SAN ANTONIO – The investigational agent AMG 479 failed to alter resistance to hormonal therapy in patients with endocrine therapy–resistant, hormone receptor–positive metastatic breast cancer in the adjuvant setting. Indeed, the drug showed a trend toward worse progression-free survival and objective response in a phase II trial.
When AMG 479 was paired with exemestane or fulvestrant, patients in the experimental arm had a median progression-free survival of 3.9 months, compared with 5.7 months for patients on exemestane or fulvestrant alone (hazard ratio, 1.17; P = .435).
"AMG 479 in combination with either fulvestrant or exemestane does not appear to delay or reverse resistance to hormonal therapy in this population of patients with prior endocrine therapy–resistant hormone receptor-positive metastatic breast cancer," Dr. Peter A. Kaufman said at the San Antonio Breast Cancer Symposium.
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AMG 479 is an investigational fully human monoclonal antibody antagonist of the type I insulinlike growth factor (IGF-I) receptor, blocking the binding of both IGF-I and IGF-II to the receptor.
Resistance to hormonal therapy is thought to possibly occur through increased IGF-I receptor (IGF-IR) signaling, and the researchers hypothesized that inhibition of the IGF-IR signaling pathway may enhance the activity of a second line of hormonal therapy in breast cancer patients, according to Dr. Kaufman of Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
In this study, patients were randomized to receive either treatment with AMG 479 along with exemestane or fulvestrant, or placebo plus exemestane or fulvestrant. (The choice was left to the investigator.) Stratification factors included which hormonal therapy the patient received, as well as the extent of disease
AMG 479 (12 mg/kg) and placebo were given intravenously every 2 weeks. Exemestane (25 mg) was given orally every day; oral fulvestrant was given in a dose of 500 mg on day 1 and then at a dose of 250 mg on days 15 and 29 and every 4 weeks thereafter. The primary end point was progression-free survival, as measured by modified RECIST (Response Evaluation Criteria in Solid Tumors) v1.0.
In all, 106 women were included in the AMG 479 group and 50 in the placebo group. In the treatment group, 98% of women were estrogen receptor positive, 70% were progesterone receptor positive, and 7% were HER2 positive. In the placebo group, 94% of women were ER positive, 70% were PR positive, and 2% were HER2 positive.
Median profession-free survival among women who received exemestane was 4.8 months with AMG 479 and 7.3 months with placebo (HR, 1.31). Among women who received fulvestrant, it was 3.7 months and 5.4, respectively (HR, 1.11).
"There really is no difference in the overall response rate," said Dr. Kaufman. The objective response rate for patients in the AMG 479 group was 8% vs. 13% for those in the control group. The overall clinical benefit rate was 35% for women on AMG 479 and 31% of women on placebo, which was not significant.
Serious adverse events occurred in 25% of patients who were given AMG 479 and 18% of the placebo group. "We saw no meaningful difference in any of those symptoms," said Dr. Kaufman. He did note elevated but nonsignificant rates of hyperglycemia, neutropenia, and thrombocytopenia for those on AMG, however.
Dr. Kaufman disclosed that he receives grant support from Amgen. He has also disclosed that he is a shareholder of Amgen. A coauthor reported that he receives grant support from Amgen. Three of the study authors are employees of Amgen. The study was sponsored by Amgen.