A phase II randomized open-label study of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with weekly paclitaxel versus weekly paclitaxel in patients with platinum-resistant/refractory ovarian cancers.

5519 Background: Heregulin induced activation of ErbB3 has been implicated as a mechanism of resistance to many targeted and cytotoxic therapies such as paclitaxel in preclinical models. MM-121 is a monoclonal antibody designed to interfere with this mechanism of resistance. Methods: This was a global, open-label, randomized Phase II study of MM-121 in patients with platinum resistant ovarian cancer. Patients were randomized (Ratio 2:1) to receive MM-121 plus paclitaxel (M+P) or paclitaxel alone (P). The primary objective was to compare progression-free survival (PFS) between the groups. Pretreatment fresh biopsies obtained from all patients were analyzed to assess a pre-specified set of mechanistically-linked biomarkers (BM): heregulin (HRG), betacellulin, EGFR, ErbB2, and ErbB3. Results: 223 patients (140 (M+P), 83 (P)) were included in the efficacy analyses. Baseline demographics and disease characteristics were balanced. Most patients (80.3%) had received 2 or more prior platinum-based regimens. Median PFS was analyzed after 171 events (115 (M+P), 56 (P)) and was 3.75 months (M+P) and 3.68 months (P) with a stratified hazard ratio (HR) of 1.027 [95% CI 0.741 - 1.425]. Two biomarkers based on pre-clinical predictions were used to identify a subset of BM positive patients (34%: 57/169 patients with BM available). In this BM positive group the HR for PFS was 0.37 [0.2 - 0.8] and the HR in the BM negative group was 1.54 [1.0 - 2.4]. The overall safety profile was consistent with expected adverse events (AEs), with the exception of an increase in the pulmonary embolism rate (5.0% (M+P) vs. 1.2% (P)). However, the overall rate of venous thromboembolic events was comparable (5.7% (M+P) vs. 7.5% (P)). Most AEs were reported as mild to moderate in severity and included diarrhea, vomiting, stomatitis, and mucosal inflammation. Conclusions: A signal of benefit was observed in a biomarker positive subpopulation, althoughthe study regimen was not effective at prolonging PFS in the overall study population. Any further development of MM-121 in ovarian cancer should focus on biomarker-selected patients. Clinical trial information: NCT01447706.