Zanidatamab Plus Tucatinib/Capecitabine Is Being Tested in Advanced HER2+ Breast Cancer

Zanidatamab is being combined with tucatinib and capecitabine in a new cohort of a phase 1 trial of patients with locally advanced and/or metastatic HER2-positive breast cancer.

Zanidatamab is being combined with tucatinib (Tukysa) and capecitabine in a new cohort of a phase 1 trial (NCT02892123) of patients with locally advanced (unresectable) and/or metastatic HER2-positive breast cancer, according to an announcement by Zymeworks, Inc., the developer of the agent.1

“Recent clinical trials have demonstrated the benefit of combining tucatinib with trastuzumab [Herceptin] and chemotherapy in patients with metastatic HER2-positive breast cancer,” said Neil Josephson, MD, interim chief medical officer at Zymeworks. “Given the antitumor activity of zanidatamab observed across a range of HER2-overexpressing tumors and preclinical studies demonstrating improved anti-tumor activity of zanidatamab compared to trastuzumab, we believe the combination of zanidatamab with tucatinib and chemotherapy has the potential to be an impactful treatment for patients with advanced HER2-positive breast cancer, including those with brain metastases.”

As of July 28, 2021, the first patient has been dosed in this new cohort. The study’s estimated primary completion date is January 31, 2022.

Zanidatamab is a bispecific antibody that binds to HER2 across expression levels and has the following mechanisms of action: formation of receptor clusters, resulting in receptor internalization and downregulation that affect signal transduction; and potently activates the immune system to elicit antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity.

In the first-in-human, 3-part trial, investigators are evaluating the efficacy, safety, and tolerability, as well as pharmacokinetics, of zanidatamab alone or in combination with select chemotherapy regimens in patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancers.

In part 1 of the trial, zanidatamab will be tested at increasing doses to determine the maximum-tolerated dose (MTD), the optimal biological dose (OBD), and/or other recommended doses in up to 7 dose-specific cohorts.

Part 2 of the trial will continue to explore efficacy, safety, and tolerability of zanidatamab in this patient population in up to 5 separate disease-specific cohorts, which will include the MTD, OBD, or recommended dose identified in part 1.

In part 3 of the study, zanidatamab will be combined with the following agents: paclitaxel, vinorelbine, or capecitabine alone or with tucatinib.

To be eligible for enrollment, patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancer have to have progressed on or are ineligible to receive all standard therapies. In part 3 of the trial, patients must have progressed on 1 to 3 prior systemic chemotherapy regimens.

Those who received experimental therapies within 4 weeks before first zanidatamab dose, anthracyclines within 90 days before first dose, history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation, have peripheral neuropathy higher than grade 2, or clinically significant interstitial lung cancer, among other factors, are excluded from enrollment.

The coprimary end points are dose-limiting toxicities and treatment-related adverse events; secondary end points include serum concentrations, detectable anti-drug antibodies, objective response rate (ORR) via RECIST v1.1 criteria, progression-free survival via RECIST v1.1 criteria, and safety.

“This new study cohort complements our ongoing trials with zanidatamab in combination with other standard-of-care treatment regimens and supports our goal of establishing zanidatamab as the foundational therapy for HER2‑expressing cancers,” Josephson concluded.

Previously, the FDA granted breakthrough therapy designation to zanidatamab as a potential therapy for patients with previously treated HER2 gene-amplified biliary tract cancer (BTC). The agent also has 2 fast track designations to zanidatamab; one is for use as a single agent for patients with refractory BTC, while the second is for use in combination with standard chemotherapy for the first-line treatment of patients with gastroesophageal adenocarcinoma.

The November 2020 breakthrough designation is based on an ongoing phase 1 study (NCT02892123) of zanidatamab in patients with locally advanced, unresectable and/or metastatic HER2-expressing cancers, including BTC. Here, the confirmed objective response rate was 33% and the disease control rate was 61% when zanidatamab was used as a monotherapy.3 These rates were 54% and 79%, respectively, when zanidatamab was given in combination with chemotherapy.

Tucatinib is currently approved by the FDA for use in combination with trastuzumab and capecitabine for the treatment of adult patients with unresectable advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have received at least 1 prior therapy.


  1. Zymeworks announces first patient with advanced her2-positive breast cancer dosed with zanidatamab in combination with Tukysa (tucatinib) and chemotherapy. News release. Zymeworks Inc. July 28, 2021. Accessed July 28, 2021.
  2. Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers. Last Updated August 4, 2021. Accessed August 23, 2021.
  3. Meric-Bernstam F, Hamilton EP, Beeram M, et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): results from a phase I study. J Clin Oncol. 2021; 39(suppl 3):164. doi:10.1200/JCO.2021.39.3_suppl.164