3575 - Safety, Anti-Tumor Activity, and Biomarker Results of the HER2-Targeted Bispecific Antibody ZW25 in HER2-Expressing Solid Tumors

Background

ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here.

Methods

Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA; pre-dose C1 D1, C2 D15, treatment end), and standard safety evaluations.

Results

A total of 43 patients, including 17, 6, 10, and 10 with gastroesophageal adenocarcinoma (GEA), biliary tract cancers, colorectal cancer, and other cancers, respectively, received single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one unique prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085).

Conclusions

ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors.

Clinical trial identification

NCT03929666.

Editorial acknowledgement

Legal entity responsible for the study

Zymeworks, Inc.

Funding

Zymeworks, Inc.

Disclosure

F. Meric-Bernstam: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Sumitomo Dainippon Pharma; Dialectica; Advisory / Consultancy: Genentech; Inflection; Pieris; Darwin Health; Samsung Bioepis; Aduro; Spectrum; OrigiMed; Debio; Xencor; Jackson Laboratory; Mersana; Seattle Genetics; Zymeworks; Kolon; Parexel International. M. Beeram: Speaker Bureau / Expert testimony, Speaker’s bureau: Genentech. K. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck; Advisory / Consultancy: Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis. J. Chaves: Shareholder / Stockholder / Stock options: Northwest Medical Specialties, PLLC. C. Vaklavas: Advisory / Consultancy, no compensaton: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Innocrin; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): H3 Biomedicine. D. Oh: Advisory / Consultancy: Genentech; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly. E. Elimova: Full / Part-time employment, spouse is employee in vaccine global division: Meric; Advisory / Consultancy: BMS; Honoraria (self): Zymeworks. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas Pharma; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony, Speaker’s bureau: Novartis; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck; Novartis; Roche/Genentech; Sanofi; Pfizer; Janssen; Zymeworks; Travel / Accommodation / Expenses: Novartis; Roche. A. Fortenberry: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. G. Rowse: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. T. Gray: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. R. Lai: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. E. Hamilton: Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Lilly; Advisory / Consultancy, No personal compensation: Lilly; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, No personal compensation: Pfizer; Research grant / Funding (institution): Genentech/Roche; Speaker Bureau / Expert testimony, No personal compensation: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Hutchinson MediPharma; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): StemCentrx; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Verastem; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Rgenix; Novartis; Mersana; TapImmune; BerGenBio; Tesaro; Medivation; Kadmon, Boehringer Ingelheim; Eisai; H3 Biomedicine; Radius Health; Acerta; Takeda; Macrogenics; Immunomedics; FujiFilm; Effector. All other authors have declared no conflicts of interest.