New findings from the phase 3 monarchE recently led to an FDA approval for abemaciclib. Joyce O’Shaughnessy, MD, presented the long-term analysis results during an ESMO Virtual Plenary.
Adjuvant treatment with abemaciclib (Verzenio), and endocrine therapy (ET) showed sustained clinical benefit in patients with hormone receptor (HR)-positive, HER2-negative, node-positive, high-risk early breast cancer with long-term follow-up in the phase 3 monarchE clinical trial (NCT03155997).1,2
Long-term results from the randomized, open-label study recently led to the FDA approval of abemaciclib in combination with ET, for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of ≥ 20%, as determined by an FDA-approved test.
In the primary analysis of monarchE, the combination of abemaciclib and ET achieved a clinically meaningful improvement in invasive disease-free survival (iDFS) as well as distant relapse-free survival (DRFS). This analysis followed patients for a median of 15.5 months, but considering the statistical significance observed, investigators set out to assess long-term outcomes at a median follow-up of 27 months.
The monarchE study population consisted of 5637 patients with HR-positive, HER2-negative, high-risk early breast cancer. Patients were determined to have high-risk disease based on their clinical pathologic features (cohort 1) or based on having a high Ki-67 score (cohort 2). Both cohorts were included in the intent-to-treat population. Per the inclusion criteria, patients could be either male or female who are pre-/post-menopausal. Patients may have received chemotherapy previously, but must have had no metastases, and by 16 months post-surgery and 12 weeks post prior ET.
Patients were randomized 1:1 to receive either abemaciclib 150 mg twice daily in combination with ET or ET only. Patients were stratified by prior chemotherapy, menopausal status, and region. In addition to the primary end point of iDFS in the overall population, multiple secondary end points were explored including, iDFS in the ki-67-positive groups, DRFS, overall survival (OS), safety, pharmacokinetics, and patient-reported outcomes. With the long follow-up, investigators also explored ki-67 as a prognostic and predictive biomarker in EBC.
At baseline, the ITT population in the abemaciclib/ET arm had a median age of 51 years (range, 22-89) compared with 51 years (range, 22-86) in the ET-only arm. About 84% of the experimental arm was notably below the age of 65, as was about 85% of the ET arm. In the experimental versus the control arms, respectively, 99.3 % and 99.5% of patients were female. The majority of patients in both arms were postmenopausal. Most patients, including 58.5% of the abemaciclib/ET arm compared with 58.2% of the ET arm received chemotherapy in the adjuvant setting rather than the neoadjuvant setting, and 4.5% versus 4.7%, respectively did not receive prior chemotherapy.
In terms of disease characteristics observed at baseline, the majority of patients in both treatment arms had an ECOG performance status of 0, a pathologic tumor size of 2 cm to 5 cm, and at least 4 positive lymph nodes.
Among the patients followed for 27 months, there were a total of 565 iDFS events, 89.6% of patients were off study treatment by the data cutoff of April 1, 2021, and 72.2% had completed the full 2 years of treatment.
Long-term follo-up data showed that the addition of abemaciclib to ET achieved a 2-year iDFS rate of 92.7% compared with 90.0% in the ET-only arm. The 3-year iDFS observed with abemaciclib/ET was 88.8% compared with 83.4% in the ET monotherapy arm (HR, 0.696; 95% CI, 0.588-0.823; P <.0001). Overall, adding abemaciclib to ET led to a 30.4% reduction in the risk of developing an iDFS event.
“This effect size is numerically consistent with the benefit previously demonstrated at the primary outcome analysis, with further follow up the km curves continue to separate, and the treatment benefit was maintained beyond the two-year treatment period of abemaciclib, given that more than 500 patients are at risk of recurrence at 36 months, we are now able to estimate the 3-year IDFS rates, which have an absolute difference of 5.4% between the two arms. In the forest plot consistent IDFs treatment benefit is observed across prespecified subgroups,” said Joyce O’Shaughnessy, MD, co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and for The US Oncology Network, who presented the data during a European Society of Medical Oncology Virtual Plenary held on October 14, 2021.
The DRFS benefit of abemaciclib plus ET was also maintained with longer follow-up. At 2 years, the DFRS rate observed with the experimental combination was 94.1% compared with 91.6% in the control arm. The 3-year DFRS rate was 90.3% with the addition of abemaciclib to ET compared with 86.1% without, for an absolute difference of 4.2%. The overall result was a 31.3% reduction in the risk of developing a DRFS event (HR, 0.687; 95% CI, 0.571-0.826).
“Within each year, we estimated for IDFS and DRFS. There was an increasing magnitude of IDFS and DRFS effect size from the first year to the second year with maintained treatment benefit beyond the 2-year study treatment period,” explained O’Shaughnessy.
Looking at the subgroups of patients with Ki-67 ≥ 20% in the ITT population, the 2-year iDFS rate with the combination of abemaciclib and ET was 91.9% versus 87.9% with ET alone. The 3-year iDFS was 86.9% with the experimental combination versus 80.8% with ET alone, for an absolute difference of 6.0%. There was a 33.7% risk of patients developing an iDFS event with abemaciclib/ET (HR, 0.663; 95% CI, 0.524-0/839; nominal P =.0006).
In cohort 1, specifically, the absolute difference in iDFS rate between the abemaciclib combination and ET monotherapy arm was 7.1% at 3 years, and the addition of abemaciclib to ET achieved a 37.4% reduction in the risk of patients developing an iDFS event.
In explanation of these findings, O’Shaughnessy stated: “Comparing the 3-year IDFS rates of the control arms of the two populations in cohort 1. As expected, high Ki-67 index was prognostic of a worse outcome. However, treatment benefit was observed in both cohort 1 high and low populations, indicating benefit from abemaciclib, regardless of Ki-67 index.”
The mature safety findings from monarchE were consistent with the prior study analyses. Patients received abemaciclib for a median of 23.7 months. The most common adverse events (AEs) observed in more than 20% of patients in either arm included diarrhea in 84% of the experimental arm versus 9% of the control arm, fatigue (41% vs 18%), arthralgia (27% vs 38%), and neutropenia (46% vs 6%).
“The most frequently noted AEs with abemaciclib were low grade. The safety data set is mature, with greater than 90% of patients being off treatment, and is consistent with the known safety profile of abemaciclib.”
Venous thromboembolic events were seen in 2.5% of the abemaciclib/ET arm versus 0.6% of the ET-only arm. Pulmonary embolisms occurred in 1.0% of the abemaciclib/ET arm compared with 0.1% of the ET monotherapy arm. Finally, interstitial lung disease occurred in 3.2% of the abemaciclib/ET arm versus 1.3% of the ET-only arm.
In the long-term follow-up analysis of monarchE, efficacy and safety assessment are ongoing until long-term OS data mature.
1. O’Shaughnessy J. Adjuvant abemaciclib combined with endocrine therapy: updated results from monarchE. Presented at: ESMO Virtual Plenary; October 14, 2021.
2. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. Published online October 14, 2021. doi: 10.1016/j.annonc.2021.09.015