Abstract P2-16-19: Fulvestrant with or without selumetinib (Sel, AZD6244), a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI): A multicenter randomized placebo-controlled double-blind phase II trial, SAKK21/08
Authors: Zaman K , Winterhalder R , Mamot C , Hasler-Strub U , Rochlitz C , Mueller A , Berset C , Wiliders H , Perey L , Biaggi Rudolf C , Rondeau S , Neven P 
Published: August 2014

Abstract
Background:
Mitogen-activated protein kinase (MAPK) pathway is one of the major signaling cascades responsible for resistance to endocrine therapy by promoting estrogen-independent tumor growth. Sel is a potent selective MEK1 and MEK2 inhibitor active in melanoma, ovarian, colorectal and non-small cell lung cancers. Fulvestrant (Fulv) is a pure antagonist and downregulator of nuclear and membranous/cytoplasmic estrogen receptor (ER). The combination of a MEK inhibitor with Fulv may improve the efficacy of endocrine therapy by reversing and/or delaying the development of resistance.
Material and methods:
Postmenopausal patients with advanced stage endocrine-sensitive (ER and/or progesterone receptors ≥10%) breast cancer progressing after aromatase inhibitor were randomized to intramuscular Fulv 500 mg (day 1, 15, 29 then every 28±2 days) combined with either oral Sel 75 mg bid or placebo bid. The primary endpoint was disease control (DC = CR + PR + stable disease ≥ 24 weeks). Sample size was calculated according to Simon's optimal two-stage design. A DC rate of ≤30% in the experimental arm was considered as not interesting and ≥50% as promising. Using a 5% significance level and 80% power, 46 patients were needed, 15 in the first stage and 31 in the second stage. In the control arm a total of 43 patients was needed to estimate the DC rate with a confidence interval width of ≤30%. An interim efficacy analysis was planned according to Herndon's modification of Simon's optimal two-stage design.
Results:
Forty-six patients were included (23 per arm). Seventy percent of the patients in the experimental arm had measurable disease and 57% had visceral metastases. Patients had received AI in the metastatic (61%) or adjuvant (39%) setting (65% had also prior tamoxifen). Five of 23 patients (22%) reached DC in the experimental arm. DC rate being inferior to the statistical hypothesis the study was terminated following the planned interim efficacy analysis. Most frequently reported adverse events (AEs) were rash and other skin disorders, fatigue, diarrhea, hypertension, edema, nausea/vomiting, anorexia, musculoskeletal symptoms, dry mouth and paresthesia. AEs were mainly grade 1 and 2 (NCI-CTCAE v4.0), but they often precluded treatment continuation. Most of the first patients exposed to Sel 75 mg bid stopped treatment before disease progression. Seven of the 23 patients (30%) were exposed to Sel for only 1 cycle or less. After an amendment facilitating early dose-reduction, patients decreasing to 75 mg qd had much better tolerance and improved treatment duration with Sel. Four out of the 5 patients reaching DC had Sel dose reduction.
Conclusion:
The combination of Sel with fulvestrant did not reach the prespecified disease control rate. The toxicity of Sel 75 mg bid led to frequent treatment interruptions/dose reductions and poor exposure to the drug.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-19.