TY - JOUR
T1 - Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer
T2 - A randomized phase II study
AU - Osborne, C. Kent
AU - Neven, Patrick
AU - Dirix, Luc Y.
AU - Mackey, John R.
AU - Robert, Jean
AU - Underhill, Craig
AU - Schiff, Rachel
AU - Gutierrez, Carolina
AU - Migliaccio, Ilenia
AU - Anagnostou, Valsamo K.
AU - Rimm, David L.
AU - Magill, Patrick
AU - Sellers, Mark
PY - 2011/3/1
Y1 - 2011/3/1
N2 - Purpose: Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)-positive metastatic breast cancer. Experimental Design: Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor. Results: In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59-1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy-naive subset (n = 158) the HR was 0.78 (95% CI, 0.52-1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63-3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein. Conclusions: In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients.
AB - Purpose: Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)-positive metastatic breast cancer. Experimental Design: Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor. Results: In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59-1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy-naive subset (n = 158) the HR was 0.78 (95% CI, 0.52-1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63-3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein. Conclusions: In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients.
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U2 - 10.1158/1078-0432.CCR-10-1869
DO - 10.1158/1078-0432.CCR-10-1869
M3 - Article
C2 - 21220480
AN - SCOPUS:79952259688
SN - 1078-0432
VL - 17
SP - 1147
EP - 1159
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -