Molecular marker correlates of clinical outcome in a phase II study of gefitinib or placebo in combination with anastrozole in postmenopausal women with hormone receptor-positive metastatic breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3131 Background: Preclinical data suggest that crosstalk between growth factor receptor pathways and estrogen receptor (ER) is involved in the development of endocrine resistance. Therefore, inhibition of epidermal growth factor receptor (EGFR) is a potential target in this setting. This phase II randomized, double-blind, multicenter study evaluated the efficacy and tolerability of gefitinib (Iressa) or placebo in combination with anastrozole (Arimidex) in postmenopausal women with newly diagnosed hormone receptor-positive (HR+) metastatic breast cancer (MBC). Methods: Patients were randomized (1:1) to anastrozole 1 mg/day and either gefitinib 250 mg/day or placebo. The primary objective was progression-free survival (PFS); and secondary objectives included clinical benefit rate (CBR; defined as objective response plus stable disease ≥24 weeks), objective response rate (ORR) by RECIST, overall survival, safety and correlative biological markers. Biomarkers in tumor tissue (ErbB family receptors including EGFR, or other downstream related effectors and other markers of proliferation and apoptosis) by immunohistochemistry were assessed to explore potential correlations with outcome. Enrollment closed early due to slow recruitment and formal statistical testing was not performed. Results: 94 women were randomized to gefitinib plus anastrozole, and 43 to placebo plus anastrozole, 50 from 30 centers in 4 countries. PFS was significantly longer for gefitinib plus anastrozole over placebo plus anastrozole (HR [gefitinib:placebo] 0.55, 95% CI 0.32-0.94; median PFS 14.5 vs 8.2 months). A numerical advantage in CBR was seen for gefitinib plus anastrozole over placebo plus anastrozole (49% [21/43; 95% CI 35-65] vs 34% [17/50; 95% CI 21-49]). ORR was 2% (1/43) with gefitinib plus anastrozole and 12% (6/50) with placebo plus anastrozole. Too few patients died before data cut-off to allow conclusions on overall survival to be drawn. Safety and tolerability profiles showed no unexpected findings. Correlative biological markers data will be available later in the year after which the abstract will be updated and resubmitted. Discussion: This clinical trial demonstrated that EGFR inhibition and estrogen deprivation with gefitinib in combination with anastrozole was associated with a marked advantage in PFS and CBR vs placebo plus anastrozole in ER+ MBC. These data suggest that EGFR inhibition in combination with anastrozole warrants further investigation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3131.