Lilly announces publication of analyses showing benefit of the addition of Verzenio® (abemaciclib) in multiple subgroups of patients with advanced breast cancer identified as having a more concerning prognosis

In Clinical Studies News by Barbara Jacoby

Source: PRNewswire


Subgroup analyses demonstrate consistent benefit in subgroups of patients with a more concerning prognosis such as those with liver metastases, PR-negative disease, high tumor grade, or shorter treatment-free interval

Eli Lilly and Company (NYSE: LLY) today announced npj Breast Cancer published results from exploratory subgroup analyses of the MONARCH 2 and MONARCH 3 trials reinforcing the clinical benefit of Verzenio® (abemaciclib) plus endocrine therapy in the treatment of women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. The analyses demonstrate that while the benefit of the addition of Verzenio was seen across all patient subgroups, consistent with the individual study intent-to-treat (ITT) populations, the largest effects were observed in patients with certain disease characteristics identified as signaling a less favorable prognosis.

“Not all patients with HR+, HER2- metastatic breast cancer are the same. Each patient presents with unique patterns of clinical factors – with some patients having particularly concerning clinical characteristics that can signal a poor prognosis to oncologists. Therefore, treatment decisions must be tailored to each patient’s individual presentation,” said Joyce O’Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research and chair, Breast Cancer Research Program, Baylor University Medical Center, Texas Oncology and U.S. Oncology, Dallas, TX. “Understanding the prognostic value of certain clinical factors and how patients with or without these factors may respond to the addition of Verzenio can help us as we seek to individualize treatment decisions.”

These exploratory post-hoc analyses pooled data from over 1,000 patients and employed a two-step approach: first, the identification of independent prognostic variables derived from the entire population regardless of treatment assignment, and second, the description of the treatment effect of endocrine monotherapy compared to endocrine therapy plus Verzenio in each of the identified prognostic subgroups within the respective studies. Across both studies, certain prognostic factors included cancer that had spread to the liver (liver metastases), cancer that was not confined to the bone, cancer cells that were dividing more quickly (high tumor grade), and cancer cells that did not express progesterone receptors (PRs) and therefore were less likely to respond to hormonal therapy (PR-negative).

“These data further reinforce that we may be able to distinguish potential benefit of CDK4 & 6 inhibitor treatment in certain groups of patients,” said Angelo Di Leo, M.D., Ph.D., medical oncologist, Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy. “By pooling data across the MONARCH 2 and MONARCH 3 studies, we were able to maximize the power to detect prognostic factors, helping to lay the foundation for optimizing treatment for our patients.”

The exploratory analyses concluded that while the benefit of the addition of Verzenio was seen across all patient subgroups, consistent with the individual study ITT populations, patients with poor prognostic factors received the largest benefit from the addition of Verzenio to endocrine therapy. In particular, patients with cancer that spread to the liver, PR-negative tumors, or cancer cells that divided more quickly consistently received a substantial benefit with Verzenio, with a greater than 30 percent difference in response rates. Additionally, in MONARCH 3, the exploratory Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of treatment-free interval (TFI), or how quickly the cancer returned after the completion of adjuvant endocrine therapy, showed those whose cancer returned quickly after the conclusion of adjuvant endocrine therapy derived larger benefit from the addition of Verzenio compared to endocrine therapy alone.

“The research published today illustrates our commitment to the ongoing investigation of Verzenio and our focus on understanding and meeting the needs of women with advanced breast cancer, including those with a more concerning prognosis,” said Maura Dickler, M.D., vice president, late phase development, Lilly Oncology.

The subgroup analyses are hypothesis-generating and require additional evaluation in prospective clinical trials, but provide the groundwork for considering and investigating more personalized therapy in HR+, HER2- metastatic breast cancer. Lilly is committed to continuing research aimed at helping oncologists optimize care for women with advanced disease.

MONARCH 2 is a Phase 3, randomized, double-blind, placebo-controlled trial that enrolled 669 patients with HR+, HER2- metastatic breast cancer who progressed on endocrine therapy. Patients were randomized 2:1 to Verzenio plus fulvestrant or placebo plus fulvestrant. Verzenio was dosed on a continuous dosing schedule until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were objective response rate (ORR), overall survival (OS), and duration of response (DoR). Patients enrolled in the study had experienced disease progression on or within 12 months of receiving endocrine treatment in the neoadjuvant or adjuvant setting or while receiving first-line endocrine therapy for metastatic disease. Patients could not have received chemotherapy or more than one line of endocrine therapy for metastatic breast cancer.

MONARCH 3 is a Phase 3, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of Verzenio in combination with an aromatase inhibitor (anastrozole or letrozole), as initial endocrine-based therapy for postmenopausal women with HR+, HER2- advanced (locoregionally recurrent or metastatic) breast cancer who have had no prior systemic treatment for advanced disease. If neoadjuvant/adjuvant endocrine therapy was administered, a disease-free interval of more than 12 months since completion of endocrine therapy was required. A total of 493 patients were randomized 2:1 to receive 150 mg of Verzenio or placebo orally twice a day, without interruption, given in combination with either 1 mg of anastrozole or 2.5 mg of letrozole once daily until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS, with key secondary endpoints of ORR, DoR, OS and safety. 

About Advanced Breast Cancer
Breast cancer is the most common cancer in women worldwide, with more than 2 million new cases diagnosed in 2018.1 An estimated 266,120 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S. in 2018.2 Advanced breast cancer includes metastatic breast cancer, meaning cancer that has spread from the breast tissue to other parts of the body, and locally or regionally advanced breast cancer, meaning the cancer has grown outside the organ where it started but has not yet spread to other parts of the body.3 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic and an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being metastatic.4 Survival is lower among women with a more advanced stage at diagnosis: 5-year relative survival is 99 percent for localized disease, 85 percent for regional disease, and 26 percent for metastatic disease. Other factors, such as tumor size, also impact 5-year survival estimates.5

About Verzenio® (abemaciclib)
Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which 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.

Verzenio is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:

  • in combination with an aromatase inhibitor for postmenopausal women as initial endocrine-based therapy
  • in combination with fulvestrant for women with disease progression following endocrine therapy
  • as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

Lilly Forward-Looking Statement
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about abemaciclib as a treatment for patients with breast cancer and reflects Lilly’s current beliefs.  However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there can be no guarantee that future study results will be consistent with the results to date or that abemaciclib will receive additional regulatory approvals or be commercially successful.  For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.