HER2 Inhibitors Demonstrate Variable Effects in Solid Cancers

Human epidermal growth factor receptor 2 (HER2)-targeted therapy results in different objective response rates (ORR) across cancer types based on mutation variants, according to recent research.


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Clinical trials are often designed to treat cancers sharing a driver mutation with a targeted therapy, regardless of tumor lineage. Results of a recent trial that treated various types of advanced solid tumors with a targeted HER2 inhibitor suggest that targeting a common driver mutation across cancer types may be more complex than currently understood.

David M Hyman, MD, Early Drug Development, Memorial Sloan Kettering Cancer Center (New York, NY), and colleagues conducted a phase II study to test the effects of an HER2 inhibitor in various forms of solid cancer, mainly lung (18.1%), breast (17.7%), and bladder/urinary (11.3%). A total of 141 patients were sampled with locally documented HER2 or HER3 mutations and were treated with 240 mg daily of the pan-HER tyrosine kinase inhibitor neratinib. The primary endpoint of the study was ORR.

Results of the trial were presented in part at the 2017 American Association for Cancer Research (AACR) annual meeting (April 1-5, 2017; Washington, DC).

Researchers reported no significant clinical activity associated with neratinib in cancer with HER3 mutations.

Responses in cancer with HER2 mutations were evaluated based on type of specific variants—such as S310, L755, and V777—which were categorized into hotspots according to their location in extracellular, transmembrane, and kinase domains. This tumor-type analysis showed significant differences in ORR by variant, suggesting that tumor lineage is likely to be a prognostic factor for benefit from an HER2 inhibitor.

“These data show that you cannot treat all HER2 mutations the same. You need to consider them at the variant level and not at the gene level,” reported Dr Hyman. “There are true differences in the ways cancers are programmed to respond to inhibitors.”

Further alluding to the multidimensionality of the HER2 oncogene and its use as a target in cancers, Dr Hyman commented, “I think this raises the possibility that certain patients will have truly private genetic alterations that may be true one-off events, and yet that will be the driver of their cancer, and they can go on to derive benefit from a targeted therapy.”

Such data may result in reorganizing attempts to understand how to target driver mutations in solid cancers, independent of tumor lineage.—Zachary Bessette