Sara Hurvitz, MD, discusses the results from a preplanned interim analysis in HR+, HER2-negative breast cancer.
Sara Hurvitz, MD
Results from a preplanned interim analysis demonstrated that neoadjuvant abemaciclib administered alone or added to anastrozole led to significantly greater reductions in tissue Ki-67 than anastrozole monotherapy in postmenopausal women with hormone receptor (HR)-positive and HER2-negative breast cancer. The results of the study were presented at the 2016 ESMO Annual Congress.
The analysis done at 9 months showed the geometric mean percent change from baseline was significantly greater after 2 weeks of treatment in the proliferation marker, Ki-67. The geometric mean percent change from baseline was -93.5% with the combination, and -93% with abemaciclib monotherapy versus -71% in patients receiving solely anastrozole (P<.001).
More patients receiving abemaciclib either alone or in combination with anastrozole showed Ki-67 levels below 2.7% at week 2; 69.6% of patients receiving abemaciclib/anastrozole and 68.4% of patients receiving abemaciclib achieved this response versus 22.7% of patients receiving anastrozole.
"Ki-67 levels below 2.7% correlate with complete cell cycle arrest," explained Sara Hurvitz, MD, director of the Breast Cancer Program at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. “The change in proliferation gene mRNAs after 2 weeks of treatment, in blood or tumor, appeared to correlate with the change in Ki67, with a greater reduction in the abemaciclib-containing arms,” she continued.
Abemaciclib is an inhibitor of CDK4/6, which phosphorylates the retinoblastoma (Rb) tumor suppressor protein resulting in G1 to S phase cell cycle transition. CD4/6 is activated by estrogen and is deregulated in breast cancer, leading to cell cycle progression, according to Hurvitz. "The increase in proliferation can be observed in breast cancer tissue samples by measuring Ki-67," she explained.
Hurvitz and colleagues evaluated Ki-67 levels following neoadjuvant abemaciclib in tumor samples obtained from postmenopausal women with untreated, early-stage HR-positive and HER2-negative breast cancer. Core biopsies were done at baseline, and at weeks 2 and 14 following treatment. In the neoMONARCH trial, 56 patients were randomized to neoadjuvant abemaciclib plus anastrozole administered at each monotherapy dose, 59 patients were administered abemaciclib monotherapy (150 mg orally every 12 hours), and 58 patients were administered anastrozole monotherapy (1 mg orally per day) for two weeks, whereupon a core biopsy was performed.
After biopsy, all patients received the abemaciclib/anastrozole combination for 14 weeks. The median patient age was 63 years and most (161) patients were ECOG status 0; 85.5% were disease stage III and 14.5% were stage II. The majority (150 patients) had progesterone and estrogen receptor-positive tumors.
The primary endpoint was the changes in tissue Ki-67 from baseline by week 2. Secondary endpoints included clinical, radiologic, and pathological response, safety, and changes from baseline in proliferation-associated genes. An exploratory analysis of cell cycle associated genes using the Modaplex platform was also performed. "Similar decreases in proliferative gene mRNA levels after 2 weeks of abemaciclib treatment were observed in patients with early and with late stage disease," said Hurvitz.
No new safety signals were observed for either abemaciclib or anastrozole in the study. The most frequently reported adverse events (AEs) included diarrhea in 45.7% of patients and constipation in 35.8% of patients. Grade 3 diarrhea and constipation were reported in 2.9% and 1.2% of patients, respectively.
Abemaciclib received breakthrough therapy designation as monotherapy for heavily pretreated patients with refractory HR-positive advanced breast cancer earlier this year.
"Further exploration of the predictive value of tumor mRNA in patients receiving abemaciclib is underway and neoMONARCH final results, including clinical outcomes and mRNA exploratory analysis of cell cycle associated genes using the Modaplex platform was also performed. The findings are expected to be presented at the end of this year,” Hurvitz said.
Van Cutsem E., Ohtsu A., Falcone A., et al. Interim results from neoMONARCH: A neoadjuvant phase II study of abemaciclib in postmenopausal women with HR + /HER2- breast cancer. Presented at: 2016 ESMO Congress; October 7-11 2016; Copenhagen, Denmark. Abstract LBA13 (BC)