Promising Phase I trial for anti-HER2 antibody

A Phase I trial of bispecific antibody ZW25, which binds to two regions on HER2 receptors simultaneously, was tolerated well and demonstrated a good response in patients with HER2-driven cancers such as those of the gullet or bowel.

Trastuzumab (Herceptin®) is currently the only approved HER2-targeting agent, and is quite effective for breast and stomach cancers. However, for patients with other cancers caused by HER2, there are no approved anti-HER2 agents, and for those with recurring HER2-positive breast or stomach cancer there are no other options.

In a study presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (13–16 November 2018, Dublin, Ireland), researchers gave 24 HER2-positive patients, who had undergone an average of four previous therapies and whose cancer had returned, between one and ten cycles of ZW25 (either 10 mg kg-1 weekly or 20 mg kg-1 fortnightly). Eight patients remain in the trial.

Tumor shrinkage occurred in 13 out of 17 patients, with the median progression-free survival being 6.21 months. The drug was well-tolerated, with mostly mild to moderate side effects such as diarrhoea or reaction to the drug infusion.

Medical oncologist and clinical investigator Muarli Beeram (START Center for Cancer Care, TX, USA) commented: “I am excited by the single agent anti-tumor activity and tolerability we are seeing with ZW25, particularly in these patients with advanced HER2 expressing cancers that have progressed after multiple prior therapies.”

Beeram also remarked on the “encouraging anti-tumor activity in patients whose tumors have stopped responding to approved therapies, and who are in desperate need of new medicines that provide anti-tumor activity without excessive toxic side effects.

“The impressive activity of ZW25, combined with its tolerability, is notable and should be investigated further.”

HER2 is a growth factor well-known for playing a major role in the proliferation of breast cancer, and it is hoped that ZW25 could lead to another line of attack against these types of cancers. Dr Beeram explains that the bispecificity of ZW25 is a “unique design”, which “results in multiple mechanisms of action, including dual HER2 signal blockade, increased binding, and removal of HER2 protein from the cancer cell surface; it also stimulates the immune system to attack the cancer cells.”

Future studies are now planned, including a Phase II/III trial next year. Zymeworks (Vancouver, Canada), the company that designed and made ZW25, has also planned to look into the effects of combination therapies using ZW25, and how the drug affects cancers with both and over- and under-abundance of HER2.

“Although these are early results on a small number of patients, they suggest that this new HER2 targeted antibody can have an effect on difficult-to-treat cancers that have either failed to respond to previous therapies or have recurred,” concluded symposium co-chair Antoni Ribas (University of California Los Angeles, CA, USA), “We look forward to further results from this study, as well as the further studies that are planned.”

Source: Single agent activity of ZW25, a HER2-targeted bispecific antibody, in HER2-expressing gastroesophageal and other cancers presented at 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Dublin, Ireland, 13–16 November 2018.