HER2 is expressed on many cancers (ca) at varying levels. ZW25, a novel bispecific antibody, targets the same HER2 domains as trastuzumab (T) and pertuzumab (P). In preclinical studies ZW25 shows increased binding, internalization and anti-tumor activity relative to T in models of low to high HER2.
3 + 3 dose escalation study in pts with HER2 IHC 1-3+ or FISH+ ca, who have progressed after standard treatment (tx) including HER2 targeted agents, and have measurable or non-measureable disease per RECIST 1.1. ZW25 was given weekly (QW; 5, 10 or 15 mg/kg) or biweekly (Q2W; 20 mg/kg) in 4 week cycles. Assessments included HER2 status (local and central read), adverse events (AEs), tumor response, PET scan, immunogenicity and PK.
16 pts (8 breast; 6 gastric/esophageal ≥; 1 colorectal [CRC]; 1 adnexal) have received ZW25 QW at 5 (n = 3), 10 (n = 6) and 15 mg/kg (n = 7); 20 mg/kg Q2W is enrolling. All pts had prior T; breast ca pts also had T-DM1 (n = 8), P (n = 6) or lapatinib (L; n = 6). 12 pts had IHC 3+/FISH+ ca (local and central read); 1 CRC ca was HER2 heterogeneous (IHC 3+/FISH+ and IHC 0/FISH -), and 3 GE were IHC 1 + (central read). No dose limiting toxicities were observed. The most common AEs were Diarrhea (44%, all grade 1), Infusion reaction (IR) (44%, grade 1 and 2), and Fatigue (31%). PK was non-linear and increased with dose of ZW25. 8/13 pts tested had anti-drug antibodies (ADA) at baseline. No increases in titers and no new detectable ADA were seen. In 7 breast ca pts (1 too early), best overall response (BoR) was 2 PR (both 10 mg with prior T, P, T-DM1, L); 2 SD (>8 cycles in 5 mg pt with prior T, P, T-DM1; >2 cycles in 15 mg pt, with T, P, T-DM1, L); and 3 PD. BoR in 5 GE pts (1 too early): 1 SD > 4 cycles (10 mg, prior T, IHC 3+) and 4 PD. BoR in adnexal (10 mg) and CRC (15 mg) pts was PD.
ZW25 was well tolerated with promising single-agent activity including SD > 6 mo and PR in pts with HER2 expressing ca who have progressed after standard tx, including multiple lines of prior HER2 targeted agents. These early signs of activity support the therapeutic potential of ZW25.
Clinical trial identification
Legal entity responsible for the study
M. Beeram, D. Rasco: Employee of START. D. Hausman: Stockholder and employee Zymeworks Biopharmaceuticals Inc. R. Korn: Employee and leadership role at Imaging Endpoints. G. Rowse: Employee of Zymeworks Inc. J. Thimmarayappa: Employee of Zymeworks Biopharmaceuticals Inc. A. Tolcher: Employee of START, leadership role at Symphogen, member of Zymeworks Clinical Advisory Board. F. Meric-Bernstam: Honoraria: Genentech, Roche Diagnostics. Consulting or Advisory Role: Celgene, Genentech, Inflection Biosciences, Novartis, Roche. All other authors have declared no conflicts of interest.