Regulatory Decision Summary for Verzenio

Verzenio (abemaciclib) was approved in Canada on January 12, 2022 (control # 249557), as adjuvant therapy in combination with endocrine therapy (ET) for the treatment of adult patients with early breast cancer (EBC) who are hormone receptor (HR) positive (HR+), human epidermal growth factor receptor 2 (HER2) negative (HER2-) are node-positive, and have high risk of disease recurrence based on clinicopathological features and a Ki-67 score ≥20%.

The sponsor filed this Supplement to a New Drug Submission (SNDS) to expand the EBC indication for Verzenio (abemaciclib) by removing the Ki67 requirement for patient selection.

The objective of this submission was to expand the current indication of Verzenio as maintenance therapy in Early Breast Cancer (EBC) with the removal of the Ki-67 score as a requirement for patient selection. In support of this change, the sponsor provided the overall survival interim analysis 2 (OS IA2) of the monarchE trial (cutoff date of 01 July 2022), which includes updated efficacy and safety information analysed by cohorts and Ki67 status.

MonarchE is a multicenter, randomized, open-label, phase 3 study that compared the efficacy of abemaciclib plus standard adjuvant Endocrine Therapy (ET) with ET alone in patients with HR +, HER2 - EBC who completed definitive locoregional therapy and were 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: In cohort 1 (C1) the high risk of recurrence was based on clinicopathological features e.g., four or more (≥4) positive axillary lymph nodes (pALN) or 1-3 pALN with tumor size ≥5 cm, grade 3 tumor or a combination of any of those. In cohort 2 (C2) the high risk of recurrence was based on a Ki67 index ≥20% and at least 1 pALN. This cohort included patients with lower risk of recurrence.

In the previous SNDS, the monarchE trial met its primary endpoint invasive disease free survival (IDFS) at the second interim efficacy analysis (IA2), cut-off date March 16, 2020, demonstrating a statistically significant reduction of 25.3 % in the risk of developing invasive disease with abemaciclib + ET over ET alone (HR = 0.747, 95% CI: 0.598, 0.932, p = .0096). Four months after, at the final IDFS analysis, cutoff date of July 8, 2020, the trial reached statistical significance in key secondary endpoints. Abemaciclib + ET showed a 30% reduction in the risk of developing invasive disease over standard therapy in patients with Ki67 ≥20% (from C1 and C2), HR = 0.691 (95% CI 0.519, 0.920) and 36% of risk reduction in patients with a Ki67 ≥20% only from C1, HR = 0.643 (95% CI 0.475, 0.872). C2 included only 9% of the ITT population, therefore it was considered only exploratory. The overall survival data were immature and indicated no survival benefit with abemaciclib over standard therapy, HR = 1.093 (95% CI 0.746,1.600) p value = 0.647. Preliminary analysis in C1 by Ki67 score suggested a positive survival trend in patients with a Ki67 ≥20% HR = 0.658 (95% CI 0.377, 1.148), while a potential detriment in those with Ki67 <20% HR = 1.49 (95% CI 0.668, 3.322), which led HC to restrict abemaciclib approval only to patients from C1 and a ki67 ≥20% .

At the time of the present SNDS data cut-off (OSIA2 data as of July 1, 2022), all patients are off treatment, with more than 80% who completed the 2-year treatment period and more than 75% who were followed for at least 36 months. This provided substantial evidence to further evaluate the efficacy and safety of abemaciclib in the context of EBC. Overall, abemaciclib plus ET showed a reduction of 33.6% in the risk of developing invasive disease compared to ET alone [HR = 0.664 (95% CI 0.578, 0.762)], with disease-free rates increasing from 2.8% at 2 years to 6.4% at 4 years, indicating that the benefit has extended beyond the planned 2 years of treatment. Although OS estimates remained immature, with additional 15 months of follow-up a numerical difference in favor of abemaciclib was observed (157 vs. 173 events), HR = 0.929 (0.748,1.153). The OS analysis by Ki67 score in C1, showed a positive and similar survival trend in both subgroups i.e., ki67 ≥20% HR = 0.733 (95% CI: 0.533, 1.175) and Ki67 <20%, HR = 0.772 (95% CI). CI: 0.506 <1.175). These results alleviate previous concerns about a potential detriment in patients with Ki67 <20%. In addition, post-hoc interaction analyses suggested no differences in the treatment effect across cohorts or Ki67 subgroups in C1, supporting that the Ki67 score should not be a requisite to start treatment with abemaciclib.

The safety profile of abemaciclib in EBC from the updated OSIA2 is consistent with what is already known about the product in the metastatic context. Comparing with standard therapy, patients treated with abemaciclib had an increased incidence of treatment-emergent adverse events (TEAEs), (98.4% vs. 88.9%); serious adverse events (SAEs), (15.5% vs. 9.1%); and discontinuations of study treatment due to AEs (6.4% vs. 1.1%). 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 and their frequency decreased over time. 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 with no treatment discontinuation required. At the time of the latest OS IA2, the majority of severe AEs recovered or resolved without major complications and no outstanding changes in the patient's quality of life or health outcomes were identified. Overall, in the EBC setting, treatment with abemaciclib + ET was generally accepted, tolerated and successfully managed with dose modification and general supportive measures.

During the review of this SNDS, numerical imbalance for arterial thromboembolism (ATE) of any grade in the abemaciclib arms compared to the control arms was further reviewed, especially in the metastatic setting. After reviewing all the information presented, it was concluded that although the evidence was not strong enough to establish a causal relationship between abemaciclib and ATE, the inclusion of this adverse event in the Warnings and Precaution section of the Product Monograph is an adequate risk minimization measure.

While some uncertainties regarding the magnitude of benefit of adding abemaciclib to ET in smaller patient subgroups with lower risk of recurrence (those included in C2) exist, the totality of the evidence provided in this SNDS demonstrates that the profile benefit/risk of abemaciclib + ET remains favorable for patients with HR+, HER2-, EBC with high risk of disease recurrence and that the Ki67 score is no longer a requirement to start treatment.

Overall, the anticipated benefits of Verzenio are expected to outweigh the potential risks when used under the conditions of use recommended in the approved Product Monograph.

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