A randomized, double-blind phase II trial of exemestane plus MM-121 (a monoclonal antibody targeting ErbB3) or placebo in postmenopausal women with locally advanced or metastatic ER+/PR+, HER2-negative breast cancer.

587 Background: Ligand-driven ErbB3 signaling has been implicated as a mechanism of resistance to conventional therapies across multiple malignancies, including endocrine resistant metastatic breast cancer (mBC). Here we present results of a trial evaluating MM-121 (M) or placebo (P) in combination with exemestane in postmenopausal women with ER/PR+ HER2-negative mBC. Methods: This study enrolled women with locally advanced or mBC who had failed adjuvant therapy or progressed in the metastatic setting. The primary endpoint was progression free survival (PFS) and the study was powered to detect a HR of < 0.5. Secondary and exploratory analyses included overall survival (OS), safety, and analyses of a pre-specified set of mechanistically-linked biomarkers ((BM), heregulin, betacellulin, EGFR, ErbB2, and ErbB3) in archived tissues. Results: 115 randomized and treated patients (56 (M), 59 (P)) were included in safety and efficacy analyses. Baseline demographics and disease characteristics were balanced. At the time of the analysis, 92 (80%) patients (78.6% (M), 81.4% (P)) had discontinued treatment, mainly due to progressive disease (66.1% (M), 76.3% (P)). PFS was analyzed after 84 events (38 (M), 46 (P)). The median PFS was 15.9 weeks (M) vs. 10.7 weeks (P), with a stratified hazard ratio (HR) of 0.772 (95% CI [0.496- 1.201]), p=0.249). OS data were immature at the time of the primary analysis (29 events: 11 (M), 18 (P)), with a stratified HR of 0.436 (95% CI [0.197 – 0.966]). In patients positive for two of the pre-specified BMs (31%: 17 of the 55 patients with BM data), the HR for PFS was 0.32 (95% CI [0.10-1.00]). Common adverse events (AEs, >20%) of any grade and causality (M vs. P), were diarrhea (50% vs. 23.7%), nausea (28.6% vs. 23.7%), fatigue (23.2 % vs. 23.7%), and arthralgia (17.9% vs. 20.3%). Conclusions: The addition of MM-121 to exemestane did not significantly prolong PFS in the unselected population, although the HR appears to favor the MM-121 arm. The biomarker findings were consistent with preclinical hypotheses, as well as an independently conducted Phase 2 study in platinum resistant ovarian cancer. Clinical trial information: NCT01151046.