A novel anti-HER2 therapy, ZW25, may be effective and well tolerated in patients with a variety of HER2-positive cancers. In a phase I trial, patients treated with the drug—most of whom had gastroesophageal or colorectal cancer—had an objective response rate of 41% and mild side effects.

A novel anti-HER2 therapy, ZW25 (Azymetric), is effective and well tolerated in patients with a variety of HER2-positive cancers, according to results presented at the 2018 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland. In a phase I basket trial, patients treated with the drug—most of whom had gastroesophageal or colorectal cancer—had a high objective response rate with only mild side effects.

HER2 can be overexpressed in various cancers, including breast, gastroesophageal, colorectal, biliary, and salivary gland. However, although several HER2-targeted therapies have been FDA approved for HER2-positive breast cancer, trastuzumab (Herceptin; Genentech) is the only one approved for a HER2-positive cancer other than breast cancer: Its use is limited to first-line treatment of metastatic gastroesophageal cancer.

“There is an unmet need towards developing better treatment approaches for these other cancers that have a high expression of the HER2 receptor,” says Murali Beeram, MD, of the START Center for Cancer Care in San Antonio, TX, who presented the findings.

ZW25 is a bispecific antibody that simultaneously binds to two HER2 epitopes: ECD4, the trastuzumab binding domain, and ECD2, the pertuzumab (Perjeta; Genentech) binding domain. Preclinical research suggested that ZW25 has strong antitumor activity at a range of HER2 expression levels and may more effectively silence HER2 signaling than trastuzumab or pertuzumab. It also stimulates the immune system. Now, researchers are testing the agent in a phase I basket trial of HER2-positive cancers.

Researchers enrolled 24 patients with HER2-positive cancers other than breast cancer, including 10 with gastroesophageal, five with colorectal, and nine with other malignancies. Patients had received a median of three prior therapies, and 71% had previously received trastuzumab.

Overall, patients had a median progression-free survival of 6.2 months. Of 17 evaluable patients, seven (41%) had an objective response to the drug, and seven (41%) had stable disease, for a disease control rate of 82%. Diarrhea, infusion reactions, and nausea were the most common side effects, and most were classified as grade 1 or 2; no grade 4 or 5 side effects were observed.

“These are very exciting results, especially for the kind of tumors that we're talking about—if we can reproduce these results consistently in additional testing, it may mean an effective treatment for patients who, at this point, don't have a treatment option,” Beeram says. He notes that the trial is still ongoing, with expansion cohorts being added for gastroesophageal cancers. Planning is also under way for phase II trials that will test the drug alone and in combination with chemotherapy.

ZW25 is also under study in HER2-positive breast cancers. Results from the same phase I trial presented at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, IL, indicated that six out of 13 patients with breast cancer (46%) responded to the drug.

To symposium co-chair Antoni Ribas, MD, PhD, of the University of California, Los Angeles, who is not involved in the research, ZW25 stands out due to its novel binding mechanism and strong early clinical data. “The fact that this HER2-targeted bispecific antibody has responses in a phase I trial, even in patients who have progressed on trastuzumab, is really remarkable,” he says.

Ribas adds that “these are promising results that warrant further clinical testing in HER2-positive cancers, and in particular, gastroesophageal cancers.” –Catherine Caruso

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