FDA approved drug called Abemaciclib ( Verzenio) : 1)investigate the background
ID: 205358 • Letter: F
Question
FDA approved drug called Abemaciclib (Verzenio) :
1)investigate the background literature surrounding their clinical development and the phase III pivotal clinical trial and then discuss:
2)How do the drugs inhibit kinase activity?
3)What biomarkers are used to select patients for the trial, if any?
4)Why do think the markers that were used, if any- were used?
5)What biomarker studies were performed, even exploratory?
6)What new biomarkers should be explored, based on the mechanism of action of the drug and what platforms could they be measured on?
Explanation / Answer
1. MONARCH 3 is a Phase 3, randomized, double-blind, placebo-controlled trial evaluating Verzenio in combination with an AI as initial endocrine-based therapy that enrolled 493 postmenopausal women with HR+, HER2- advanced breast cancer who had no prior systemic treatment for advanced disease. In patients who received neoadjuvant/adjuvant endocrine therapy, a disease-free interval of more than 12 months since completion of endocrine therapy was required. This Verzenio new drug application was given Priority Review as part of the FDA's Expedited Programs for Serious Conditions, a program used for therapies that address an unmet medical need in the treatment of serious or life-threatening conditions, such as metastatic breast cancer. Verzenio was also granted Breakthrough Therapy Designation in 2015 based on the Phase 1 JPBA trial.
1. Eli Lilly and Company was developed the Verzenio (abemaciclib). It underwent three clinical trial before being approved by FDA in 2017.
MONARCH 1 was a Phase II, clinical trial. It was a single-arm clinical trial, enrolling 132 patients with HR+ and HER2- metastatic breast cancer. Verzenio™ 200mg dose was administered orally twice daily to the patients. An objective rate response (ORR) of 19.7% and a median duration of response (DoR) of 8.6 months was obtained/
MONARCH II was a randomized phase III trial which was double-blind, and placebo-controlled. There were 669 patients with HR+, HER2- metastatic breast cancer enrolled and randomized in a 2:1 ratio of Verzenio™ plus fulvestrant or placebo plus fulvestrant. Verzenio plus fulvestrant obtained a median progression free-survival (PFS) of 16.4 months, as compared to 9.3 months in patients administered with placebo plus fulvestrant. ORR was 48.1% in drug treated patients vs 21.3% in Placebo treated patients.
The phase III clinical trial was called MONARCH 3 in April 2015. This phase III trial was randomized, double-blind, placebo-controlled trial evaluating Verzenio in combination with an AI. 493 postmenopausal women with HR+, HER2- advanced breast cancer with no prior systemic treatment for advanced disease were inducted in the study. The placebo included patients treated with neoadjuvant/adjuvant endocrine therapy.
Verzenio was administered orally (150mg) on a continuous schedule along with aromatase inhibitor (AI) to postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. Mean disease progression free survival for 28 months was seen in women with metastatic disease vs women with placebo treatment (14.8 months).
2. Verzenio is a cocktail of cyclin-dependent kinases (CDK) 4 and 6 inhibitors that inhibit D type cyclins. This inhibits cell cycle progression. In estrogen receptor-positive (ER+) breast cancer, cyclin D1 and CDK4/6 phosphorylates retinoblastoma protein (Rb), cell cycle progression. This results in cell proliferation. Exposure to the drug inhibits Rb phosphorylation. Thus, there is a block to cell cycle progression from G1 to S phase. As a result, there is senescence, and apoptosis in cancer cells.
3. Estrogen receptor and epidermal growth factor receptor-2 were the two biomarkers selected for inducting patients. Estrogen receptor binds to estrogen and induces mitosis in breast tissues. The tumor in the patients should be positive for ER. Epidermal growth factors (EGF) bind to its receptors (EGFR) and regulate epithelial-mesenchymal transition. HER2 increase the metastatic as compared to HER2- cancers. The patients induced had HER2- tumors.
4. Nearly 80% of the breast cancers are ER+. They respond to the hormone estrogen, which induces mitosis or cell division. ER positive tumors respond to therapy much more than ER- tumors. Human epidermal growth factor receptor 2 (HER) is a protein expressed in 20% tumors. Most of the breast tumors are HER negative. ER positive, HER negative tumors respond better to estrogen blocking tumors. The HER2- tumors are less aggressive. Selection of the biomarkers helps to categorize the tumor for appropriate treatment.
As per Chegg’s rule, only one question is mandatory to be answered.
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