Regulatory Decision Summary for Verzenio

Two randomized phase 3 trials performed in the specific target patient populations provided the primary efficacy and safety data for the proposed indications of Verzenio (abemaciclib) in combination with an aromatase inhibitor or fulvestrant, and a single-arm Phase 2 trial was the primary source of data supporting the proposed single-agent Verzenio indication.

For Verzenio in combination with an aromatase inhibitor as initial therapy for metastatic breast cancer, progression-free survival (PFS) was significantly prolonged in the Verzenio plus non-steroidal aromatase inhibitor (NSAI) treatment arm, with a hazard ratio at the final PFS analysis of 0.540 [95% CI: 0.418, 0.698, p<0.0001], as assessed by the investigator. This corresponds to a statistically significant and clinically meaningful reduction in the risk of disease progression or death of 46% for patients treated with Verzenio plus NSAI. Blinded independent review gave consistent results, and other secondary efficacy endpoints were supportive. As for the data cut-off date, overall survival data (OS) were still immature, with 32 events (9.8%; deaths) occurring in the Verzenio plus NSAI arm and 17 events (10.3%; deaths) in the placebo plus NSAI arm. The hazard ratio was 1.057 (95% CI: 0.683, 1.633), and the 2-sided stratified log-rank test p-value was 0.8017.

This pivotal study was performed in the target patient population, with Verzenio administered in combination with letrozole or anastrozole; there are no clinical trial data of Verzenio in combination with exemestane. An extrapolation of the studied combination to an indication for Verzenio in combination with any AI for the first-line treatment of postmenopausal women with advanced breast cancer is considered reasonable and acceptable, due to evidence found in published literature, clinical practice guidelines and the overall similar efficacy-safety profiles of the aromatase inhibitors.

For Verzenio in combination with fulvestrant in women whose metastatic breast cancer relapsed after initial endocrine therapy, PFS was significantly prolonged in the patients treated with Verzenio plus fulvestrant compared to placebo plus fulvestrant, with a hazard ratio = 0.553 [95% CI: 0.449, 0.681]; p <0.0000001, corresponding to a reduction in the risk of disease progression or death of 45%. These data were supported by secondary efficacy endpoints. As of the data cut-off date, OS data were still immature, and survival benefit has not yet been demonstrated.

For Verzenio monotherapy, the primary efficacy endpoint of MONARCH 1 was confirmed objective response rate (ORR) as assessed by the investigator, and was determined to be 19.7% (95% CI: 13.3, 27.5). Blinded independent review gave similar data, and the key secondary endpoint, investigator-assessed duration of response, had a reported median of 8.6 months (95% CI: 5.8, 10.2). For both investigator and independent assessments of ORR, the lower bound of the 95% confidence interval did not exclude the pre-defined threshold for clinical significance based on historical data as an ORR representative of what might be expected for approved chemotherapies used in this setting. However, there are limited effective treatment options for this heavily pre-treated MONARCH 1 patient population. These patients have exhausted endocrine-based treatment options and have received 1 or 2 cytotoxic chemotherapies for metastatic disease. Verzenio is an oral therapy that appears to have similar efficacy, but different toxicities compared to the current treatment options for these breast cancer patients, and provides a treatment option for patients with limited available therapies.

The 3 pivotal registrational studies also provided the primary safety data supporting abemaciclib use in combination with endocrine therapy and as a single-agent. Verzenio at a dose of 150 mg twice daily in combination with endocrine therapy or used as a single agent at a dose of 200 mg twice daily demonstrated an acceptable safety profile in the studied patient populations. Despite differences in the enrolled patient populations, the lines of therapy, and the stages of disease studied, the 3 pivotal trials revealed a consistent toxicity profile in patients treated with Verzenio.

The most frequently reported AEs were diarrhea, neutropenia, fatigue, nausea, vomiting, abdominal pain, decreased appetite, and anemia. Diarrhea was reported in up to 90% of patients, with Grade 3 diarrhea occurring in ≥9% of patients in each of the pivotal studies. The incidence was greatest during the first month of Verzenio treatment. Early use of antidiarrheals and Verzeniodose adjustments were important recommended management guidelines in clinical trials for limiting the severity and duration of diarrhea. This information is included in the Product Monograph. Severe neutropenia (Grade 3 or Grade 4) was reported as a treatment emergent adverse event (TEAE) in up to 24% and 5% of patients, respectively. A relationship between severe neutropenia or lymphopenia and concurrent severe infection was not observed; however, serious infection secondary to neutropenia is a significant risk. Based on the severity of neutropenia, Verzenio may require dose modification, and relevant monitoring recommendations are included in the Product Monograph.

Venous thromboembolic events (VTEs) were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor in MONARCH 3, and in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 (compared to 0.6% and 0.9% in the respective comparator arms of these studies). Patients in both study arms had pre-existing risk factors in addition to their underlying metastatic breast cancer that may predispose to the occurrence of thromboembolism; however, risk factors were balanced between the arms, and there was no specific risk factor that could be predictive of VTE on treatment with Verzenio. Across the Verzenio clinical development program, deaths due to venous thromboembolism were reported. The Product Monograph presents this data, and risk management includes relevant monitoring and treatment recommendations.

Increases in alanine aminotransferase (ALT) were reported as a TEAE in up to 16% of patients receiving Verzenio in the registration studies, with up to 6% reporting Grade ≥3 increased ALT, most frequently occurring within the first 2 months. Severe ALT elevations were unlikely to occur after 4 months of therapy. Based on the level of ALT elevations, Verzenio may require dose modification, and monitoring recommendations are included in the Product Monograph.

Subgroup analyses of the safety data reported from each of the 3 pivotal studies suggested that Verzenio in combination with endocrine therapy (aromatase inhibitors or fulvestrant) or Verzenio as a single agent also had increased toxicity in patients ≥65 years of age compared to those <65, as well as in Asian patients compared to Caucasian patients. Appropriate labelling in the final Product Monograph is considered to adequately manage these risks.

The Product Monograph is the primary risk management strategy to manage the risks associated with Verzenio. It provides warnings pertaining to the significant adverse events reported in clinical trials, and recommendations to the prescriber regarding dose modifications/interruptions that may be required to manage adverse events. Recommendations for monitoring are also provided. The Product Monograph is considered an appropriate measure for risk management of Verzenio.