from a primary outcome analysis of the phase 3 monarchE trial that were presented during the 2020 San Antonio Breast Cancer Symposium.1,2

Specifically, results showed that, with 395 events and a median follow-up of 19.0 months, the invasive disease-free survival (iDFS) benefit was found to be statistically significant and clinically meaningful (HR, 0.713; 95% CI, 0.583-0.871; 2-sided P = .0009). The 2-year iDFS rates were 92.3% and 89.3% with abemaciclib and endocrine therapy alone, respectively, translating to a 3.0% difference.

“Abemaciclib combined with standard endocrine therapy continued to demonstrate a reduction in the risk of developing iDFS and distant relapse-free survival events for patients with hormone receptor–positive, HER2-negative, high-risk early breast cancer, and resulted in a statistically significant improvement in iDFS in patients with high Ki-67 tumors,” senior study author Priya Rastogi, MD, associate professor of medicine at the University of Pittsburgh School of Medicine, said in a press briefing ahead of the virtual meeting. “Abemaciclib in combination with endocrine therapy is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for [this patient population].”

Abemaciclib is an oral, continuously dosed CDK4/6 inhibitor that is currently approved by the FDA for the treatment of patients with hormone receptor–positive/HER2-negative advanced or metastatic breast cancer in combination with a nonsteroidal, fulvestrant, or as monotherapy.

In the monarchE trial, patients with hormone receptor–positive/HER2-negative, node-positive, high-risk early breast cancer were enrolled onto 1 of 2 cohorts: 1 was based on clinicopathological risk factors, which included 4 or more positive axillary lymph nodes (ALN) or 1 to 3 ALNs and at least a grade 3 histology or a tumor size 5 cm or larger; the second cohort was based on Ki-67 status and comprised patients with 1 to 3 ALNs, a centrally tested Ki-67 index of 20% or higher, no grade 3 histology, and a tumor size below 5 cm. The intent-to-treat (ITT) population (n = 5637) included patients in both cohorts.

All patients were randomized 1:1 to receive standard endocrine therapy for 5 to 10 years as clinically indicated alone or with abemaciclib at 150 mg twice daily for up to 2 years. Patients were stratified based on prior chemotherapy, menopausal status, and region.

The primary end point of the trial was iDFS based on Standardized Definitions for Efficacy End Points criteria and secondary outcome measures included iDFS in the Ki-67–high (≥20%) population (n = 2498), distant relapse-free survival (DRFS), overall survival (OS), safety, patient-reported outcomes, and pharmacokinetics.

Data from an earlier interim analysis, which were presented during the 2020 ESMO Virtual Congress, showed that at a median follow-up of 15.5 months, 323 invasive disease-free events occurred. Results showed that abemaciclib reduced the risk of invasive disease by 25.3% versus endocrine therapy alone (HR, 0.747; 95% CI, 0.598-0.932; 2-sided P = .0096).3 Additionally, the 2-year iDFS rates were 92.2% in the abemaciclib arm versus 88.7% in the endocrine-alone arm, reflecting an absolute improvement of 3.5%.

Ki-67 was evaluated in all patients in cohorts 1 and 2 with suitable untreated breast tissue.

Additional findings at the primary outcome analysis showed that, in the Ki-67–high population, the risk of developing an iDFS event was reduced by 30.9% with abemaciclib (HR, 0.691; 95% CI, 0.519-0.920; 2-sided P = .0111), which was found to be statistically significant and clinically meaningful in this subgroup. The 2-year iDFS rates were 91.6% with abemaciclib and 87.1% with endocrine therapy alone, which translated to a 4.5% difference.

When evaluating for DRFS in the ITT population, results showed that abemaciclib reduced the risk of DRFS by 31.3% versus endocrine therapy (HR, 0.687; 95% CI, 0.551-0.858; 2-sided P = .0009), which was a clinically meaningful benefit. The 2-year DRFS rates were 93.8% and 90.8%, which was a 3.0% difference favoring abemaciclib.

The safety data of the abemaciclib regimen is consistent with the findings reported in the second interim analysis and the known tolerability profile of the CDK4/6 inhibitor. Most discontinuations, due to adverse effects (AEs), occurred within the first 5 months of study treatment. Additionally, most patients who required dose holds or reductions could remain on therapy.

At this analysis, the most common AEs were diarrhea, fatigue, and neutropenia, according to Rastogi. Rare AEs included interstitial lung disease and venous thromboembolism, she added.

At the earlier interim analysis presented at ESMO Virtual Congress 2020, 463 patients (16.6%) discontinued abemaciclib due to AEs; 306 of these patients continued on endocrine therapy. The most common reason for discontinuation was diarrhea (5%), which was managed with antidiarrheals and dose adjustments. Dose reductions from 150 mg to 100 mg twice daily were permitted if necessary.

C. Kent Osborne, MD, professor in the Department of Medicine, Hematology Oncology, breast medical oncologist at Baylor St. Luke's Medical Center, the Dudley and Tina Sharp Chair for Cancer Research, Baylor College of Medicine, and founding director of the Dan L Duncan Comprehensive Cancer Center, provided commentary on the phase 3 findings.

“The additional 4 months follow-up of this trial […] continues to show improved invasive disease-free survival for the addition of abemaciclib to standard endocrine therapy in a very high-risk group of patients with hormone receptor–positive breast cancer. I think these results are very encouraging, especially in the subgroup of tumors with high proliferation,” Osborne said. “Caution in these data is needed, given the still rather short follow-up and estrogen receptor–positive disease is known for its persistent recurrence rate, even past 10 years, and given that this class of inhibitors is largely cytostatic rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells. An important question remains: Will the invasive disease-free survival curves come together when the drug is stopped? With these caveats in mind, this is still a very important trial.”

The monarchE trial is ongoing until the final assessment for OS; all patients will be followed for 10 years, Rastogi concluded.


1. O’Shaughnessy J, Johnston SRD, Harbeck N, 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.

2. Updated monarchE trial data shows abemaciclib continues to benefit patients with high-risk, HR-positive, HER2-negative, early-stage breast cancer. News release. San Antonio Breast Cancer Symposium. December 9, 2020. Accessed December 9, 2020.

3. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high risk, early breast cancer (monarchE). Ann Oncol. 2020;31(4):S1143-S1144. Abstract: LBA5_PR. doi:10.1016/j.annonc.2020.08.2238

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