Abstract P5-20-06: Phase 1 dose escalation with ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-high breast cancer (BC)
Authors: Hamilton E , Meric-Bernstam F , Infante J , Murthy R , Patnaik A , Piha-Paul SA , Tolcher A , Hausman D , Royer N , Beeram M 
Published: February 2018

Abstract
Background: ZW25, a novel IgG1-like bispecific antibody, targets the same domains of HER2 as trastuzumab (T) and pertuzumab (P). In preclinical studies, ZW25 demonstrated increased tumor cell binding density and internalization relative to T and activity in T-resistant cell lines as well as models of HER2-low to high cancers. Initial dose escalation data demonstrated that once-weekly ZW25 was well tolerated at all doses evaluated and associated with single-agent anti-tumor activity in pts with heavily pre-treated (tx) HER2-expressing cancers.
Methods: 3+3 dose escalation of ZW25 given weekly (QW; 5, 10 or 15 mg/kg) or biweekly (Q2W; 20 mg/kg) in 4-week cycles. Eligibility included HER2 IHC 1, 2 or 3+ or FISH+ BC, progression after T, P and T-DM1, and measurable or non-measureable disease per RECIST 1.1. Active brain metastases were excluded. Baseline brain MRI was performed in QW cohorts only if pts had prior history (hx) of CNS mets, and in all Q2W pts regardless of hx. Assessments included AEs, LVEF, immunogenicity, PK and tumor response every 2 cycles.
Results: 8 pts with HER2-high BC were tx with ZW25 QW at 5 (n=2), 10 (n=2) or 15 mg/kg (n=4); 20 mg/kg Q2W is enrolling. 5/8 pts were HR+; 7 had measurable disease, 6 visceral disease, and 3 stable CNS disease. Median years since initial dx was 6 (range 5-16). Prior tx included T and T-DM1 (n=8); P (n= 6), and lapatinib (n=5). Median number of prior HER2-targeted regimens for metastatic disease was 6 (range 3-7) and non-hormonal HER2 regimens was 5 (range 3-7).
ZW25 was well tolerated with no DLTs or decreases in cardiac function. Most common related AEs (all Gr 1 or 2) were diarrhea (n=4), infusion reaction (IR) (n=4) and vomiting (n=3). All IRs occurred only with 1st dose. There were no treatment-related SAEs. Related Gr 3 AEs (hypophosphatemia, fatigue and arthralgia) were reported in 1 pt (10 mg/kg).
At data cut-off, pts had received 2-10 cycles of treatment, with 3 pts active. Best overall response was 2 PR (10 mg/kg), 3 SD (1 at 5 mg/kg, 2 at 15 mg/kg), and 3 PD (1 at 5 mg/kg, 2 at 15 mg/kg) for a disease control rate of 63%. Decreases in target lesions were seen in 6/7 patients with at least one tumor re-staging. One pt with SD (5 mg/kg; active on study) had an 8% decrease after C2, and 29% decrease after C8. One PR pt with prior hx of brain mets had a 33% decrease after C2 and 44% decrease after C4, although was found to have new leptomeningeal disease (LMD) at that time. Two additional pts with systemic SD (15 mg/kg; no prior hx of CNS mets) were also considered to have PD due to symptomatic brain mets. One of these pts remains on study after receiving stereotactic radiotherapy.
Conclusions: ZW25 was associated with single-agent anti-tumor activity and systemic disease control in HER2-high BC pts after a median of 6 prior HER2-targeted regimens for metastatic disease. Systemic disease control was maintained despite PD due to brain mets or LMD. The presence of CNS disease in an unscreened population is consistent with the biology of late-stage HER2-high BC. The activity and tolerability of ZW25 support further evaluation as a single agent and in combination including with CNS-directed therapies in early and late lines of treatment for HER2-expressing BC.
Citation Format: Hamilton E, Meric-Bernstam F, Infante J, Murthy R, Patnaik A, Piha-Paul SA, Tolcher A, Hausman D, Royer N, Beeram M. Phase 1 dose escalation with ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-high breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-06.