A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer

Purpose Increased epidermal growth factor receptor ( EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial. Patients and Methods Postmenopausal women with stage I to IIIB hormone receptor-positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2: 5: 5 to receive, in addition, gefitinib 250 mg/ d orally for 16 weeks: placebo 1 tablet/ d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response ( OR). Results Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were - 77.4% and - 83.6%, respectively, between baseline and 16 weeks ( geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P =.26), - 80.1% and - 71.3% between baseline and 2 weeks ( geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P =.22) and - 19.3% and - 43% ( geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P =.16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% ( estimated difference = - 13.1%; 95% CI, - 27.3% to 1.2%), respectively, with a nonsignificant trend against the combination ( P =.08) and 48% versus 72% ( estimated difference = - 24.1%; 95% CI, - 45.3% to - 2.9%) in the progesterone-receptor-positive subgroup, which was significant ( P =.03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction. Conclusion Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis.