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Poster display session

3207 - Phase 1 Dose-escalation Study of Single-Agent ZW25, a HER2-targeted Bispecific Antibody, in Patients (pts) with HER2-expressing Cancers

Date

11 Sep 2017

Session

Poster display session

Topics

Cytotoxic Therapy;  Clinical Research;  Breast Cancer

Presenters

Muralidhar Beeram

Citation

Annals of Oncology (2017) 28 (suppl_5): v74-v108. 10.1093/annonc/mdx365

Authors

M. Beeram1, E. Hamilton2, M. Blum Murphy3, D. Hausman4, J.R. Infante2, R. Korn5, A. Patnaik1, S.A. Piha-Paul3, D. Rasco1, G. Rowse6, J. Thimmarayappa4, A. Tolcher1, F. Meric-Bernstam3

Author affiliations

  • 1 Medical Oncology, South Texas Accelerated Research Therapeutics (START), 78229 - San Antonio/US
  • 2 Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, 37203 - Nashville/US
  • 3 Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston/US
  • 4 Clinical Development, Zymeworks Biopharmaceuticals Inc, 98121 - Seattle/US
  • 5 Radiology, Imaging Endpoints LLC, Scottsdale/US
  • 6 Therapeutics Research And Development, Zymeworks Inc, Vancouver/CA
More

Resources

Abstract 3207

Background

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.

Methods

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.

Results

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.

Conclusions

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

NCT02892123

Legal entity responsible for the study

Zymeworks Inc

Funding

Zymeworks Inc

Disclosure

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.

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