Results from a phase 1 clinical trial show that zanidatamab, a novel HER2-targeted bispecific antibody, demonstrates encouraging antitumor activity when combined with chemotherapy in patients with heavily pretreated HER2-positive breast cancer.
Promising Efficacy in Advanced Disease
The data, presented at the San Antonio Breast Cancer Symposium (SABCS), revealed that among 22 efficacy-evaluable patients, the combination of zanidatamab with single-agent chemotherapy achieved a confirmed objective response rate (cORR) of 36.4% and a disease control rate (DCR) of 86.4%. The median progression-free survival (PFS) reached 7.3 months across all treatment regimens, with 42% of patients still on study at the time of data cutoff.
Dr. Philippe L. Bedard of Princess Margaret Cancer Centre, who led the study, noted that these results are particularly significant given the limited options currently available for patients who have progressed after multiple lines of HER2-targeted therapies.
"Zanidatamab together with chemotherapy shows encouraging antitumor activity and a manageable safety profile in patients with HER2-positive breast cancer that has progressed after treatment with multiple HER2-targeted agents," explained Dr. Neil Josephson, Chief Medical Officer at Zymeworks, the company developing the drug.
Novel Mechanism of Action
Zanidatamab (ZW25) is a humanized bispecific antibody with a unique design that simultaneously targets two distinct sites on HER2 - the juxtamembrane domain (ECD4) and the dimerization domain (ECD2). This dual-targeting approach results in multiple mechanisms of action, including:
- Dual HER2 signal blockade
- Increased antibody binding
- Receptor clustering and internalization
- Removal of HER2 from the cell surface
- Potent effector function
The drug was developed using Zymeworks' proprietary Azymetric™ platform and has shown activity across various HER2-positive cancers.
Study Design and Patient Population
The trial enrolled 24 patients with heavily pretreated HER2-positive metastatic breast cancer who received zanidatamab in combination with one of three chemotherapy agents:
- Vinorelbine (n=12)
- Capecitabine (n=8)
- Paclitaxel (n=4)
Patients had received multiple prior regimens containing HER2-targeted agents, including trastuzumab (96%), pertuzumab (96%), and ado-trastuzumab emtansine/T-DM1 (96%). Many had also received tyrosine kinase inhibitors.
The median number of prior systemic regimens in the metastatic setting was 2.0, with a range of 0-6 treatments. Thirty-eight percent of patients had a prior history of brain metastases.
Response by Chemotherapy Partner
When examining responses based on the chemotherapy partner, zanidatamab showed varying degrees of efficacy:
- With paclitaxel: 50.0% ORR (95% CI, 6.8%-93.2%)
- With capecitabine: 42.9% ORR (95% CI, 9.9%-81.6%)
- With vinorelbine: 27.3% ORR (95% CI, 6.0%-61.0%)
The duration of response ranged from 1.6 months to an impressive 22.1+ months, with the majority of patients experiencing tumor shrinkage.
Manageable Safety Profile
The combination therapy demonstrated a manageable safety profile, with most treatment-related adverse events (TRAEs) being mild to moderate in severity (Grade 1 or 2). The most common TRAEs included:
- Diarrhea (71% any-grade, 8% Grade 3 or higher)
- Nausea (33%, all Grade 1-2)
- Stomatitis (29%, all Grade 1-2)
- Fatigue (25%, all Grade 1-2)
- Peripheral neuropathy (25%, 4% Grade 3 or higher)
- Palmar-plantar erythrodysesthesia (25%, all Grade 1-2)
- Decreased neutrophil count (25%, all Grade 3 or higher)
- Neutropenia (17%, 13% Grade 3 or higher)
"Diarrhea is the most frequent TRAE observed across regimens and is manageable, with the majority (>90%) being low grade," the study authors noted. Few infusion-related reactions or cardiac events were observed, and none were severe.
One patient discontinued treatment due to treatment-related Grade 3 diarrhea, while 13 patients stopped due to disease progression.
Clinical Context and Significance
HER2-positive breast cancer accounts for approximately 15-20% of all breast cancer cases. While HER2-targeted therapies have significantly improved outcomes, patients with advanced disease who progress after standard treatments typically face limited options.
Current standard approaches for these patients generally involve a HER2-targeted antibody (such as trastuzumab) combined with a single chemotherapeutic agent. However, this approach typically yields response rates below 25%, with median progression-free survival less than 6 months and median overall survival less than 2 years.
"We were impressed by the activity and durability of disease control with zanidatamab, with over half of patients experiencing a confirmed response or stable disease lasting over 6 months," Dr. Josephson commented. "These results, together with data presented earlier this year in both HER2-expressing biliary tract cancer and gastroesophageal adenocarcinoma, build on our belief that zanidatamab has the potential to be a foundational therapy across multiple HER2-expressing solid tumor indications."
Future Directions
James Priour, Chief Commercial Officer at Zymeworks, highlighted the commercial potential for zanidatamab: "With the majority of HER2-positive breast cancer patients benefitting from new therapies and surviving longer than ever before, there is a significant commercial opportunity in the third- and fourth-line setting."
Zymeworks plans to share additional data with zanidatamab in HER2-positive breast cancer from other ongoing trials in the first half of 2022, including combinations with Ibrance and fulvestrant in late-line hormone receptor-positive disease, as well as with docetaxel in the first-line setting.
The vinorelbine and capecitabine cohorts of the current trial continue to enroll patients, and the company is considering breast cancer as the next indication to pursue a potential label, following ongoing pivotal trials in biliary tract and gastric cancers.
Dr. Bedard and colleagues concluded that "these data support further investigation of zanidatamab plus single-agent chemotherapy as a novel therapeutic option for treatment of patients with HER2-positive locally advanced or metastatic breast cancer after 3 or more lines of prior therapy."
