Eli Lilly's Abecili Tablets Adds Indications, Opening a New Era of Early Breast Cancer Treatment

On January 6, Eli Lilly announced that the National Medical Products Administration (NMPA) approved a new indication for Abemaciclib (trade name: Weizhe), a new anti-tumor drug
.

That is, abeccil tablets combined with endocrine therapy (tamoxifen or aromatase inhibitor) as adjuvant therapy are suitable for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, lymph node positive, high Adult patients with early-stage breast cancer at risk of recurrence and Ki-67 ≥20%
.

 PART.
01 Breast cancer and CDK4/6 inhibitors Breast cancer, one of the most common malignancies in women
.

According to the latest global cancer burden data in 2020, breast cancer has become the number one cancer in the world
.

In China, the number of new cases of breast cancer in 2020 alone is about 420,000
.

According to epidemiological studies, the incidence of breast cancer is gradually increasing.
Although the age of 40-50 is the peak incidence, the age of onset is gradually advancing
.

 Breast cancer has previously been classified into different subtypes based on the levels of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expressed by breast cancer
.

However, an article on the classification of HER2 expression in breast cancer published in The Lancet Oncology showed that "patients with breast cancer clinically classified as HER2 negative have different biological and clinicopathological characteristics, and are sensitive to treatment.
, and there are also significant differences in survival prognosis
.

” This actually brings some difficulties to clinical treatment
.

Although the latest epidemiological survey shows that the decline in breast cancer mortality has slowed year by year, its long-term risk has not decreased significantly
.

Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer accounts for about 70% of the total breast cancer and is the most common subtype.
The pathological complete response rate (pCR) is low, less than 20%.
%
.

Moreover, about 30% of patients with diagnosed HR+, HER2- early breast cancer are at risk of cancer recurrence or progression to incurable metastatic cancer
.

Several studies have confirmed that CDK4/6 inhibitors combined with ET can significantly improve the prognosis of advanced breast cancer patients with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-)
.

Previously, it was controversial whether CDK4/6 inhibitors could further improve the advanced prognosis of high-risk patients through adjuvant treatment of early breast cancer patients
.

However, the approval of the new indication of Eli Lilly Abecili Tablets confirms that CDK4/6 inhibitor combined with ET adjuvant therapy can improve the IDFS of HR+, HER2- high-risk early breast patients
.

CDK4/6, cyclin-dependent kinase 4/6, is one of the important regulators in the process of mitosis and is closely related to the occurrence and development of various cancers
.

Through transcriptional and post-transcriptional mechanisms, mitotic signals can cause downstream cyclin D1 and CDK4/6 to form and activate complexes, thereby causing a series of responses
.

Cyclin D1 is also an important link in the CDK4/6 pathway, and cyclin D1 protein is overexpressed in most breast cancers
.

When cyclin D1 is overexpressed, the activity of CDK4/6 will also increase, which will lead to abnormal regulation of downstream cell cycle and eventually lead to abnormal cell proliferation.

.

 CDK inhibitors include INK4 family and CIP/KIP family proteins in humans
.

The INK4 protein family includes p16INK4A, p15INK4B, p18INK4C and p19INK4D, and the CIP/KIP protein family includes p27KIP1, p21CIP1 and p57KIP2
.

Synthetic inhibitors Synthetic inhibitors Palbociclib, Ribociclib and Abemaciclib are currently the three CDK4/6 inhibitors approved by the FDA
.

 In addition to Abemaciclib, Palbociclib, and Ribociclib, which are also used as breast cancer treatments, Palbociclib or Ribociclib in combination with letrozole are the first-line treatment options for breast cancer
.

PART.
02 About Abemaciclib Abemaciclib Abemaciclib, an oral cyclin-dependent kinase (CDK4/6) inhibitor, was approved by the FDA on September 28, 2017.
The indication is that it has been combined with fulvestrant Second-line therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer with disease progression after endocrine therapy, or monotherapy for disease after endocrine therapy and chemotherapy Progressive HR+/HER2- advanced or metastatic breast cancer
.

In February 2018, the FDA re-approved abeciclib in combination with an aromatase inhibitor as an initial endocrine therapy for HR+, HER2- postmenopausal women with advanced or metastatic breast cancer
.

The new indication approved by NMPA on January 6 has also become the first and only CDK4/6 inhibitor approved for early breast cancer in China
.

The approval of this new indication is based on the results of a randomized, open-label, multicenter Phase III clinical trial, monarchE
.

The purpose of this study is to verify the efficacy and safety of abeccil combined with ET therapy, compared with ET therapy, in patients with HR+, HER2- high-risk early breast cancer
.

The study enrolled 5,637 patients, including 501 Chinese patients, from 603 centers in 38 countries, among adult men and women with HR+, HER2-, and node-positive early-stage breast cancer
.

All patients were randomized (1:1) to receive 150 mg of ambecilli with standard ET or standard ET alone for two years
.

The primary endpoint was invasive disease-free survival (IDFS) in the ITT population (cohorts 1 and 2), and secondary endpoints were IDFS, no distant Relapse survival (DRFS), overall survival and safety
.

According to the results of the study, the combination therapy of abeccil and ET can significantly improve the invasive disease-free survival (IDFS) of patients with HR+ and HER2- high-risk early breast cancer
.

In adult patients with HR+, HER2-, lymph node-positive, high recurrence risk and Ki-67 ≥20% early breast cancer, abeccil combined with standard endocrine therapy significantly reduces the risk of recurrence in high-risk early breast cancer patients compared with standard endocrine therapy 37% (HR 0.
63, 95%CI 0.
49-0.
80, p=0.
0002), and the absolute benefit of 3-year invasive disease-free survival (IDFS) rate was 7.
1%; at the same time, abecilli combined with standard endocrine therapy also significantly reduced distant The risk of metastasis was 40% (HR 0.
60, 95%CI 0.
46-0.
79, p=0.
0002), and the absolute benefit of the 3-year distant metastasis-free survival (DRFS) rate was 5.
2%
.

PART.
03 Conclusion and Prospects In fact, in October 2021, the FDA has approved abecici for the adjuvant treatment of patients with early breast cancer.
This NMPA approval is a boon for domestic patients
.

Although compared with Palbociclib and Ribociclib, the inhibition of CDK4/6 by abecillin is only 9 times that of CDK9, but the drug activity is not affected by the mutation of PIK3CA, and it also has potential significance in other tumors
.

With the demonstrated role of CDK4/6 inhibitors in the treatment of high-risk early breast cancer, accurate diagnosis, typing and treatment have become the key to the future
.

References: 1.
Eli Lilly's official website 2.
C.
Louwrens Braal, Elisabeth M.
Jongbloed, Saskia M.
Wilting, Ron HJ Mathijssen, Stijn LW Koolen, and Agnes Jager.
Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences[J].
Drugs.
2021; 81(3): 317–331.
3.
N.
Harbeck et.
Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study[J].
Ann Oncol.
2021 Sep 29;S0923-7534(21)04494-X.
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