The prespecified overall survival analysis of the phase 3 monarchE trial when abemaciclib was added to endocrine therapy in patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer.
Results from the phase 3 monarchE trial (NCT03155997) showed abemaciclib (Verzenio) in addition to endocrine therapy improved invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer, according to the respecified overall survival (OS) analysis which was presented at the 2022 San Antonio Breast Cancer Symposium (SABCS).1,2
he data from 2 years post primary efficacy analysis for the intention-to-treat population were presented at the 2022 San Antonio Breast Cancer Symposium and simultaneously published in Lancet Oncology.1,2 At a median follow-up of 42 months, the median IDFS was not reached for patients who received adjuvant abemaciclib plus endocrine therapy (n = 2808) or those who received endocrine therapy alone (n = 2829). The benefit of adjuvant abemaciclib was maintained (HR, 0.664; 95% CI, 0.578-0.762; nominal P < .0001) and the 4-year IDFS rates were 85.8% vs 79.4%, with and without abemaciclib, respectively.
The absolute difference in IDFS was 6.4%, an increase compared with 2.8% at 2 years (92.7% vs 89.9%) and 4.8% at 3 years (89.2% vs 84.4%).
At the time of data analysis, no patients were still receiving abemaciclib and OS data were immature; however, investigators reported that a lower number of deaths were reported among patients who received abemaciclib (n = 157; 5.6%) vs endocrine therapy alone (n = 173; 6.1%). The HR for reduction in the risk of death was 0.929 (95% CI, 0.748-1.153; log-rank P = .503) and the median duration of treatment in both groups was 24 months during the study period.
“With further follow-up, the Kaplan-Meier curves continue to separate beyond completion of the 2-year treatment period suggesting a potential carry-over effect [with abemaciclib],” lead study author Stephen Johnston, MBBS, said in a presentation of the data. Johnson is head of medical oncology, head of the Breast Unit, professor of breast cancer medicine and consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, England. “These data further support the addition of abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive, high-risk, early breast cancer.”
Updated data for the secondary end point of DRFS demonstrated that the addition of abemaciclib reduced the risk of distant recurrence by approximately 34% (HR, 0.659; 95% CI, 0.567-0.767; nominal P < .0001). The 4-year DRFS rate for those who received abemaciclib was 88.4% vs 82.5% for an absolute difference of 5.9%. DRFS also trended toward sustained improvement compared with an absolute difference of 2.5% at 2 years (94.0% vs 91.6%) and 4.1% at 3 years (90.8% vs 86.8%).
In a detailed analysis of DRFS events, fewer patients with metastatic disease were reported in the abemaciclib arm (n = 329) compared with the endocrine therapy–alone arm (n = 422). In the experimental arm, 125 patients were alive with metastatic disease, 118 died because of breast cancer, and 39 died of causes not related to breast cancer. In the standard-of-care arm, 249 patients were alive with metastatic disease, 139 died because of breast cancer, and 34 died from other causes.
IDFS improvement was sustained across subgroups at 3 years with the greatest benefit observed in those with primary tumor size less than 2 cm (HR, 0.48; 95% CI, 0.358-0.646) and stage IIA tumors (HR, 0.525; 95% CI, 0.318-0.866).2 Similarly, the benefit of adjuvant abemaciclib in monarchE was seen in subgroup analysis for DRFS with the greatest benefit among those with primary tumor size less than 2 cm (HR, 0.456; 95% CI, 0.327-0.636) and stage IIA tumors (HR, 0.527; 95% CI, 0.299-0.929).
monarchE was a phase 3 trial that randomly assigned patients to receive 150 mg of abemaciclib twice daily for 2 years in addition to standard-of-care endocrine therapy or standard of care alone following surgery and either radiotherapy and/or adjuvant or neoadjuvant chemotherapy as directed. The follow-up period was endocrine therapy for 3 to 8 years as clinically indicated.
As previously reported, the baseline characteristics for the cohorts were well balanced with a median age of 51 years (range, 44-60) and 56.5% of women in each arm being postmenopausal. Most patients in both cohorts (59%) had 4 or more positive axillary lymph nodes and approximately half (49%) of patients had grade 2 histopathological grade disease at diagnosis. In terms of prior treatments, approximately 61% of patients received adjuvant chemotherapy and 63% received adjuvant endocrine therapy.
Those in the high-risk cohort based on clinicopathological features including at least 4 axillary lymph nodes or 1 to 3 axillary lymph nodes and grade 3 disease and/or tumor size 5 cm or greater also had improvements in IDFS and DRFS at the updated data cutoff (cohort 1). Ninety-one percent of patients were included in this cohort. The 4-year IDFS rate was 85.5% vs 78.6% for those who received abemaciclib (n = 2555) and those who did not (n = 2565), respectively (HR, 0.653; 95% CI, 0.567-0.753). The absolute difference grew from 3.1% at 2 years, to 5.0% at 3 years, to 6.9% at 4 years.
The 4-year DRFS rates were 87.9% vs 81.8%, respectively (HR, 0.652; 95% CI, 0.558-0.761). The absolute difference improved from 2.8% at 2 years, to 4.3% at 3 years, to 6.1% at 4 years. At the time of analysis 39 survival events occurred in the abemaciclib arm compared with 50 in the endocrine therapy alone arm (HR, 0.772; 95% CI, 0.506-1.175).
