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Verzenio (Abemaciclib) became the first early breast cancer at high risk treatment among CDK4/6 inhibitors, and Lilly Korea (CEO Christopher J. Strokes) held a press conference to lay emphasis on the clinical value of Verzenio in early breast cancer on the 14th.

The Ministry of Food and Drug Safety approved on Nov. 18 as a treatment used in combination with endocrine therapy as adjuvant therapy of HR+(hormone receptor-positive)/HER2-(human epithelial cell growth factor 2 negative, early breast cancer patients at high risk of recurrence of lymph node-positive.

Most breast cancers are detected early, but about 20~30% of HR+/HER2- breast cancer patients develop metastatic breast cancer that recurs and cannot be cured even after undergoing resection.

The majority of patients have a high risk of recurrence in the first year, relapse within five years, and there is a risk of recurrence even after five years.

In particular, the risk of recurrence is high if the lymph node is positive, the tumor grade is high, the size of the tumor is large and the cell proliferation rate is fast.

As a way to lower the risk of recurrence after surgery, various postoperative adjuvant therapies such as endocrine therapy, chemotherapy and suppression of ovarian function have been implemented.

Endocrine therapy is most widely used after HR+/HER2- early breast cancer surgery, but resistance develops within two years in most cases.

Accordingly, a new alternative was needed to reduce the risk of recurrence among HR+/HER2- early breast cancer patients.

CDK 4/6 inhibitors such as Verzenio have confirmed their value in various areas of HR+/HER2- breast cancer.

CDK 4/6 inhibitors started in patients with a lot of previous treatment experience and are now the basis of first-line treatment. According to the treatment results of primary treatment therapies for HR+/HER2- breast cancer that is being implemented in actual clinical settings recently reported in the Journal of American Medical Association, three therapies, including the first among the top five therapies, are based on CDK4/6 inhibitors.

While CDK4/6 inhibitors are expanding their presence in HR+/HER2- breast cancer patients, Verzenio was the first CDK4/6 inhibitor to derive positive data through the phase 3 trial of monarchE in early breast cancer prior to the progression stage.

This study was conducted on a total of 5,637 patients with HR+ HER2-, lymph node positive and high-risk early breast cancer (based on random assignment), and participants were in the study regardless of gender, menopausal status, or whether adjuvant chemotherapy was performed.

The study was divided into groups of high-risk patients with 4 or more lymph node metastases, a grade 3 tumor, or a tumor size of 5 cm or more and 3 or more lymph node metastases (Cohort 1) and patients with a Ki-67 of 20% or more at baseline (Cohort 2).

The patients who participated in the study were administered Verzenio additionally to endocrine therapy for two years as postoperative adjuvant therapy or only endocrine therapy.

The primary endpoint of the study was Invasive Disease-Free Survival (IDFS), and the secondary endpoint was IDFS and Distant Relapse-Free Survival (DRFS) in patients with high Ki-67 (20% or more), overall survival (OS), safety and pharmacokinetics.

As a result of the study, Verzenio combination therapy improved the primary endpoint, IDFS rates or DRFS rates, by more than 30% compared to endocrine monotherapy, and in particular, the OS rates increased the gap with the monotherapy group by 4 years.

In October of last year, ESMO Virtual Plenary released the results of the three-year analysis of this study.

While the completeness of the planned OS data was not sufficient, the benefits of IDFS and DRFS of the Verzenio administration group compared to the control group increased over time.

IDFS in all patients (Cohort 1 and Cohort 2) was 92.7% in the Verzenio plus endocrine therapy and 90.0% in the endocrine therapy alone at the point of two years of the Verzenio treatment period was completed.

This difference continued until the three-year, one year after the two-year period of Verzenio administration was completed, and the IDFS of the Verzenio group was 88.8% and the endocrine therapy alone group was 83.4%, showing absolute differences from 2.7%p to 5.4%p.

Of the approximately 2,800 patients in the Verzenio group and the endocrine therapy alone group, a total of 232 invasive disease-related cases occurred in the Verzenio group and 333 cases in the endocrine therapy alone group at three-year, with a lower risk of invasive disease or death in the Verzenio group. (HR=0.696, P<0.0001)

DRFS was 94.1% in the Verzenio group at two-year, 91.6% in the endocrine therapy alone, and 90.3% in the Verzenio group and 86.1% in the endocrine therapy alone at three-year. The absolute differences widened further to 2.5%p at the two-year and 4.2%p at the three-year.

At three-year, there were 191 cases in the Verzenio group and 278 cases in the endocrine therapy alone, indicating a 31.3% lower risk of distant relapse or death with Verzenio (HR=0.687, P<0.0001).

Furthermore, in the additional analysis (median follow-up of 42 months) released through SABCS 2022, the four-year IDFS was 85.8% and 79.4%, with an absolute difference of 6.4%p, which was wider than in the two and three-year analyses.

The four-year DRFS was also 88.4% and 82.5%, with an absolute difference of 5.9%p, wider than in the two and three-year analyses.

IDFS hazard ratio (HR) of the Verzenio group versus the control group was 0.664 (95% CI 0.578-0.762) and DRFS HR of 0.659 (CI 0.567-0.767), indicating a lower risk of invasive disease, distance relapse, or death in the Verzenio group by about 33~34%.

However, OS data were not sufficiently complete until the four-year analysis, with 5.6% deaths in the Verzenio group and 6.1% in the control group (HR=0.929, 95% CI 0.748-1.153, p=0.053), showing low mortality rate in Verzenio’s.

In this regard, Professor Sohn Joo-hyuk of the Department of Oncology at Severance Hospital summarized the study results at a press conference on the 14th to commemorate the expansion of Verzenio’s permission and said, “If you administer Verzenio as adjuvant therapy for two years, you could prevent six patients from dying.”

“If you reduce the relapse rate, the patient will not die in the end,” Sohn added. “On the other hand, most people die when recur, so in the metastatic stage, they can only get help to prolong survival.”

Sohn pointed out that oncology uses good drugs first and it is more important to reduce recurrence in adjuvant therapy.

“In this study, the difference in survival time by four-years is meaningful in that the effect is maintained even after 2 years of administration (carry-over effect),” Sohn said. “It is unknown whether this will continue to happen in the future, but for now, the two years of administration are still affecting later on.”

Regarding follow-up treatment options after administering CDK4/6 inhibitors in early therapy, Sohn said that various studies are being conducted, such as studies reusing CDK4/6 inhibitors.

"It was a great burden because 20% of early breast cancer patients experience intractable metastasis and recurrence,” said Christopher J. Stokes, representative of Lilly Korea. “Verzenio is the first CDK4/6 inhibitor to be approved for HR+ HER2- early breast cancer, and it will be a hope for patients with high-risk recurrence of early breast cancer.”