Phase Ib study of open-label AMG 386 plus paclitaxel (P) and trastuzumab (T) or capecitabine (C) and lapatinib (L) in patients (pts) with HER2+ locally recurrent or metastatic breast cancer (MBC).

Abstract

529 Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis by blocking interaction of angiopoietins 1 and 2 with the Tie2 receptor. This interim analysis evaluates the tolerability and efficacy of AMG 386 + P/T or C/L in HER2+ MBC. Methods: In part 1, pts in cohorts A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P 80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14 Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg; A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were expanded to n = 20 if ≤ 1 of 6 or ≤ 2 of 9 pts had dose-limiting toxicities (DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary endpoints included efficacy and pharmacokinetics (PK). Interim results from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at interim analysis; all received ≥ 1 dose of study treatment (A1, A3, B1; n = 20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and 31.3 wks. Across cohorts, there was 1 DLT in A1. AEs > 50% were peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined, and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), and peripheral edema in B1. AEs grade ≥3 occurring in > 2 pts were peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n = 5, 4, 3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia (n = 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1, 50% in A3, and 50% in B1. Median (95% CI) progression-free survival was 14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes were apparent in any PK parameters in these combinations relative to within study or historical monotherapy PK data. Conclusions: In this ongoing phase 1b study of pts with HER2+ MBC, interim results suggest that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity. Updated data will be presented.