Regulatory Decision Summary for Verzenio

The purpose of this Supplement to a New Drug Submission (SNDS) was to expand the use of Verzenio for the adjuvant treatment of Early Breast Cancer (EBC), in addition to the previously approved indication for Advanced /Metastatic Breast Cancer. To support the efficacy, safety and labelling of the new indication, the sponsor submitted the pivotal trial MonarchE, a population PK/PD study and supplemental toxicology studies.

Following review the recommended indication for EBC is: “Verzenio is indicated in combination with endocrine therapy for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score ≥20%.”

To support the safety and efficacy of the proposed indication the sponsor submitted the pivotal study MonarchE. This was a multicenter, randomized, open-label, phase 3 study that compared the efficacy of abemaciclib plus standard adjuvant endocrine therapy (ET) (Arm A) to ET alone (Arm B) in patients with HR +, HER2 - EBC who completed definitive locoregional therapy and are at high risk of disease recurrence based on clinicopathological features or Ki-67 index. Patients with at least 1 positive lymph node were enrolled into 2 cohorts. Cohort 1 included patients with a high risk of recurrence based on clinicopathological features as follows: Four or more (≥4) positive axillary lymph nodes (pALN); 1-3 pALN, tumor size ≥5 cm, grade 3 tumor or a combination of any of those. Cohort 2 included patients with a high risk of recurrence based on a Ki-67 index ≥20% and at least 1 pALN.

The primary endpoint of this trial was invasive disease free survival (IDFS) in the intention-to-treat (ITT) population (all randomized patients in cohort 1 and 2). Secondary endpoints included: 1) IDFS in all patients with Ki-67 index ≥20 % named Ki-67H population (cohort 1 and 2); 2) IDFS in patients with Ki-67 index ≥20% only from cohort 1 named C1-Ki-67H; 3) overall survival (OS); 4) distant relapse free survival (DRFS); safety, quality of life (QoL) and health outcomes.

At the second interim efficacy analysis (IA2) with a median follow-up of 15.5 months, the monarchE trial met the primary endpoint (IDFS). Abemaciclib plus ET demonstrated a statistically significant reduction of 25.3% in the risk of developing invasive disease (HR = 0.747, 95% CI: 0.598, 0.932, p = 0.0096) and a higher 2-year invasive disease free rate (92.3% versus 89.3%) with an absolute difference of 3.5 % favoring arm A. At the final IDFS analysis, with a median follow-up of 19.2 months, a greater benefit in IDFS was observed for abemaciclib + ET evidenced by a statistically significant reduction of 28.7% in the risk of developing invasive disease (HR = 0.713, 95% CI: 0.583, 0.871; p = 0.00089). At the final IDFS analysis, it was demonstrated a statistically significant reduction of 30% in the risk of developing invasive disease in the Ki-67H group (HR = 0.691, 95% CI: 0.519, 0.920, p = 0.0111) and a statistically significant reduction of 36% in the risk of developing invasive disease (HR = 0.643, 95% CI: 0.475, 0.872, p = 0.0042) in the C1-Ki-67H group. With respect to DRFS, IA2 abemaciclib + ET showed a statistically significant reduction in the risk of developing a distant relapse of 28.3% (HR = 0.717, 95% CI: 0.559, 0.920), which improved in the final analysis to 31% (HR = 0.687, 95% CI: 0.551, 0.858). In summary, the efficacy results from the monarchE trial indicate that the treatment with abemaciclib plus ET offers a significant benefit in reducing the risk of invasive / metastatic disease compared with ET alone. This benefit was demonstrated in all the subpopulations analyzed, but it was particularly notable in patients with high-risk clinicopathological characteristics and a ki-67 index ≥20% (C1-Ki-67H).

In terms of overall survival (OS), data were immature in both IA2 and the final IDFS analysis. At the IA2 there were 76 deaths (39 in Arm A and 37 in Arm B) with a HR = 1.146 (95% CI: 0.726, 1.809, p = 0.5587) and at the final IDFS analysis there were 106 deaths (55 in Arm A and 51 in Arm B) with a HR = 1.093 (95% CI: 0.746, 1.6, p = 0.64712). Although, there is a downward trend with a HR closer to 1 in the last analysis, the HR estimates remained above 1. Preliminary OS analysis in cohort 1 by Ki-67 index ≥20% vs <20%, suggested a positive trend towards an OS benefit in C1-Ki-67 with a Ki-67 score ≥20% (HR = 0.658, CI 95%: 0.377, 1.148, p = 0.1381), while a detrimental OS effect in C1-Ki-67 with Ki-67 <20% (HR = 1.490, 95% CI: 0.668, 3.322 p = 0.327). Since OS data are still highly immature, the treatment effect on OS is uncertain at this moment and will require a larger number of events and a longer follow-up. In the meantime, the indication will be restricted to patients for which the survival benefit appears to be consistently positive both for the primary IDFS and preliminary OS results.

In terms of safety, patients treated with abemaciclib plus ET had an increased incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and discontinuations of study treatment due to AE in comparison with ET alone i.e., (97.9% vs. 87.2%); (13.3% vs. 7.8%) and (6.2% vs. 0.8%) respectively. In the abemaciclib group, the most frequently reported TEAEs (>20%) included diarrhea, neutropenia, fatigue, leukopenia, abdominal pain, nausea, and anemia. Most of these adverse events were mild to moderate. The highest incidence of severe events (≥ grade 3) was seen for neutropenia and leukopenia. Similar to what was observed in the metastatic setting, the adverse events of special interest (AESI) identified in monarchE included neutropenia, diarrhea, liver events, venous thrombotic events (VTE), and interstitial lung disease (ILD) / pneumonitis. Most AESIs were mild to moderate and no treatment changes were required. However, to manage and control the severity of these events, dose modification, supportive measures, and additional medication (e.g., antidiarrheals, anticoagulants) were often needed. At the time of the final IDFS analysis, the majority of AESIs ≥ grade 3 recovered or resolved without major complications and no outstanding changes in the patient's quality of life or health outcomes were identified. In summary, the safety profile of abemaciclib in monarchE was predictable, manageable, reversible, tolerable, and above all consistent with the safety profile observed in the metastatic setting.

It is clear that there is a consistent treatment benefit as measured by IDFS and DRFS across all Ki-67 populations in Cohort 1. The information available at this time indicates that the greatest benefit of the treatment was observed in patients most likely to develop recurrence, (i.e., cohort 1 with Ki-67 score ≥20%). Furthermore, the preliminary (immature) analysis of OS in cohort 1 by Ki-67 index ≥20% vs <20% suggests a positive trend towards an OS benefit in C1-Ki-67 with a Ki-67 score ≥20%, while a detrimental OS effect was seen for C1-Ki-67 with Ki-67 <20%. In terms of safety, although abemaciclib toxicity was generally consistent with that reported in the setting of advanced or metastatic breast cancer, in patients in an early stage of the disease abemaciclib imposes additional toxicity (especially gastrointestinal and hematologic). While the OS result remains immature, the potential detrimental effect of abemaciclib on C1-Ki-67L patients does not allow us to conclude a positive Benefit-Harm-Uncertainty profile for these group of patients in its entirety. It is recognized that a higher number of events and a longer follow-up might provide evidence to support this in the future. Given this, the recommended indication is restricted to those patients in whom a greatest benefit was observed i.e., those with high-risk clinicopathological features and a Ki-67 index ≥20%.

For further details about Verzenio, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.