Reference Detail

Ref Type

PMID

Authors

M. Beeram, E. Hamilton, M. Blum Murphy, D. Hausman, J.R. Infante, R. Korn, A. Patnaik, S.A. Piha-Paul, D. Rasco, G. Rowse, J. Thimmarayappa, A. Tolcher, F. Meric-Bernstam

Title

Phase 1 dose-escalation study of single-agent ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-expressing cancers

Journal	Vol	Issue	Date	Pages	Journal Short Title
Ann Oncol

URL

https://www.annalsofoncology.org/article/S0923-7534(20)37679-1/fulltext

Abstract Text

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

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ZW25	ZW25	0	6

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ZW25		ZW-25\|Zanidatamab	HER2 (ERBB2) Antibody 72	Zanidatamab (ZW25) is a bispecific antibody targeting ERBB2 (HER2), which induces anti-tumor immune response against Erbb2 (Her2)-expressing tumors (Ann Oncol 2017, Vol 28, Suppl 5, Abstract # 255P, PMID: 32054397).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References