Abemaciclib Shows Promise for Early Breast Cancer

Treatment with the CDK4/6 inhibitor abemaciclib (Eli Lilly), alone or in combination with endocrine therapy, significantly lowered expression of Ki67—a key marker of cell proliferation—in women with hormone receptor (HR)–positive, HER2-negative breast cancer, according to preliminary data from the phase II neoMONARCH trial. The findings, presented during the 2016 San Antonio Breast Cancer Symposium in Texas, December 6–10, suggest that CDK4/6 inhibition, which is already used to treat advanced disease, may be effective for neoadjuvant treatment of early breast cancer.

Estrogen stimulates increased activity of CDK4/6, which plays an important role in regulating cell-cycle progression. The neoMONARCH investigators hypothesized that inhibiting CDK4/6 would help slow cell cycling, as measured by changes in Ki67 expression. Earlier studies have shown that lowered Ki67 expression after 2 weeks of treatment may be predictive of improved disease-free survival.

In the proof-of-concept study, 223 postmenopausal women were randomly assigned to receive either endocrine therapy (anastrozole), abemaciclib, or both for 2 weeks; all of the patients then received both drugs for 14 weeks, followed by optional surgery. Researchers analyzed biopsies taken from evaluable patients in each arm before and after the first 2 weeks of treatment. The results showed significantly reduced Ki67 expression in 107 patients who received abemaciclib or the combination compared with 54 patients who received only anastrozole.

In particular, reduced Ki67 expression was observed in significantly more patients who took abemaciclib or the combination therapy (59% and 66%, respectively) compared with those who took anastrozole alone (15%). The majority of patients who took the combination therapy also experienced shrinkage of their tumors, said Sara Hurvitz, MD, medical director of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center Research Unit, who presented the data.

Reduced Ki67 expression also appeared to trigger infiltration of antitumor immune cells, noted Hurvitz. Tissue analysis after 4 months of treatment showed that patients who took abemaciclib plus anastrozole showed an increase in cytotoxic/suppressor T cells in their tumors, but no increase in regulatory T cells, which are thought to dampen the immune response.

This is the first large study to show that CDK4/6 inhibition may be effective in neoadjuvant treatment of early-stage breast cancer, she said. Currently, one CDK4/6 inhibitor, palbociclib (Ibrance; Pfizer), is approved for initial endocrine-based therapy to treat advanced or metastatic disease. Another, ribociclib (Novartis), is under investigation and was granted Breakthrough Therapy status earlier this year.

The data also suggest that abemaciclib may be less toxic than palbociclib, said Hurvitz. Palbociclib is typically given on a 3 weeks on/1 week off regimen to allow neutrophils to recover, but experts worry that the medication break could trigger a rebound in cell cycling, leading to resistance. In the neoMONARCH trial, abemaciclib was taken continuously with a relatively low rate (8.2%) of grade 3 or 4 neutropenia.

The investigators are continuing to evaluate pathologic responses and long-term outcomes in an effort to discover more about how CD4/6 inhibitors work, said Hurvitz.

“These data will not change the standard of care, but they provide an enormous opportunity for discovery,” she said. “We hope to uncover important information about the mechanisms and biomarkers of resistance to endocrine-based therapy with CD4/6 inhibitors.” –Janet Colwell

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