Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.

Background: HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.
Methods: This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing.
Findings: Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths.
Interpretation: These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.
Funding: Zymeworks.
Competing Interests: Declaration of interests FM-B reports consulting or personal fees from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F Hoffman-La Roche, Genentech, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seagen, Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, and Chugai; advisory board participation for Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology, Seagen, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; and research support, unrelated to this work and paid to institution, from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology, and Taiho Pharmaceutical. EH reports consulting fees or research grants outside of the scope of this work and paid to the institution from AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, Arcus, ArQule, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Daiichi Sankyo, the Dana-Farber Cancer Institute, Dantari, Deciphera, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, Greenwich LifeSciences, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, InvestisBio, iTeos, Jacobio, Janssen, Karyopharm, Leap Therapeutics, Lilly, Loxo, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millennium, Molecular Templates, Myraid Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Puma Biotechnology, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks. D-YO reports consulting fees or Advisory Board participation for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, and research support outside the scope of this work from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. Y-KK reports consulting fees from ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, Bristol Myers Squibb, MSD, and Roche. EE reports consulting fees from Bristol Myers Squibb, Zymeworks, Adaptimmune, BeiGene; research support outside the scope of this work from Bristol Myers Squibb, Zymeworks, and AstraZeneca; and a family member employedby Merck. RG reports consulting fees or advisory board participation for Pfizer, Apobiologix, Ipsen, Novartis, Eisai, Incyte, Bristol Myers Squibb, AstraZeneca, Merck, Roche, and Advanced Accelerator Applications; and education grants from Pfizer, Apobiologix, and Ipsen. SP reports consulting fees or advisory board participation for Xencor, 4D Pharma, Zymeworks, Ipsen, Novartis, and Janssen; research support outside the scope of this work and paid to institution from Mirati Therapeutics, Pfizer, Lilly, Xencor, Novartis, Bristol Myers Squibb, Ipsen, Astellas Pharma, Purple Biotech, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Zymeworks, and BioNtech. KR reports personal fees from AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, and Seattle Genetics; and research support from Bayer, Daiichi-Sankyo, Genentech/Roche, Guardant Health, Janssen, Lilly, and Medimmune outside the submitted work. JWK reports consulting fees from AstraZeneca, BeiGene, Beyond Bio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD, ONO, Sanofi-Aventis, Servier, and TCUBEit. AP reports consulting or advisory fees from Genentech/Roche, Merck, Bristol Myers Squibb, Bayer, Novartis, Seagen, Gilead Sciences, Silverback Therapeutics, Daiichi, and HalioDx. TG, RD, and MAO report employment by Zymeworks at the time of the study and ownership of Zymeworks stock. JW reports employment by Zymeworks at the time of the study and ownership of Seagen stock. K-WL reports consulting fees from ISU ABXIS, Bayer, Daiichi Sankyo, Merck Sharp and Dohme, Bristol Myers Squibb, Vifor Pharma, Ono Pharmaceutical, and Boryung; and research grants outside of the scope of this work from AstraZeneca, Ono Pharmaceutical, Merck Sharp and Dohme, Merck KGaA, Pfizer, BeiGene, Astellas Pharma, ALX Oncology, Macrogenetics, Five Prime Therapeutics, Seagen, Bolt Therapeutics, Trishula Therapeutics, Oncologie, Pharmacyclics, LSK BioPharma, MedPacto, Green Cross Corp, ABLBIO, Y-BIOLOGICS, Genexine, Daiichi Sankyo, Taiho Pharmaceutical, InventisBio, and Leap Therapeutics. All other authors declare no competing interests.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)