Emerging Therapies in the Treatment of Breast Cancer

Promising data on several new breast cancer agents, including one new cytotoxic, were presented at the American Society of Clinical Oncology Breast Cancer Symposium 2011 held September 8-10 in San Francisco, California.

The addition of the novel histone deacetylase (HDAC) inhibitor entinostat to exemestane significantly delayed recurrences and showed a trend for a survival benefit in the phase 2 ENCORE 301 (ENtinostat Combinations Overcoming REsistance) study reported by Denise Yardley, MD, of Sarah Cannon Research Institute and Tennessee Oncology in Nashville.

The regimen is based on the concept that HDAC inhibitors can restore estrogen receptor (ER) sensitivity in the tumor, allowing patients to respond again to an endocrine agent. “This combination may allow patients to remain on hormonal therapy longer, delaying the need for chemotherapy,” she suggested.

ENCORE 301 randomized 114 post-menopausal patients with ER-positive advanced breast cancer progressing on a nonsteroidal aromatase inhibitor to exemestane alone or exemestane plus weekly entinostat. Median progressionfree survival (PFS) was 4.28 months with entinostat/exemestane versus 2.27 months with exemestane alone, a 27% statistically significant reduction in risk. Median overall survival (OS) was 26.9 months and 20.3 months, respectively, a 54% reduction in risk that trended toward significance.

HDAC inhibitors induce hyperacetylation of lysines on histones and a number of other proteins. In a biomarker analysis of 49 patients, protein lysine acetylation measured in blood samples found that subjects who hyperacetylated experienced a 77% reduction in risk with the combination; median PFS was 8.54 months on the combination versus 1.92 months with exemestane alone. The finding suggests that hyperacetylation “may be a potential marker of benefit,” Yardley said.

Symposium session moderator Joyce O’Shaughnessy, MD, of Baylor Sammons Cancer Center in Dallas, called the use of entinostat in advanced ER-positive breast cancer “very, very promising,” and added, “It’s time for a phase 3 trial of this agent.”

Topoisomerase Inhibitor Shows Significant Activity
NKTR-102, an intravenous topoisomerase- 1 inhibitor-polymer conjugate, showed significant antitumor activity in metastatic breast cancer, including poor-prognosis patients with triplenegative disease having received prior anthracycline/taxane therapy. The phase 2 study evaluated the drug in 70 patients, most with visceral metastases. The response rate was 29%, and the clinical benefit rate (response + stable disease) was 46%, including 2 complete and 4 near-complete re sponses. Fully 39% of the triple-negative subset responded, reported Agustin Garcia, MD, of the Uni versity of Southern California Norris Comprehensive Cancer Center, Los Angeles.

Median PFS was 4.6 months, and median OS was 10.3 months. The most common grade 3/4 side effect was diarrhea (20%-23%), typically occurring after 3 months of treatment.

NKTR-102, given every 21 days, is being evaluated in multiple cancer indications, and phase 3 planning is under way in advanced breast cancer and platinum-resistant ovarian cancer.

William Gradishar, MD, director of the Maggie Daley Center for Women’s Cancer Care at Northwestern Uni - versity, Chicago, said the key questions are how NKTR-102 will compare with other salvage cytotoxics (eribulin, ixabepilone) and whether there is an optimal sequence into which to incorporate the new cytotoxic.

Insulin Growth Factor Inhibitor Intriguing
The list of agents targeting the insulin growth factor (IGF) is steadily growing, with almost 20 tyrosine kinase in - hibitors and monoclonal antibodies in preclinical and clinical trials. Joining this list is a neutralizing antibody, MEDI-573. The drug neutralizes IGF-I and IGF-II ligands and inhibits IGF receptor signaling pathways.

The first-in-human safety and pharmacokinetic profiles were described at the symposium by Paul Haluska, MD, of the Mayo Clinic, Rochester. In a phase 1 study in 37 patients who received various doses and schedules of the intravenous agent, IGF-I and IGFII levels were fully suppressed, and no clinically significant changes in glucose, insulin, or somatotropin levels were observed. A phase 2 study of MEDI-573 plus an aromatase inhibitor is ongoing.

Everolimus Shows Promise in Triple-Negative Breast Cancer
Clinical benefit was observed in 8 of 12 evaluable patients (56%) in a phase 2 study of 14 heavily pretreated meta - static patients receiving everolimus plus carboplatin. The average responder has been stable for 22 weeks, and response approaches 1 year in several patients. Dose-limiting thrombocytopenia was an unexpected side effect that required protocol amendment, but the results are impressive, according to J. C. Singh, MD, and colleagues at New York University School of Medicine.