INDIANAPOLIS—On Oct. 6, Eli Lilly and Co. announced that interim results from its MONARCH 3 clinical trial were published online in the Journal of Clinical Oncology, providing promising data in support of a combo approach of Verzenio (abemaciclib), the company’s cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with a nonsteroidal aromatase inhibitor (NSAI) (either anastrozole or letrozole).
The data from the Phase 3 double-blind, placebo-controlled study were presented publicly at the European Society for Medical Oncology 2017 Congress in September, showing that abemaciclib plus an NSAI resulted in a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) compared to an NSAI alone in women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.
“The significant results seen in MONARCH 3 confirm the clinical value of combining abemaciclib with an aromatase inhibitor in patients with endocrine-sensitive advanced breast cancer, and we look forward to seeing the final PFS data in the coming months,” said lead author Dr. Matthew P. Goetz, a professor of oncology and pharmacology at the Mayo Clinic and co-lead investigator of the MONARCH 3 study. “These data further demonstrate that abemaciclib is an effective treatment in the CDK4 and 6 class. This class represents a new standard of care in the treatment of advanced breast cancer.”
MONARCH 3 met what Lilly called “a rigorous threshold” for demonstrating efficacy at the time of preplanned interim analysis, with a 46-percent reduction in the risk of progression or death in patients receiving initial therapy for metastatic disease. The median PFS for abemaciclib in combination with an NSAI was not reached (i.e., the disease had not progressed significantly), compared to 14.7 months in the placebo arm. These results are supported by an improvement in response rate, with a 59.2-percent ORR in patients with measurable disease, including five patients (1.5 percent) achieving a complete response. Median duration of response (DoR) was not reached in the abemaciclib-plus-NSAI arm. Final PFS results are expected at the end of the year and will be presented at a scientific congress in the first half of 2018.
“At Lilly, we remain deeply committed to delivering standard of care-changing medicines that improve the lives of many cancer patients,” said Dr. Levi Garraway, senior vice president of global development and medical affairs at Lilly Oncology. “We now have evidence from two randomized trials showing that the addition of Verzenio to an endocrine therapy provides clinical benefit to women with metastatic breast cancer and we look forward to further advancing our MONARCH clinical program.”
In MONARCH 3, abemaciclib in combination with an NSAI was generally well tolerated. The most frequent adverse events (AEs) of any grade in the abemaciclib-plus-NSAI arm were diarrhea, neutropenia, fatigue, infections and nausea.
The MONARCH 3 study also included exploratory subgroup analyses that underscored consistency of results (when compared to the overall intention-to-treat results) in patients with certain challenging disease characteristics. Further studies are needed to explore these findings.
MONARCH 3 was designed to evaluate the efficacy and safety of abemaciclib in combination with NSAIs as initial endocrine-based therapy for postmenopausal women with 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 abemaciclib 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, overall survival and safety.
Verzenio is an inhibitor of CDK4 and CDK6, which are activated by binding to D-cyclins. In estrogen receptor-positive breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression and cell proliferation. Verzenio disrupts the cell cycle. Preclinically, Verzenio dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size. 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). 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.
However, bad news about Verzenio dropped around the same time. Lilly had hoped to give the therapeutic a leg up in the market—especially in light of the fact the compound is going head to head with Pfizer’s Ibrance and Novartis’ Kisqali in the CDK 4/6 market—by positioning Verzenio for treatment of KRAS-mutated non-small cell lung cancer as well. But the drug recently missed its endpoint in a Phase 3 clinical trial, failing to significantly beat out Roche’s Tarceva at extending overall survival in patients who had already undergone platinum-based chemotherapy.