Adjuvant abemaciclib improves outcomes for certain patients with high-risk breast cancer
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Extended follow-up of a randomized phase 3 trial presented at the virtual San Antonio Breast Cancer Symposium showed the addition of abemaciclib to endocrine therapy continued to benefit certain patients with high-risk breast cancer.
The regimen appeared associated with reduced risk for invasive DFS and distant RFS events for patients with hormone receptor-positive, HER2-negative, high-risk early disease, results of the monarchE study showed.
It also led to a significant improvement in invasive DFS among patients with high Ki-67 expression, defined as positivity in at least 20% of tumor cells.
The findings “may mark a notable treatment advance,” according to study author Priya Rastogi, MD, associate professor in the department of medicine at University of Pittsburgh and medical director of National Surgical Adjuvant Breast and Bowel Project Foundation.
“These clinically meaningful results have the potential to change how high-risk, hormone receptor-positive, HER2-negative early breast cancer is treated,” Rastogi said in a press release.
Many patients with hormone receptor-positive early breast cancer do not experience recurrence while on treatment with endocrine therapy alone. However, approximately 20% experience disease recurrence in the first 10 years, frequently in the form of incurable metastatic breast cancer, Rastogi said.
“The risk [for] 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 said. “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.”
Abemaciclib (Verzenio, Eli Lilly) is an oral, continually dosed cyclin-dependent kinase (CDK) 4/6 inhibitor.
In the international, open-label monarchE study, Rastogi and colleagues assessed the addition of abemaciclib to standard adjuvant endocrine therapy for 5,637 men and women with node-positive, hormone receptor-positive, HER2-negative early-stage breast cancer at high risk for relapse.
The study included two cohorts of eligible patients. Cohort 1 included patients with four or more positive axillary lymph nodes, as well as patients with one to three involved nodes who either had grade 3 disease or whose tumors measured at least 5 cm. Cohort 2 included patients with one to three involved axillary lymph nodes plus centrally assessed high Ki-67 expression, defined as positivity in at least 20% of tumor cells.
All patients underwent surgery, as well as radiotherapy and/or chemotherapy as indicated.
The investigators randomly assigned patients to standard adjuvant endocrine therapy alone or with abemaciclib dosed at 150 mg twice daily for 2 years.
Invasive DFS in the intention-to-treat population served as the primary endpoint. Secondary endpoints included invasive DFS among patients with high Ki-67 expression, distant RFS, OS, safety, patient-reported outcomes and pharmacokinetics.
As Healio previously reported, an interim analysis performed after 323 invasive disease-free events — with median follow-up of 15.5 months — showed the addition of abemaciclib to endocrine therapy reduced the risk for invasive disease by about 25% (HR = 0.74; 95% CI, 0.59-0.93). Researchers reported 2-year invasive DFS rates of 92.2% with abemaciclib and 88.7% with endocrine therapy alone.
At the symposium, Rastogi and colleagues presented updated invasive DFS results after 395 disease-free events, based on median follow-up of 19 months.
At data cutoff, 3,281 patients (58.2%) remained in their 2-year treatment period and 1,437 patients (25.5%) had completed it. Median duration of abemaciclib treatment was 17.3 months; median duration of endocrine therapy was comparable between those who received it alone and those who received it with abemaciclib (18.7 months vs. 18.3 months).
Updated results from the intention-to-treat population continued to show improved invasive DFS among abemaciclib-treated patients (HR = 0.71; 95% CI, 0.58-0.87). Two-year invasive DFS rates were 92.3% with abemaciclib and 89.3% with endocrine therapy alone. The benefit persisted across all prespecified subgroups.
Researchers also reported improved distant RFS among abemaciclib-treated patients (HR = 0.68; 95% CI, 0.55-0.85), with 2-year distant RFS rates of 93.8% for abemaciclib plus endocrine therapy and 90.8% for endocrine therapy alone.
Rastogi and colleagues also assessed efficacy among 2,498 patients with centrally assessed high Ki-67 expression, which suggests the presence of a fast-growing aggressive tumor and greater risk for recurrence.
In this subgroup, results showed a statistically significant improvement in invasive DFS (HR = 0.69; 95% CI, 0.51-0.92) and a higher 2-year invasive DFS rate (91.6% vs. 87.1%) with abemaciclib. Researchers also observed an improvement in distant RFS with abemaciclib in this group.
Abemaciclib exhibited a safety profile consistent with the results of the previous interim analysis and the agent’s known safety profile, Rastogi said.
“Most discontinuations due to adverse events occurred within the first 5 months of study treatment, and most patients who required a dose hold or reduction were able to remain on study treatment,” Rastogi said during her presentation.
OS data remained immature at data cutoff, and the study will continue until those final assessments are conducted.
Perspective
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C. Kent Osborne, MD
The additional 4 months of follow-up of this important trial — now out to about 19 months — continues to show improved invasive DFS with the addition of abemaciclib to standard endocrine therapy in a very high-risk group of patients with hormone receptor-positive breast cancer.
These results are very encouraging, especially in the subgroup of patients who have tumors with high proliferation.
However, caution in the interpretation is needed given the still rather short follow-up; the fact ER-positive disease is known for its persistent recurrence rate, even past 10 years; and 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 DFS curves come together when the drug is stopped? With these caveats in mind, this is still an extremely important trial that could be practice-changing in this very high-risk patient population with ER-positive, HER2-negative breast cancer if the results continue to be positive and show improved OS with longer follow-up.
Baylor College of Medicine
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O’Shaughnessy JA, et al. Abstract GS1-01. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
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