In 2017 the U.S. Food and Drug Administration (FDA) approved a CDK 4/6 inhibitor, Abemaciclib (tentatively known as bomacitinib), for marketing, bringing a new option to advanced breast cancer.Abemaciclib  nbsp;Used primarily in hormone receptor-positive, HER2 (i.e., human epidermal growth factor receptor 2)-negative advanced metastatic breast cancer, it can be used not only alone, but also in combination with fulvestrant, an aromatase inhibitor.
How does bomacitinib work?
In human cells, there is a protein called CDK4/6 (i.e., cell cycle protein-dependent kinases 4 and 6), which is a key factor in regulating the cell cycle and is able to modulate the proper conduct of the cell cycle, thereby promoting cell proliferation and growth. It is naturally no exception for cancer cells.
CDK4/6 inhibitors precisely block the cell cycle, stopping the proliferation of tumor cells and acting as an inhibitor of tumor proliferation. As a member of the CDK4/6 inhibitor family, Abemaciclib prevents breast cancer progression in just this way.
MONARCH 1 study: single agent benefits 40% of patients
In the phase II clinical study MONARCH 1 Abemaciclib showed better control of tumor progression, but also showed some degree of adverse effects.
The study enrolled 132 hormone receptor-positive, HER2 -negative patients with metastatic breast cancer who had received 1 to 2 types of chemotherapy and experienced disease progression during or after endocrine therapy. The results found that the objective remission rate after patients received Abemaciclib treatment was 19.7%, with 42.4% of patients achieving complete remission, partial remission, or stable disease and maintaining ≥6 months (clinical benefit), and patients had a median progression-free survival of  nbsp;6.0 months, with a median overall survival of 17.7 months.
Diarrhea was Abemaciclib the most common adverse reaction, with an incidence of 90.2 %, of which grade 1 1, 2 2, and 3 3 accounted for 41.7%, 28.8%, and 19.7%, respectively, and only 1  Neutropenia was another common adverse effect, with the incidence of grade 3 and 4 adverse reactions at 22.3% and 4.6%, respectively, with 49.2% of patients experiencing serious adverse reactions due to Abemaciclib (excluding diarrhea) and reduce the drug dose. Other adverse reactions included fatigue, nausea, and loss of appetite.
MONARCH 2 Study: Combining Fulvestrant Doubles Objective Remission Rate
The MONARCH 2 study provided the rationale for the Abemaciclib combination fulvestrant (Fulvestrant) regimen. This phase III clinical study enrolled a total of 669 hormone receptor-positive, HER2 -negative patients with advanced breast cancer who had progressed on endocrine therapy. The results showed that Abemaciclib combined with fulvestrant compared with fulvestrant alone significantly prolonged progression-free survival by 7.1 months ( 16.4 months, 9.3 months, respectively), reduced the risk of tumor progression by 45%, and doubled the objective remission rate over ( 48.1%, 21.3%, respectively).
Likewise, diarrhea (87.3%, 23.8%), neutropenia (59.2%, 7.1%), and leukopenia (43.7%, 4.8%) were the most common adverse reactions among patients who were coadministered with Abemaciclib in this study.
MONARCH 3 study: combination aromatase inhibitors advance to first-line therapy
The MONARCH 3 study, conducted in 493 postmenopausal hormone receptor-positive, HER2 -negative patients with advanced breast cancer, validated Abemaciclib in first-line therapy, none of whom had previously received advanced cancer treatment , which included premenopausal or perimenopausal patients 114 and postmenopausal patients 555 in the study. The patients all received an aromatase inhibitor [anastrozole (Anastrozole) or letrozole (Letrozole)] in the study.
The results were that the combination of Abemaciclib resulted in significantly longer median progression-free survival, with more than half of the patients on the combination Abemaciclib remaining tumor-free at a median follow-up of 17.8 months, compared with 14.7 months Half of the patients on aromatase inhibitors alone had progressed by Abemaciclib reduced the risk of tumor progression by 46%.
In addition, tumors decreased in all treated patients, and receiving Abemaciclib resulted in a significant increase in the absolute objective remission rate by 15% ( 59%, 44%, respectively). Overall survival was similar in both groups, with mortality rates of 9.8% and 10.3% in patients combined with and without Abemaciclib respectively.
For safety, diarrhea remains the more common adverse effect, with a higher incidence of both grade 1 (44.6%, 21.7%) and grade 2 (27.2%, 6.8%) diarrhea in patients on Abemaciclib . However, the majority (76.3%) of patients on Abemaciclib had diarrhea that did not require treatment, and only 2.3% of patients discontinued Abemaciclib due to severe diarrhea. of patients on Abemaciclib had 41.3% developed neutropenia, with reversible changes occurring after discontinuation. In addition, the incidence of infection was slightly higher in those applying Abemaciclib (39.1%, 28.6%).
Continued exploration: more populations, more combinations
A search of the US Clinical Trials Platform (https://www.clinicaltrials.gov/) and the China Drug Clinical Trials Registry and Information Publicity Platform (http://www.chinadrugtrials.org.cn/) reveals information about Abemaciclib Research continues on additional applications in breast cancer, mainly in the following directions.
- More types of breast cancer. In addition to continuing to explore in existing hormone receptor-positive, HER2 -negative breast cancers, investigators have focused on metastatic triple-negative breast cancer ( NCT03130439) and hormone receptor-positive and HER2 -positive breast cancer (NCT02747004).
- Combination with additional regimens. In addition to continued attempts to combine with different endocrine agents, such as tamoxifen (NCT02747004), combination with immunotherapeutic agents has become one of the directions (NCT03280563).
- Exploring applications in the Chinese population. Studies in the Chinese population are still focused on hormone receptor-positive, HER2 -negative breast cancer, and studies in combination with anastrozole, letrozole, or fulvestrant in patients with locally recurrent or metastatic breast cancer (CTR20160365) are in patient enrollment, and in addition, for high-risk early-stage breast cancer, investigators will also attempt to use Abemaciclib monotherapy or in combination with endocrine therapy (CTR20171172), and patient enrollment is about to begin.
Summary
For hormone receptor-positive, HER2 -negative advanced breast cancer, the option is Abemaciclib:
- After progression of endocrine therapy, Abemaciclib monotherapy has an objective remission rate of nearly 20%;
- After progression on endocrine therapy, progression-free survival was further extended by 7.1 months with the addition of Abemaciclib when fulvestrant was applied;
- The addition of Abemaciclib to an aromatase inhibitor at the time of first-line endocrine therapy further reduced the risk of tumor progression by 46%.
Abemaciclib in combination with endocrine agents or even alone, has shown good results in controlling tumor progression in hormone receptor-positive, HER2 -negative advanced breast cancer. Of course, adverse reactions such as diarrhea and neutropenia need to be noted, and although most diarrhea does not need to be treated, adverse reactions are a point that patients need to consider when choosing this drug. We look forward to more evidence from the data on the use of Abemaciclib in more breast cancer, especially in Chinese patients.