Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Verzenio™ - abemaciclib (LY2835219)
Therapeutic area: Cancer - Oncology
- cell cycle inhibitor/cyclin dependant kinase inhibitor. Abemaciclib (LY2835219) is a cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting CDK 4 and 6. Although abemaciclib inhibits both CDK 4 and CDK 6, the results from the cell-free enzymatic assays have shown that it was most active against Cyclin D 1 and CDK 4.
Company: Eli Lilly (USA -IN)
- refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer
- • On 26 July 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion,
recommending the granting of a marketing authorisation for Verzenios®, intended for the treatment of locally advanced or metastatic breast cancer. Verzenios will be available as film-coated tablets (50 mg, 100 mg and 150 mg). The benefit with Verzenios® is its ability to significantly improve progression-free survival in combination with an aromatase inhibitor or fulvestrant. The most common side effects are diarrhoea, infections, neutropenia, anaemia, fatigue, nausea, vomiting and decreased appetite.
- The full indication is: "Verzenios is indicated for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising
hormone-releasing hormone (LHRH) agonist."
- • On February 26, 2018, Eli Lilly announced that the FDA has approved Verzenio™ (abemaciclib) in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. This additional FDA approval marks the third indication for Verzenio® within five months. In September 2017, Verzenio became the first and only cyclin-dependent kinase (CDK)4 & 6 inhibitor approved in combination and as a single agent in metastatic breast cancer. Specifically, Verzenio was approved for use in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy, and as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
- The recommended dose of Verzenio in combination with an AI is 150 mg orally twice daily, continued until disease progression or unacceptable toxicity. Verzenio is available in four tablet strengths (200 mg, 150 mg, 100 mg, and 50 mg).
This approval of Verzenio as initial therapy in combination with an AI is based on the efficacy and safety demonstrated in the pivotal MONARCH 3 clinical trial. 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.
In MONARCH 3, Verzenio dosed orally at 150 mg twice daily on a continuous schedule with an AI demonstrated a greater than 28-month median progression-free survival (PFS) in patients who received initial endocrine-based therapy for metastatic disease (28.2 months [95% CI: 23.5-NR] vs 14.8 months [95% CI: 11.2-19.2] with placebo plus an AI [HR: 0.54; 95% CI: 0.418-0.698, P < 0.0001]). In patients with measurable disease who received Verzenio plus an AI (n=267), an objective response rate of 55.4 percent was achieved (ORR; defined as complete response plus partial response [CR + PR], and based upon confirmed responses; PR defined as ?30% reduction in target lesions)1 (n=148; 95% CI: 49.5-61.4), with 52.1 percent of patients having achieved a PR (n=139) and 3.4 percent having achieved a CR (n=9).2 In comparison, in the placebo-plus-AI group of patients with measurable disease (n=132), ORR was 40.2 percent (n=53; 95% CI: 31.8-48.5), with all women being partial responders. Median duration of response (DoR) was 27.4 months with Verzenio plus an AI (95% CI: 25.7-NR) versus 17.5 months with placebo plus an AI (95% CI: 11.2-22.2).
- • On September 28, 2017, the FDA approved abemaciclib (Verzenio®) in combination with fulvestrant for women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. In addition, abemaciclib was approved as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. The approval in combination with fulvestrant was based on MONARCH 2, a randomized, placebo-controlled, multicenter trial in women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. The trial randomized 669 patients to receive either abemaciclib or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Patients remained on continuous treatment with abemaciclib until development of progressive disease or unmanageable toxicity. Median progression-free survival for patients taking abemaciclib with fulvestrant was 16.4 months compared with 9.3 months for those taking placebo with fulvestrant (HR 0.553; 95% CI: 0.449, 0.681; p<0.0001). The objective response rate in patients with measurable disease taking abemaciclib with fulvestrant was 48.1% (95% CI: 42.6, 53.6) compared to 21.3% (95% CI 15.1, 27.6) in the placebo with fulvestrant treated patients.
- The approval as monotherapy was based on MONARCH 1, a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received one or two prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg abemaciclib orally twice daily on a continuous schedule until progressive disease or unmanageable toxicity. Objective response rate was 19.7 percent (95% CI: 13.3, 27.5) with a median response duration of 8.6 months (95% CI: 5.8, 10.2).
- The most common adverse reactions in greater than 20% of patients taking abemaciclib were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia. The most frequently reported (?5%) grade 3 or 4 adverse reactions in patients taking abemaciclib with fulvestrant were neutropenia, diarrhea, leukopenia, anemia, and infections.
- The recommended starting doses are 150 mg twice daily in combination with fulvestrant or 200 mg twice daily as monotherapy.
- • On July 10, 2017, Eli Lilly announced that the FDA has accepted and filed its New Drug Application (NDA) for abemaciclib, and given the NDA a Priority Review designation. The NDA includes the company's submission of abemaciclib for two indications:
- - abemaciclib monotherapy for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who had prior endocrine therapy and chemotherapy for metastatic disease;
- - and for abemaciclib in combination with fulvestrant in women with HR+, HER2- advanced breast cancer who had disease progression following endocrine therapy. This submission is based on the MONARCH 1 and MONARCH 2 studies, respectively.
- With Priority Review of a new drug, the FDA's goal is to take action within eight months of receiving an application, compared with the standard review timeframe of 12 months.1 Lilly is working closely with the FDA and anticipates agency action on this application in the first quarter of 2018. In addition, Lilly intends to submit abemaciclib to European regulators in the third quarter of 2017 and to Japanese regulators before the end of 2017.
• On October 8, 2015, Eli Lilly announced that the FDA has granted Breakthrough Therapy Designation to abemaciclib, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer. This designation is based on data from the breast cancer cohort expansion of the company's Phase I trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. Patients in this cohort had received a median of seven prior systemic treatments. These data were presented at the San Antonio Breast Cancer Symposium in 2014.
- Lilly has an active clinical development program studying abemaciclib in breast cancer. MONARCH 1 is a Phase II trial evaluating the use of abemaciclib as monotherapy in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. In addition, Lilly is evaluating abemaciclib in two Phase III clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant in postmenopausal patients with HR+, HER2- advanced or metastatic breast cancer, and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in patients with HR+, HER2- locoregionally recurrent or metastatic breast cancer.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
UE authorization: 2017-09-28
Favourable opinion UE: 2018-07-26
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: