Since September 2017, abemaciclib has been approved in the US for "adults who have hormone receptor (HR)-positive,human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient's hormones".[6]
In studies that comparedfulvestrant plus abemaciclib to fulvestrant plusplacebo in breast cancer patients,progression-free survival under abemaciclib therapy was 16.4 months on average, as compared to 9.3 months under the placebo arm.
Side effects that occurred in 20% or more of patients in studies were diarrhea,nausea and vomiting,leukopenia (low white blood cell count) includingneutropenia,anemia (low red blood cell count),thrombocytopenia (low platelet count), stomach pain, infections,fatigue, decreased appetite, and headache.[7][8]
As abemaciclib is mainly metabolized by the liver enzymeCYP3A4, inhibitors of this enzyme (such asketoconazole) are expected to increase itsblood plasma concentrations. Conversely, CYP3A4 inducers lower plasma concentrations of abemaciclib, as has been shown in a study withrifampicin.[8]
Like the related drugspalbociclib andribociclib, abemaciclib inhibits the enzymescyclin-dependent kinase 4 (CDK4) andcyclin-dependent kinase 6 (CDK6).[8] These enzymes are responsible forphosphorylating and thus deactivating theretinoblastoma protein, which plays a role incell cycle progression from the G1 (first gap) to the S (synthesis) phase.[9] Blocking this pathway prevents cells from progressing to the S phase, thereby inducingapoptosis (cell death).[8]In vitro analysis using cancer cell lines, it is reported that abemaciclib induces non-apoptotic cell death characterized by formation of cytoplasmic vacuoles derived from lysosomes. This result suggests that there may be a mechanism of action other than inhibition of a cyclin-dependent kinase.[10]
After oral intake, absolutebioavailability is 45%. Highest blood plasma concentrations are reached after 8 hours on average (range: 4.1–24.0 hours). When in the circulation, 96.3% of abemaciclib is bound toplasma proteins. The substance is mainly metabolized by the liver enzyme CYP3A4 toN-desethylabemaciclib (M2), and to a lesser extent tohydroxy derivatives (M18, M20) and anotheroxidative metabolite (M1). These metabolites have high plasma protein binding rates similar to the parent substance.[8]
Abemaciclib is excreted mainly via the feces (81%) and to a small extent via the urine (3%). Itselimination half-life is 18.3 hours on average.[8]
Successful trials against pre-treated metastatic breast cancer were announced for Phase I in May 2014,[11] Phase II in December 2014,[12] and Phase III in February 2017.[13] Abemaciclib was approved by the FDA in September 2017 either in combination with fulvestrant or as a monotherapy for women with HR+, HER2- advanced or metastatic breast cancer that had progressed while receiving endocrine therapy.[14] Abemaciclib was approved for the adjuvant treatment of HR+, HER2-, node-positive adjuvant breast cancer at high risk of recurrence in March 2023.[15][16]
As of 2023, abemaciclib was involved in twoPhase III clinical trials:
The SARC041 study compares abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.[17]
The CYCLONE 3 study compares abemaciclib versus placebo in combination with abiraterone and prednisone in patients with high-risk, metastatic, hormone-sensitive prostate cancer.[18]
^Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. (September 2017). "MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy".Journal of Clinical Oncology.35 (25):2875–2884.doi:10.1200/JCO.2017.73.7585.PMID28580882.{{cite journal}}: CS1 maint: overridden setting (link)
