Adding the oral cyclin-dependent kinase (CDK)4/CDK6 inhibitor abemaciclib (Verzenio) to endocrine therapy led to a significant reduction in the risk for invasive disease recurrence versus endocrine therapy alone in patients with high-risk hormone receptor (HR)-positive, HER2-negative early-stage breast cancer, according to findings from the phase 3 monarchE clinical trial. The results were presented at the European Society for Medical Oncology (ESMO) virtual Congress 2020 and were featured at the meeting press conference.
Experts at the ESMO press conference predicted that this would be a practice-changing study. The study results were published online to coincide with this presentation (Johnston SRD, et al. J Clin Oncol. 2020 Sep 20).
Abemaciclib reduced the risk for invasive recurrence by 25.3% compared with endocrine therapy alone (P = .0096). In addition, the 2-year invasive disease-free survival (DFS) rates were 92.2% with abemaciclib versus 88.7% with endocrine therapy alone, for an absolute improvement of 3.5%.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead author Stephen R.D. Johnston, MD, MA, PhD, FRCP, Head, Breast Unit, Royal Marsden Hospital NHS Foundation Trust, London, England.
HR-positive, HER2-negative breast cancer is the most common form of breast cancer, affecting 70% of patients. The majority of patients are diagnosed with early disease, and although many patients are cured with surgery, radiotherapy, chemotherapy, and hormone therapy, “about 20% have high-risk disease and will develop a recurrence either locally in the breast or elsewhere in the body over the first 10 years of treatment,” Dr Johnston emphasized.
For patients with high-risk HR-positive, HER2-negative breast cancer, the risk for recurrence is even greater, especially during the first few years on adjuvant endocrine therapy.
Abemaciclib is FDA approved for patients with HR-positive, HER2-negative advanced breast cancer in combination with endocrine therapy. Based on the overall survival advantage abemaciclib has shown in combination with fulvestrant (Faslodex) in the metastatic setting, the monarchE study evaluated abemaciclib in combination with endocrine therapy earlier in the disease course as adjuvant therapy.
“These patients with high-risk early breast cancer show a degree of resistance to hormone therapy, relapsing early, despite everything we currently give them,” Dr Johnston said. “CDK4/6 inhibitors, such as abemaciclib, have transformed the way we treat metastatic breast cancer over the last few years, overcoming primary endocrine resistance and improving survival. So, it was an obvious step to see whether adding abemaciclib to hormone treatment in patients with high-risk early breast cancer could reduce the risk of their cancer returning.”
MonarchE was an international phase 3 clinical trial that enrolled 5637 patients with pre- and postmenopausal high-risk HR-positive, HER2-negative early breast cancer. Patients were eligible for the study if they received previous neoadjuvant and adjuvant chemotherapy. Distant metastases were an exclusion criterion.
For purposes of the study, high-risk disease was defined as having ≥4 positive axillary lymph nodes or 1 to 3 axillary lymph nodes and ≥1 of several disease characteristics, including tumor size ≥5 cm, histologic grade 3 disease, and centrally tested Ki67 of ≥20%.
After completing primary therapy, patients were randomized in a 1:1 ratio to 150 mg abemaciclib twice daily, for up to 2 years, plus 5 years to 10 years of endocrine therapy (N = 2808), as clinically indicated, or to endocrine therapy alone (N = 2829). Patient stratification factors were previous chemotherapy, menopausal status, and region.
Additional results demonstrated that the addition of abemaciclib to endocrine therapy also had a significant impact on distant relapse-free survival (RFS) across all prespecified subgroups, reducing the risk for distant recurrence by 28.3% (P = .0085). The 2-year distant RFS rates were 93.6% with abemaciclib versus 90.3% with endocrine therapy alone.
A total of 92 patients who received abemaciclib had distant disease recurrence versus 142 who received endocrine therapy alone. The greatest reduction in sites of metastatic disease with abemaciclib was seen in bone and liver, followed by the brain, lymph nodes, pleura, and central nervous system.
The safety outcomes of abemaciclib therapy were consistent with the known profile of the drug. A total of 463 (16.6%) patients discontinued abemaciclib therapy because of adverse effects; of these, 306 patients continued with endocrine therapy.
The most common reason for treatment discontinuation was diarrhea (5%), which was manageable with antidiarrheals and dose adjustments. Notably, the study protocol allowed for dose reduction from 150 mg to 100 mg twice daily, if necessary.
“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” said Giuseppe Curigliano, MD, PhD, Associate Professor of Medical Oncology, University of Milan, Italy, and Chair of the ESMO Guidelines Committee, who commented on the study results.
“This is the first study to show that adding a CDK4/6 inhibitor to endocrine therapy significantly improves invasive DFS in the adjuvant setting,” Dr Curigliano stated.
“This is a very important trial, and the findings will change practice. Once approved for high-risk HR-positive, HER2-negative early breast cancer, the new standard of care for these patients will be to add 2 years of abemaciclib to endocrine therapy,” he added.
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