Abstract LB-146: A phase II randomized placebo-controlled study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, plus paclitaxel (P) vs P alone in patients (pts) with low HER2-expressing advanced breast cancer (BC) (THYME).
Authors: Baselga José , Hegg Roberto , Losada Maria Vidal , Vidaurre Tatiana , Lluch Ana , Petrakova Katerina , Mann Helen , Ghiorghiu Serban , Stuart Mary , Landers Dónal , Thress Kenneth , Klinowska Teresa , Cortes Javier 
Published: August 2014

Abstract
Background: AZD8931 is an oral, equipotent inhibitor of EGFR, HER2, and HER3 signaling. Preclinical evidence indicates that AZD8931 may be particularly potent when HER signaling is ligand driven, which is thought to be the signaling mechanism that is more prevalent in low HER2-expressing BC.
Methods: In this double-blind multicenter phase II study, women with low HER2- expressing locally advanced or metastatic BC (ineligible by HER2 status for either trastuzumab or lapatinib) were randomized 1:1 to AZD8931 40mg bid + P (90mg/m2; d1, 8 and 15, q4 weeks) or matched placebo + P (NCT00900627). The primary objective was prolonged progression-free survival (PFS; assessed by RECIST v1.1); secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.
Results: Between July 2010 and April 2011, 190 pts (median age, 55 years [range, 32-80]; 83% metastatic disease) were randomized to AZD8931 + P (n=94) or placebo + P (n=96). No significant difference in PFS was observed with AZD8931 + P vs P alone (HR=1.08, 95% CI [0.76, 1.52], P=0.679; median PFS, 8.7 vs 9.1 months); this lack of treatment effect was consistent across subgroups. A significant increase in ORR (59% vs 41%; OR=2.02, 95% CI [1.09, 3.75], P=0.026) and in mean % change in tumor size at week 8 vs baseline (difference, -9.9%, 95% CI [-18.4%, -1.4%], P=0.023; exploratory objective) was observed with AZD8931 + P vs P alone. At data cut-off (April 2012), OS data were immature (52 [27%] pts had died), with no difference between treatment arms (HR=1.15, 95% CI [0.67, 2.01], P=0.607). The hazard ratio for the time to deterioration of health-related quality of life (assessed by FACT-B TOI; exploratory objective) was 1.46 (95% CI [1.04, 2.05], P=0.028).
The most common adverse events (AEs) were rashes and acne (grouped term; 91% [AZD8931 + P] vs 26% [P alone]) and diarrhea (83% vs 35%). Grade ≥3 AEs were reported for 65% and 41% of pts in the AZD8931 + P and the P alone arm, respectively, the most common being rashes and acne (grouped term; 19% vs 2%), diarrhea (12% vs 4%), neutropenia (7% vs 15%) and peripheral neuropathy (7% vs 2%). Discontinuation of AZD8931 or placebo treatment due to AEs was reported for 12 (13%) and 8 (9%) pts, respectively. Fatal AEs were reported in two pts in the AZD8931 + P arm (neither considered AZD8931 treatment-related) and three pts in the P alone arm. No new or unexpected safety concerns were reported with this treatment combination. Paclitaxel delivery was not compromised by combination with AZD8931.
Conclusion: The THYME study did not meet its primary objective of prolonging PFS when AZD8931 was added to weekly P in pts with low HER2-expressing advanced BC. AZD8931 40mg bid can be administered in combination with weekly P with a manageable toxicity profile. Exploratory biomarker analyses are ongoing and will be presented.
Citation Format: José Baselga, Roberto Hegg, Maria Vidal Losada, Tatiana Vidaurre, Ana Lluch, Katerina Petrakova, Helen Mann, Serban Ghiorghiu, Mary Stuart, Dónal Landers, Kenneth Thress, Teresa Klinowska, Javier Cortes. A phase II randomized placebo-controlled study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, plus paclitaxel (P) vs P alone in patients (pts) with low HER2-expressing advanced breast cancer (BC) (THYME). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-146. doi:10.1158/1538-7445.AM2013-LB-146