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The addition of adjuvant abemaciclib to endocrine therapy resulted in a clinically meaningful reduction in the risk of developing invasive disease, particularly incurable distant metastatic disease, in patients with high-risk, hormone receptor–positive, HER2-negative, early breast cancer who comprised cohort 1 of the phase 3 monarchE trial.
The addition of adjuvant abemaciclib (Verzenio) to endocrine therapy resulted in a clinically meaningful reduction in the risk of developing invasive disease, particularly incurable distant metastatic disease, in patients with high-risk, hormone receptor–positive, HER2-negative, early breast cancer who comprised cohort 1 of the phase 3 monarchE trial (NCT03155997).1
The data from cohort 1, which were presented during the 2022 ESMO Breast Cancer Congress, showed that abemaciclib plus endocrine therapy (n = 2555) improved invasive disease-free survival (iDFS) vs endocrine therapy alone (n = 2565), with 218 and 318 events reported, respectively; this translated to a relative risk reduction of 32% (hazard ratio [HR], 0.680; 95% CI, 0.572-0.808; nominal P < .0001). The 3-year iDFS rate in the investigative arm was 88.6% vs 82.9% in the control arm, translating to an absolute risk reduction of 5.7% with abemaciclib.
Moreover, the addition of abemaciclib to endocrine therapy also resulted in a clinically meaningful improvement in distant relapse-free survival (DRFS) vs endocrine therapy alone in this cohort of patients, with 179 and 266 events reported, respectively, equating to a relative risk reduction of 33% (HR, 0.669; 95% CI, 0.554-0.809; nominal P < .0001). The 3-year DRFS rates in the investigative and control arms were 90.2% and 85.7%, respectively, translating to an absolute risk reduction of 4.5% with the addition of abemaciclib.
“Consistent with the intent-to-treat [ITT] population [of the monarchE trial], cohort 1 demonstrated robust efficacy results,” Mattea Reinisch, MD, of Kliniken Essen-Mitte, Essen, Germany, said in a presentation on the data. “The benefit of abemaciclib combined with endocrine therapy in patients with hormone receptor–positive, HER2-negative breast cancer at a high risk of recurrence is predominantly driven by cohort 1. These data represent the first major advance in the treatment of this early breast cancer subtype in almost 2 decades.”
The trial enrolled patients who were at least 18 years of age and who had hormone receptor–positive, HER2-negative disease.2 Those in cohort 1 (n = 5120) were high risk, which was defined as having 4 or more positive axillary lymph nodes or 1 to 3 positive axillary lymph nodes and at least 1 of the following: a tumor that was 5 cm or larger or histologic grade 3 disease.
Patients who had high-risk disease based on Ki-67 were enrolled to cohort 2 (n = 517). Specifically, these patients had 1 to 3 axillary lymph nodes and Ki-67 of 20% or higher and a tumor size that was smaller than 5 cm; this subset did not have grade 3 disease. Cohorts 1 and 2 comprised the ITT population.
Study participants (n = 5637) were randomized 1:1 to receive abemaciclib at a twice-daily dose of 150 mg in combination with endocrine therapy or endocrine therapy alone. Patients received study treatment for 2 years and then entered a follow-up period of 3 to 8 years, where they received only endocrine therapy.
Stratification factors included prior chemotherapy (neoadjuvant, adjuvant, or none), menopausal status (as determined at diagnosis), and region (North America/Europe, Asia, or other). The primary end point of the trial was iDFS, and secondary end points comprised iDFS in the high Ki-67 population, DRFS, overall survival (OS), safety, pharmacokinetics, and patient-reported outcomes.
In October 2021, the FDA approved abemaciclib in combination with endocrine therapy for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-positive, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of 20% or higher based on earlier data from monarchE.3
Among those in cohort 1 who had a Ki-67 score of 20% or higher (n = 2003), 104 patients who received abemaciclib plus endocrine therapy (n = 1017) experienced an iDFS event vs 158 of those who received endocrine therapy alone (n = 986; HR, 0.626; 95% CI, 0.488-0.803; P = .0042). The iDFS rate at 3 years in the investigative and control arms were 86.1% (95% CI, 82.8%-88.8%) and 79.0% (95% CI, 75.3%-82.3%), respectively.3,4
Moreover, at a median follow-up of 27 months, in this subset, 85 of the patients in the investigative arm experienced a DRFS event vs 135 patients in the control arm (HR, 0.599; 95% CI, 0.456-0.787). The 3-year DRFS rate achieved with the addition of abemaciclib was 87.8% vs 82.6% with endocrine therapy alone.
“Here, we present the efficacy data from the largest monarchE subpopulation, which is cohort 1, defined by a combination of high-risk clinicopathological criteria familiar to breast oncologists, and easily identified in clinical practice,” Reinisch said.
The baseline characteristics of cohort 1 were equally distributed between the treatment arms. In both arms, the median age of patients in cohort 1 was 51 years (range, 22-89), and most patients were younger than 65 years.
“[When looking at] the clinically pathologic features…more than 65% of patients had at least 4 or more positive axillary lymph nodes, resulting in a higher-risk profile,” Reinisch noted. Most patients in the investigative and control arms, respectively, had grade 2 (46.2% vs 46.5%) or grade 3 (41.6% vs 40.9%) disease, a tumor size ranging between 2 cm and less than 5 cm (48.3% vs 49.8%), and a Ki-67 of 20% or higher (39.8% vs 38.4%).
With a median follow-up of 28 months, 8.4% of those in the abemaciclib/endocrine therapy arm were still on treatment vs 8.5% of those in the endocrine therapy–alone arm. In the investigative arm, 0.5% of patients were not treated, 17.8% discontinued treatment before completing 2 years, and 73.3% completed 2-year treatment; these rates were 1.1%, 17.0%, and 73.4%, respectively, in the control arm.
Additionally, 203 patients in the abemaciclib/endocrine therapy arm experienced disease recurrence vs 308 of those in the endocrine therapy–alone arm. The majority of recurrences were distant metastases, with a lower incidence of recurrence with abemaciclib; this occurred in 71.9% of those in the investigative arm vs 75.6% of those in the control arm.
In the abemaciclib arm, most patients experienced distant recurrence in the bone (62%), followed by the liver (42%), and the lung (31%). Moreover, 16.3% of patients in this arm experienced local or regional recurrence, 3.9% experienced contralateral recurrence, and 9.4% experienced second primary neoplasm.
Adjuvant abemaciclib plus endocrine therapy has been found to have an acceptable toxicity profile in patients with high-risk early breast cancer.5
The most common grade 3 or higher adverse effects (AEs) experienced in the investigative arm (n = 2791) and the control arm (n = 2800), respectively, include diarrhea (7.8% vs 0.2%), infections (5.6% vs 3.0%), neutropenia (19.6% vs 0.8%), fatigue (2.9% vs 0.1%), nausea (0.5% vs 0.1%), anemia (2.0% vs 0.4%), headache (0.3% vs 0.2%), vomiting (0.5% vs 0.1%), stomatitis (0.1% vs 0%), thrombocytopenia (1.3% vs 0.1%), decreased appetite (0.6% vs 0.1%), alanine aminotransferase increase (2.8% vs 0.7%), aspartate aminotransferase increase (1.9% vs 0.5%), and rash (0.4% vs 0%).