Perseverance Is the Name of the Game With HER3 Research in Solid Tumors

Jane De Lartigue, PhD
Published: Wednesday, Feb 05, 2020
Although the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) plays a central role in the development of human cancers, efforts to target its activity therapeutically have focused thus far on 2 of its now famous members. Therapies aimed at the epidermal growth factor receptor (EGFR/ HER1) and HER2, renowned as major drivers of lung and breast cancer, respectively, were among the first targeted agents in the anticancer armamentarium.

However, after more than a decade of studies, none of these drugs have emerged triumphant from clinical trials, hampered by a lack of clinically meaningful efficacy. Despite a reasonable expectation that expression of HER3 and its ligand heregulin (HRG) would be predictive biomarkers for HER3-targeted therapy, their usefulness in clinical trials has been hit-and-miss.

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Nevertheless, investigators have persevered, and new types of drugs have largely supplanted the first generation in clinical trials. These include bispecific antibodies targeting HER2 in addition to HER3 and a HER3-targeting antibody-drug conjugate (ADC). The latter, U3-1402, recently showed encouraging activity in heavily pretreated patients with HER3-overexpressing breast cancer and, in a separate trial, in patients with EGFR inhibitor–resistant, EGFR-mutant non–small cell lung cancer (NSCLC).1,2

Meanwhile, the hunt continues for predictive biomarkers and appropriate partners for combination therapy. Recently, fusions involving the NRG1 gene, which encodes the HRG ligand, were identified in a small number of patients with a variety of tumor types. Clinical trials have already begun to enroll patients with these abnormalities.

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