FDA Expands Adjuvant VERZENIO® Indication in High-Risk Early Breast Cancer

SUMMARY: The FDA on March 3, 2023, approved VERZENIO® (Abemaciclib) with endocrine therapy (Tamoxifen or an Aromatase Inhibitor) for the adjuvant treatment of adult patients with Hormone Receptor (HR)-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence. Patients defined as high risk included those having either four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes and either tumor grade 3 or a tumor size 5 cm or more. VERZENIO® was previously approved for the above high-risk population with the additional requirement of having a Ki-67 score of 20% or more. The present approval removed the Ki-67 testing requirement.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and HR-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites. Factors associated with high risk of recurrence in HR-positive, HER2-negative early breast cancer include positive nodal status, the number of positive nodes, large tumor size (5 cm or more), and high tumor grade (Grade 3).

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

The monarchE trial is an international, open-label, two-cohort, randomized, Phase III study, conducted to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer. This study included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). To be enrolled in Cohort 1 (N=5,120), which is the FDA-approved population, patients had to have 4 or more positive nodes or 1-3 positive nodes and either tumor grade 3 or a tumor size 5 cm or more. To be enrolled in Cohort 2 (N=517), patients could not be eligible for Cohort 1 and must have had 1-3 positive nodes and tumor Ki-67 score of 20% or more. Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included Distant Relapse Free Survival (DRFS), Overall Survival (OS), and Safety.

The FDA label expansion is supported by four-year data from the monarchE trial. There was significantly more Invasive Disease Free Survival (IDFS) benefit beyond the two-year treatment course with adjuvant VERZENIO® and the absolute difference in IDFS between the two treatment groups increased over time. The IDFS at 48 months was 85.5% for VERZENIO® plus standard endocrine therapy and 78.6% for standard endocrine therapy alone, with an absolute difference in IDFS of 6.9%. At two years and at three years, the absolute differences between treatment groups were 3.1% and 5.0%, respectively. The addition of VERZENIO® to standard endocrine therapy reduced the risk of recurrence by 35% compared to endocrine therapy alone (HR=0.653). This benefit was primarily among patients in Cohort 1 and there were no new safety findings. However, in Cohort 2, more deaths were observed with VERZENIO® plus standard endocrine therapy compared to standard endocrine therapy alone and the FDA label therefore is restricted to Cohort 1. The Overall Survival (OS) data was immature across the entire study, but there was an OS trend in favor of VERZENIO® in the Cohort 1 population.

It was concluded that the use of adjuvant VERZENIO® in patients with high-risk Hormone Receptor-positive, HER2-negative early breast cancer reduced the risk of recurrent disease, and this benefit was sustained beyond the completion of treatment, with an absolute increase noted at 4 years. Overall Survival data was immature at the time of this analysis.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Johnston SRD, Toi M, O’Shaughnessy J, et al. Lancet Oncol. 2023;24:77-90.