Abstract P3-11-03: A randomized, phase 2 trial of preoperative MM-121 with paclitaxel in triple negative (TN) and hormone receptor (HR) positive, HER2-negative breast cancer
Authors: Holmes Frankie A , McIntyre Kristi J , Krop Ian E , Osborne Cynthia R , Smith II John W , Modiano Manuel R , Gupta Manish , Downey Leona B , Nanda Rita , Saleh Mansoor N , Young Jonathan R , Horgan Kerry E , Kubasek William , MacBeath Gavin , Danso Michael A , O'Shaughnessy Joyce A 
Published: May 2015

Abstract
Background: MM-121 is a fully human monoclonal antibody that targets ErbB3 and blocks heregulin (HRG), the principal ligand for ErbB3, from binding. HRG-driven ErbB3 signaling has been widely implicated in the development of resistance to conventional chemotherapies and targeted agents. Recently, as part of a broader Phase 2 program designed to identify responders to MM-121, HRG was identified as a key biomarker that correlates with poor response to standard-of-care therapies and benefit from co-treatment with MM-121 in the metastatic setting in patients with NSCLC, ovarian cancer and breast cancer. Here we present data on the impact of HRG and MM-121 co-treatment in the pre-operative setting in HER2- breast cancer.
Methods: Patients enrolled had locally advanced HR+, HER2-negative invasive breast cancer (Group 1) or TN (Group 2), no distant metastatic disease, no prior treatment for the disease under study, and ≥T2. Patients were randomized in a 2:1 fashion to receive MM-121 plus paclitaxel or paclitaxel alone followed by doxorubicin and cyclophosphamide, followed by surgery. The primary endpoint of this study was to describe pCR rates, defined as the absence of invasive cancer in the breast and lymph nodes (i.e. ypT0, ypN0). Residual cancer burden index (RCBI) was also recorded for each patient. Pre- and post-treatment tumor biopsies were collected in order to assess the levels of HRG and other potential biomarkers.
Results: 200 patients (101 HR+, 99 TN) entered the study. For Group 1 (HR+), 96 of the 101 patients were Efficacy Evaluable (EE) and the pCR rate in the MM-121 treatment arm was 7/66 (10.6%, 95% CI [5.2%, 20.3%]) compared to 1/30 (3.3%, 95% CI [0.6%, 16.7%]) on the control arm. For Group 2 (TN), 85 of the 99 patients were Efficacy Evaluable (EE) and the pCR rate in the MM-121 treatment arm was 23/56 (41.1%, 95% CI [29.2%, 54.1%]) compared to 14/29 (48.3%, 95% CI [31.4%, 65.6%]) on the control arm. Preliminary analysis of pretreatment biopsies (52% of samples analyzed) suggests a potential link between HRG levels and both pCR rates and RCBI. For both groups, the overall incidence of adverse events, regardless of relationship, was comparable between the two arms. A higher frequency of any grade AEs (Treatment vs. Control) was reported for diarrhea, rash, stomatitis, fatigue, epistaxis, nail disorder and dysgeusia. A higher frequency of Grade 3 or higher AEs (Treatment vs. Control) was reported for febrile neutropenia (HR+: 10.4% vs. 3.0%), diarrhea (HR+: 7.5% vs. 0%, TN: 7.8% vs. 0%), fatigue (HR+: 6.0% vs. 3.0%), anemia (HR+: 7.5% vs. 3.0%, TN: 7.8% vs. 3.1%), hypokalemia (HR+: 7.5% vs. 3.0%), infusion-related reactions (TN: 4.7% vs. 0%), pulmonary embolisms (TN: 4.7% vs. 0%), and hyperglycemia (TN: 4.7% vs. 0%).
Conclusion: Although a potential signal of benefit from MM-121 was observed in the HR+ group, the same was not observed in the TN group, and overall the results are inconclusive. Biomarker analyses, including pharmacodynamics studies, are ongoing. The observed safety profile is consistent with the expected toxicities associated with ErbB inhibitors and weekly paclitaxel, and did not impact exposure or compliance on treatment.
Citation Format: Frankie A Holmes, Kristi J McIntyre, Ian E Krop, Cynthia R Osborne, John W Smith II, Manuel R Modiano, Manish Gupta, Leona B Downey, Rita Nanda, Mansoor N Saleh, Jonathan R Young, Kerry E Horgan, William Kubasek, Gavin MacBeath, Michael A Danso, Joyce A O'Shaughnessy. A randomized, phase 2 trial of preoperative MM-121 with paclitaxel in triple negative (TN) and hormone receptor (HR) positive, HER2-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-03.