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First Steps Down the HER3 Pathway in NSCLC Signal Early Success

*March 2022*

Note: Those who progress on osimertinib and/or chemo with no actionable mutations are candidates for this treatment since HER3 overexpression is found in many EGFR+ lung cancer tumors.

Disease progression and acquired resistance to approved EGFR tyrosine kinase inhibitors (TKIs) have resulted in a treatment void in the third- and later-line settings for patients with non–small cell lung cancer. Targeted approaches in these settings rely on the identification of overexpression of resistance mechanisms such as MET amplification. Otherwise, options for patients without actionable genomic alterations rely on treatment with chemotherapy, which has limited efficacy.1

The identification of an overexpressed, targetable mutation would present a pathway forward for investigators. One such target under exploration is HER3.

Intracellular tyrosine kinase activity is limited in HER3, making this member of the EGFR family a prime target for investigators hoping to overcome resistance in non–small cell lung cancer (NSCLC).2,3 Findings from studies conducted over the past 15 years have identified that PI3K/AKT signaling and the upregulation of HER3 play key roles in the resistance to EGFR-targeted therapies.4

In an analysis of tissue samples from patients with NSCLC, HER3 expression was identified in 82.7% of the primary tumors, 86.6% of lymph nodes, and 91.2% of brain metastases.5 Other studies have noted that overexpression of HER3 (immunohistochemistry [IHC] staining 2+ or 3+) was identified in 42.2% NSCLC tissue samples with 70.7% of samples demonstrating expression at any level (IHC 1+ to 3+).6

Although HER3 expression has been identified as a favorable target, which resulted in several investigational studies, no agents have been approved by the FDA. However, in December 2021 the FDA granted a breakthrough therapy designation to novel antibody-drug conjugate (ADC) patritumab deruxtecan. Read more.