Abstract P4-16-09: Phase 1b/2 trial of the HER3 inhibitor patritumab (U3-1287) in combination with trastuzumab plus paclitaxel in newly-diagnosed patients with HER2+ metastatic breast cancer (MBC)
Authors: Carraro S , Campos D , Copigneaux C , Saintilien C , Beckman RA , Korbenfeld E , Coppola MP , Halabe K , Cazap E 
Published: August 2014

Abstract
Background: Patritumab is a fully human anti-HER3 monoclonal antibody that has shown potent antitumor activity in vivo. HER3 is a key dimerization partner for other HER family members, and studies suggest that the HER3:HER2 heterodimer is the most potent signaling pair. Therefore, combined inhibition of HER3 and HER2 may synergistically inhibit breast cancer tumor growth. In the CLEOPATRA trial, pertuzumab combined with trastuzumab and docetaxel prolonged progression-free survival compared to trastuzumab and docetaxel alone, demonstrating the benefit of comprehensive blockade of HER2 dimer signaling. Trastuzumab is approved in combination with paclitaxel for first-line treatment of HER2+ MBC. This phase 1b/2 study is investigating patritumab in combination with trastuzumab and paclitaxel in patients (pts) with newly-diagnosed MBC. Results of the phase 1b portion are reported here.
Methods: Eligible pts had HER2+ newly-diagnosed MBC. In the open-label, phase 1b portion of this trial, pts received intravenous (IV) patritumab 18 mg/kg in combination with trastuzumab (8 mg/kg IV loading dose; 6 mg/kg IV maintenance dose) and paclitaxel (175 mg/m2 IV) every 3 weeks (Q3W). In the event that 18 mg/kg was not tolerated based on dose-limiting toxicity (DLT) assessment, sequential cohorts were to receive de-escalating doses of patritumab. Phase 1b study end points included adverse event (AE) incidence, human antihuman antibody (HAHA) formation, pharmacokinetics (PK), and tumor response.
Results: Six pts were enrolled in the phase 1b portion of the trial, with a median age of 61 years (range, 51-78). There were no reported DLTs. Grade ≥3 treatment-related AEs occurred in 3 pts: 1 pt had a serious AE of grade 3 pneumonia; 1 pt had grade 3 worsening of arm pain; 1 pt had grade 3 oral mucositis, prolonged QTc, flu-like syndrome, and increased transaminases. In this limited pt population, most ECG changes were within or slightly above normal limits of the QTc interval. Only 2 pts had increased values close to 50 msec compared with baseline. It should be noted that baseline QTc values for 3 pts (including the pt that experienced grade 3 prolonged QTc) were close to the upper limit of normal. There were no grade 4 AEs, and no other serious AEs. All other treatment-related AEs were grades 1 or 2. All 6 pts tested negative for HAHA formation after drug administration. PK data are consistent with previous studies with patritumab. Two pts had complete response (CR) as their best overall response, 2 pts had partial response (PR), 1 pt had stable disease, and 1 pt was not evaluated for tumor response. All 6 pts have discontinued treatment; 2 due to progressive disease, 3 due to pt decision (2 with CR and 1 with PR), and 1 at the investigator's discretion.
Conclusions: Results to date indicate that the combination of patritumab with trastuzumab and paclitaxel is generally well tolerated, with a promising response rate. As no DLTs were reported, the recommended phase 2 dose is patritumab 18 mg/kg with trastuzumab (8 mg/kg loading; 6 mg/kg maintenance) and paclitaxel 175 mg/m2 Q3W.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-09.