Eli Lilly’s Verzenio in combo with endocrine therapy gets US FDA approval for certain people with HR+ HER2- high risk early breast cancer

The US Food and Drug Administration (FDA) has approved Eli Lilly and Company's Verzenio (abemaciclib), in combination with endocrine therapy (tamoxifen or an aromatase inhibitor), for the adjuvant treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score of =20% as determined by an FDA-approved test. Ki-67 is a marker of cellular proliferation. Verzenio is the first and only CDK4/6 inhibitor approved for this patient population.
"Over time, the collective results of the Verzenio clinical development programme have demonstrated a differentiated CDK4/6 inhibitor profile, and the landmark data from the monarchE trial that supported this new indication in HR+ HER2- early breast cancer represent another important step forward for people who are in need of new treatment options," said Jacob Van Naarden, senior vice president, CEO of Loxo Oncology at Lilly and president, Lilly Oncology. "We are pleased with this initial approval in the adjuvant setting and as these data continue to mature, we look forward to further opportunities to work with health authorities to expand the use of Verzenio in this setting."

The Verzenio phase 3 monarchE trial is a randomized (1:1), open-label, two cohort, multicenter study in adult women and men with HR+ HER2-, node-positive, resected EBC with clinical and pathological features consistent with a high risk of disease recurrence. In the trial, patients were randomized to receive two years of Verzenio 150 mg twice daily plus physician's choice of standard endocrine therapy, or standard endocrine therapy alone. Patients in both treatment arms were instructed to continue to receive adjuvant endocrine therapy for up to 5-10 years as recommended by their clinician. The primary endpoint of the study is invasive disease-free survival (IDFS) and was met at a pre-specified interim analysis in the intent-to-treat (ITT) population, with a statistically significant improvement in IDFS for patients treated with Verzenio plus ET compared to those treated with ET alone. Consistent with expert guidelines, IDFS was defined as the length of time before breast cancer comes back, any new cancer develops, or death.

Having achieved the study's primary endpoint in the entire enrolled population, a pre-specified analysis of IDFS was also conducted in patients with high-risk clinical and pathological factors and a Ki-67 score =20%. This subgroup analysis (N=2,003) included patients with =4 positive axillary lymph nodes (ALN), or 1-3 positive ALN with either Grade 3 disease and/or tumor size =5 cm, and whose tumors had a Ki-67 score of =20%. There was also a statistically significant improvement in IDFS for this pre-specified subgroup of patients receiving Verzenio plus ET compared to those who received ET alone (HR=0.643, 95% CI: 0.475, 0.872, p=0.0042).

This approval is based on efficacy results from an analysis of this subgroup with additional follow-up, conducted post-hoc. In this analysis, Verzenio given in combination with ET continued to demonstrate a clinically meaningful benefit, with a 37 per cent decrease in the risk of breast cancer recurrence or death compared to standard adjuvant ET alone for patients with high risk clinical and pathological features and a Ki-67 score =20% (HR: 0.626 [95% CI: 0.49-0.80]), and an absolute benefit in IDFS event rate of 7.1 per cent at three years. The number of IDFS events at the time of this analysis was 104 with Verzenio plus ET compared to 158 with ET alone. Overall survival data were not mature and additional follow up is ongoing.

Adverse reactions from monarchE were consistent with the known safety profile for Verzenio. Safety and tolerability were evaluated in 5,591 patients. The most common adverse reactions reported (>10%) in the Verzenio plus ET (tamoxifen or an aromatase inhibitor) arm, and >2% higher than the ET arm alone, were diarrhea, infections, fatigue, nausea, headache, vomiting, stomatitis, decreased appetite, dizziness, rash, and alopecia. The most common laboratory abnormalities (all grades =10%) were creatinine increased, white blood cell count decreased, neutrophil count decreased, anemia, lymphocyte count decreased, platelet count decreased, ALT increased, AST increased, and hypokalemia.

This FDA approval builds on the established body of evidence for Verzenio, which is already approved for the treatment of certain types of HR+ HER2- advanced or metastatic breast cancer. Concurrent with this approval, the FDA has expanded the use of Verzenio in all indications, when given in combination with endocrine therapy, to include men. Verzenio is available in tablet strengths of 200 mg, 150 mg, 100 mg, and 50 mg.

"The design and results of the monarchE study are practice-changing and represent the first advancement in adjuvant treatment of HR+ HER2- breast cancer in a very long time," said Sara M. Tolaney, MD, MPH, Harvard Medical School, Dana-Farber Cancer Institute, and investigator on the monarchE study. "This FDA approval for Verzenio in combination with endocrine therapy in the early breast cancer setting has the potential to become a new standard of care for this population. We are encouraged by the marked reduction in the risk of recurrence even beyond the two-year treatment period in these patients, and I'm grateful to be able to offer this as a treatment option to my patients."

"Women and men living with high risk HR+ HER2- early breast cancer want to do all they can to reduce the risk of the disease coming back, with the hope of living free of cancer. The approval of Verzenio provides a new treatment option to help them do just that," said Jean Sachs, chief executive officer, Living Beyond Breast Cancer. "This approval brings new optimism to the breast cancer community."

The labelling for Verzenio contains warnings and precautions for diarrhea, neutropenia, interstitial lung disease (ILD/pneumonitis), hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. Perform complete blood counts and liver function tests prior to the start of Verzenio treatment, every two weeks for the first two months, monthly for the next two months and as clinically indicated. Based on results, Verzenio may require dose modification. Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. Advise patients of potential risk to a fetus and to use effective contraception.

monarchE is a global, randomized, open-label, two cohort, multicenter phase 3 study in adult women and men with HR+ HER2-, node-positive resected EBC with clinical and pathological features consistent with a high risk of disease recurrence. A total of 5,637 patients were randomized (1:1) to receive two years of Verzenio 150 mg twice daily plus physician's choice of standard endocrine therapy, or standard endocrine therapy alone. Patients in both treatment arms were instructed to continue to receive adjuvant endocrine therapy for up to 5-10 years as recommended by their clinician. Cohort 1 enrolled patients with =4 positive axillary lymph nodes (ALN), or 1-3 positive ALN and either Grade 3 disease or tumor size =5 cm. Cohort 2 enrolled patients with 1-3 positive ALN and centrally determined Ki-67 score of =20%. The primary endpoint was IDFS in the ITT population (Cohorts 1 & 2). Secondary endpoints were IDFS in patients with high Ki-67 score (in the ITT population and in the Cohort 1 population), DRFS, overall survival, and safety.

It is estimated that 90 percent of all breast cancers are detected at an early stage. Although the prognosis for HR+ HER2- EBC is generally positive, 20 per cent of patients will experience recurrence potentially to incurable metastatic disease. Risk of recurrence is greatest within the initial two to three years post-diagnosis, particularly in patients with node-positive, high risk EBC. Factors associated with high risk of recurrence include: positive nodal status, large tumor size (=5 cm), high tumor grade (Grade 3), and high rate of cellular proliferation [Ki-67 score (=20%)].

Node-positive means that cancer cells from the tumor in the breast have been found in the lymph nodes in the armpit area. Although the breast cancer is removed through surgery, the presence of cancer cells in the lymph nodes signifies that there is a higher chance of the cancer returning and spreading.

Verzenio abemaciclib is a targeted treatment known as a CDK4/6 inhibitor. Verzenio is a non-chemotherapy oral tablet.

Verzenio works inside the cell to block CDK4/6 activity and help stop the growth of cancer cells, so they may eventually die (based on preclinical studies). Cyclin-dependent kinases (CDK)4/6 are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4/6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly's first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.



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