Those with high-risk disease and Ki-67 index 20% or greater had a 4-year IDFS rate of 83.6% with abemaciclib (n = 1017) vs 74.7% without (n = 986; HR, 0.618; 95% CI, 0.501-0.762). The absolute difference of 8.9% was improved from the 2-year absolute difference of 5.3% and the 3-year absolute difference of 6.6%.
The 4-year DRFS rate was 86.3% vs 77.7% (HR, 0.612; 95% CI, 0.488-0.767) for an absolute difference of 8.6% compared with 6.0% at 2 years and 6.2% at 3 years. At the time of analysis 68 survival events occurred in the abemaciclib arm compared with 88 in the endocrine therapy–alone arm (HR, 0.733; 95% CI, 0.533-1.007).
For those with Ki-67–low disease in cohort 1, the 4-year IDFS rates were 88.8% with abemaciclib (n = 946) vs 82.4% with endocrine therapy alone (n = 968; HR, 0.624; 95% CI, 0.478-0.814).1 The 4-year DRFS rates in this cohort were 91.0% with abemaciclib vs 85.4% with endocrine therapy alone (HR, 0.613; 95% CI, 0.458-0.821).
“Ki-67 as a marker of cell proliferation was analyzed in a pretreatment biopsy centrally in pretreated patients in cohort 1 and what we could see is that Ki-67 was clearly prognostic, but not predictive of abemaciclib benefit in this trial,” Johnston said, highlighting that patients with a high Ki-67 index treated with endocrine therapy alone had a much worse prognosis. “[For those who received endocrine therapy alone], 25% have relapsed by 4 years, compared with 17% with a low Ki-67 [index].”
Data are immature for cohort 2—patients with intermediate-risk disease by clinicopathological features. At the time of cutoff, the 4-year IDFS rate was not reached in either arm (HR, 0.773; 95% CI, 0.420-1.420).1 The 4-year DRFS rate was also not reached (HR, 0.764; 95% CI, 0.383-1.526).
“In an exploratory analysis, piecewise HRs for within [each] year were estimated for both IDFS and DRFS, what you can see is the magnitude of abemaciclib benefit increases year over year beyond treatment of the study period suggesting a carryover effect,” Johnston said. Years 0 to 1 and year 1 to 2, represented the study period.
For IDFS the piecewise HR for year 0 to 1 was 0.782 (95% CI, 0.583-1.018); 0.674 (95% CI, 0.521-0.858) for year 1 to 2; 0.618 (95% CI, 0.477-0.788) for year 2 to 3; and 0.602 (95% CI, 0.428-0.803) for year 3 forward.
For DRFS, the piecewise HRs were 0.725 (95% CI, 0.519-0.983); 0.691 (95% CI, 0.521-0.887); 0.651 (95% CI, 0.497-0.851); and 0.581 (95% CI, 0.391-0.818), respectively.
In terms of toxicity, data were consistent with what was previously reported, and investigators noted that no new venous thrombotic events were reported since the prior interim analysis. The rates of grade 1/2, grade 3, and grade 4 venous thromboembolic events in the abemaciclib plus endocrine therapy arm were 1.2% (n = 33), 1.1% (n = 32), and 0.2% (n = 6). In the endocrine therapy–alone arm these rates were 0.4% (n = 10), 0.3% (n = 0), and 0%, with 1 patient experiencing a grade 5 event (pulmonary embolism). Grade 3 and grade 4 pulmonary embolism was reported among 24 patients and 4 patients, respectively, in the abemaciclib arm. Three patients in the endocrine therapy–alone arm had pulmonary embolism which were grade 3 in severity.
Further, 3.3% of patients in the abemaciclib arm experienced interstitial lung disease vs 1.3% of patients in the endocrine therapy–alone arm.
For abemaciclib, dose holds due to adverse effects (AEs) were reported for 61.7% of patients with 43.6% of patients receiving a dose reduction. The discontinuation rate was 18.5% with 8.9% of the discontinuations following a dose reduction.
The most frequent grade 1/2 treatment-emergent AEs for abemaciclib plus endocrine therapy vs endocrine therapy alone included diarrhea (75.7% vs 8.5%), fatigue (38.0% vs 17.9%), arthralgia (26.2% vs 36.8%), neutropenia (26.3% vs 4.8%), leukopenia (26.3% vs 6.3%), abdominal pain (34.3% vs 9.6%), nausea (29.1% vs 9.0%), hot flush (15.3% vs 22.6%), and anemia (22.4% vs 3.4%).2 The most frequent grade 3 events were neutropenia (19.0%) with abemaciclib plus endocrine therapy and hypertension (1.8%) with endocrine therapy alone.
“monarchE results are practice changing and the updated analyses presented here, including the 4-year estimated rates, show the persistent and deepening benefit of adjuvant abemaciclib in a high-risk early breast cancer population,” the study authors wrote. “With a tolerable safety profile, these results further strengthen the positive benefit–risk for the adjuvant use of abemaciclib. Long-term follow-up to study the outcomes in these patients with high-risk early breast cancer is ongoing.”