Exploratory subset analysis according to prior endocrine treatment of two randomized phase II trials comparing gefitinib (G) with placebo (P) in combination with tamoxifen (T) or anastrozole (A) in hormone receptor-positive (HR+) metastatic breast cancer (MBC)

Abstract

1014 Background: Preclinical and clinical data suggest that increased EGFR and HER-2 activity contribute to acquired resistance to endocrine therapy. Strata of two clinical trials recently showed that the addition of G to T or A in HR+ MBC prolonged progression free-survival (PFS). Certain preclinical data also suggested that G should be combined with T or A from the start of endocrine therapy rather than waiting for resistance to develop. To examine this clinically a post hoc analysis compared the subsets of patients (pts) who had received prior endocrine therapy (may have already upregulated HER receptors) to those that were endocrine therapy naïve (not yet upregulated HER receptors). Methods: One trial evaluated G (250 mg/day orally) + A (1 mg/day orally) versus A+P ( NCT00077025 ) and one trial evaluated G (250 mg/day orally) + T (20 mg/day orally) versus T+P ( NCT00229697 ). Post hoc analysis of PFS was performed in two pt subgroups; previously treated with endocrine therapy (ET) and endocrine naïve (EN). The PFS HR and associated 95% CI and p-value for G relative to P were estimated using the Cox proportional hazards model along with interaction test for treatment by subset. Results: In the ET subgroup of the G+A versus A+P study, 31 PFS events were reobserved in 51 pts (hazard ratio [HR] 0.65 95% CI 0.32, 1.33; median PFS: G+A 11.2 mo, A+P 7.1 mo). In the EN subgroup, 23 PFS events were reobserved in 42 pts (HR 0.39, 95% CI 0.16, 0.97; median PFS: G+A 20.2 mo, A+P 8.4 mo). The interaction test p-value was 0.28. In the ET subgroup of the G+T versus T+P study, 95 PFS events were reobserved in 131 pts (HR 1.22, 95% CI 0.81, 1.86; median PFS: G+T 9.4 mo, T+P 10.9 mo). In the EN subgroup, 106 PFS events were reobserved in 158 patients (HR 0.78, 95% CI 0.52, 1.15; median PFS: G+T 12.1 mo, T+P 8.9 mo). The interaction test p-value was 0.13. Conclusions: The EN pt subgroups of both trials demonstrated prolonged PFS when G was combined with A or with T compared with A or T alone, respectively. A further prospective clinical trial of EGFR inhibition combined with endocrine therapy in EN pts with HR+ MBC is warranted on the basis of these findings. [Table: see text]