Phase II, Randomized Trial to Compare Anastrozole Combined with Gefitinib or Placebo in Postmenopausal Women with Hormone Receptor–Positive Metastatic Breast Cancer

Abstract

Purpose: This phase II randomized trial evaluated the efficacy and tolerability of anastrozole combined with gefitinib or anastrozole with placebo in women with hormone receptor-positive metastatic breast cancer (MBC).Experimental Design: Postmenopausal women with hormone receptor-positive measurable or evaluable MBC who had not received prior endocrine therapy for this disease stage or who developed metastatic disease during/after adjuvant tamoxifen were eligible. The primary response variable was progression-free survival (PFS) and secondary response variables included clinical benefit rate, objective response rate, overall survival, safety and tolerability, and pharmacokinetics. Tumor biomarker evaluation was an exploratory objective.Results: Forty-three patients were randomized to anastrozole plus gefitinib and 50 patients were randomized to anastrozole plus placebo of a planned total of 174 patients (enrollment was prematurely discontinued due to slow recruitment). PFS for patients receiving the combination of anastrozole and gefitinib was longer than for patients receiving anastrozole plus placebo [hazard ratio (gefitinib/placebo), 0.55; 95% confidence interval, 0.32-0.94; median PFS, 14.7 versus 8.4 months]. The clinical benefit rate was 49% versus 34%, and the objective response rate was 2% versus 12% with anastrozole plus gefitinib and anastrozole plus placebo, respectively. No evidence of interaction between baseline biomarker levels and relative treatment effect was found. No unexpected adverse events were observed.Conclusion: This small randomized study showed that anastrozole in combination with gefitinib is associated with a marked advantage in PFS compared with anastrozole plus placebo, and that the combination was tolerated in postmenopausal women with hormone receptor-positive MBC. Further investigation of epidermal growth factor receptor inhibition in combination with endocrine therapy may be warranted.

New and translational perspectives of oestrogen deprivation in breast cancer

“…Some data however from a recently reported study of anastrozole plus or minus gefitinib in advanced disease showed greater promise [15]. This study reported a prolongation of progression free survival from a…”

A Review of an Unfavorable Subset of Breast Cancer: Estrogen Receptor Positive Progesterone Receptor Negative

“…Polychronis et al [22] studied patients with ER ϩ EGFR ϩ primary breast cancer in the preoperative setting; patients were exposed for 4 -6 weeks to gefitinib monotherapy or combination therapy with anastrozole. Both monotherapy and combination therapy were associated with a notable reduction in tumor size and Ki-67 activity [19]. Based on these sets of data, gefitinib seems to be promising in patients with these tumors, but clinical trials are warranted for the use of gefitinib with anastrozole, specifically in the ER ϩ PR Ϫ subset of patients.…”

“…Clinically, it is crucial to block this crosstalk by inhibiting signaling networks to achieve optimal therapeutic activity [3]. This process can be delayed or reversed by inhibiting EGFR and ER signaling by simultaneous treatment with growth factor pathway inhibitors with endocrine therapy [19]. The strategies to inhibit growth factor signaling include mTOR inhibitors (everolimus, temsirolimus), PI3K inhibitors, tyrosine kinase inhibitors, IGF receptor inhibitors, and EGFR inhibitors [20].…”

“…A phase II prospective, randomized, double-blind trial was conducted by Cristofanilli et al [19] to evaluate the efficacy and tolerability of anastrozole and gefitinib, compared with anastrozole plus placebo, in postmenopausal women with hormone-positive metastatic breast cancer and ER ϩ cancers that were tamoxifen resistant. There was a marked advantage in terms of the progression-free survival interval in patients treated with anastrozole plus gefinitib, compared with anastrozole plus placebo (14.7 months versus 8.4 months), and the clinical benefit rates were 49% and 34%, respectively [19]. These results are consistent with those from stratum 1 of a comparison of tamoxifen plus gefitinib or placebo by Osborne et al [21].…”

Endocrine Therapy for Postmenopausal Women with Hormone Receptor–Positive her2–Negative Advanced Breast Cancer after Progression or Recurrence on Nonsteroidal Aromatase Inhibitor Therapy: A Canadian Consensus Statement

“…Furthermore, many patients with initial response to et will acquire secondary resistance, commonly defined as disease progression more than 6 months after et initiation 11,12 . While there appears to be clinical benefit in combining therapies targeted to the human epidermal growth factor receptor 2 (her2) with et in her2-positive (her2+) abc 13,14 , attempts at combining other receptor tyrosine kinase inhibitors with et in the her2-negative (her2-) setting have met with limited success [14][15][16] , highlighting an unmet clinical need in this population.…”