Interim Phase 2 Results on Abemaciclib in Women with HR+/HER2– Breast Cancer

Abemaciclib is a potent, oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 that has shown evidence of antitumor activity when combined with an aromatase inhibitor in patients with refractory hormone receptor–positive (HR+) metastatic breast cancer. The purpose of the phase 2 neoMONARCH study was to evaluate the biologic effects of abemaciclib in combination with anastrozole (an aromatase inhibitor) and compare those with the effects of abemaciclib alone and anastrozole alone in the tumors of postmenopausal women with untreated, early-stage invasive HR+/human epidermal growth factor receptor 2–negative (HER2–) breast cancer.

All patients in neoMONARCH were randomized (1:1:1) to receive combination therapy, abemaciclib alone, or anastrozole alone for the first 2 weeks (cycle 1), followed by 14 weeks of combination therapy (cycle 2). Abemaciclib was administered at an oral dose of 150 mg every 12 hours, and anastrozole was administered at an oral dose of 1 mg daily. As previous studies have shown the most common adverse effect associated with abemaciclib treatment to be diarrhea, loperamide was additionally administered as primary prophylaxis with every abemaciclib dose. The primary objective in this study was the change in tissue Ki67 levels from baseline to week 2. All patients had Ki67 levels ≥5% at baseline. Additional objectives included safety; clinical, radiologic, and pathologic response; and changes in proliferation-associated genes (PAGs), which had previously been validated in breast cancer cell lines, tumors, and human studies.

The treated patient population in this study included 173 women, all of whom had safety data available at the prespecified 9-month interim analysis. Data were also available for Ki67 in 64 patients, and PAGs in 51 patients. Reduction from baseline in Ki67 was significantly greater (one-sided P <0.001) with combination therapy (geometric mean percent change, –93.5%; n = 23) and abemaciclib monotherapy (–93.1%; n = 19) than with anastrozole alone (–71.0%, n = 22). Additionally, there were numerically greater numbers of Ki67 responders, defined as patients with Ki67 <2.7% at week 2 (complete cell-cycle arrest) in combination and abemaciclib therapies than with anastrozole alone (69.6%, 68.4%, and 22.7%, respectively). In patients with available PAG data, a substantial association was seen between the reduction of Ki67 and the reduction of E2F transcription factor activators and targets.  

In cycle 1, combination therapy was associated with a similar safety profile as abemaciclib alone. Patients receiving combination therapy most commonly reported diarrhea (25.0%; 3.6% were grade 3) and constipation (17.9%; 1.8% were grade 3), compared with 25.9% and 19.0%, respectively, of patients receiving abemaciclib alone (none were grade 3). During cycle 2, in which 162 patients had more than 1 postbaseline assessment, increased creatinine (93.2%; 0.6% were grade 3) and neutropenia (64.8%; 6.2% were grade 3; 1.2% were grade 4) were reported.

The results of this study show that abemaciclib therapies reduced Ki67 and PAGs more than anastrozole alone at the 2-week end of treatment. Further exploration of the predictive value of baseline tumor mRNA and/or changes in plasma exosome mRNA is currently underway. No new safety concerns were identified during this study, and diarrhea was less frequent and severe due to prophylaxis with loperamide. “These results are encouraging,” said Dr Marco Colleoni from Milan, Italy, who was unaffiliated with the study. “Neoadjuvant studies on endocrine therapy, such as these, are an important option for patients with ER+ disease,” he added.

Hurvitz S, et al. ESMO 2016. Abstract LBA13.