The emergence of treatment resistance to targeted agents is currently inevitable and inherently heterogeneous in cancer, presenting significant challenges for improving survival outcomes in patients. This is not an exception for cancers harboring EGFR mutations, one of the most prevalently observed oncogenic alterations in non–small cell lung cancer (NSCLC) targeted clinically. Currently, numerous efforts have attempted to delay or overcome acquired resistance to EGFR–tyrosine kinase inhibitors (TKI), changing the treatment landscape of EGFR-mutant NSCLC. Haikala and colleagues have developed a unique strategy using patritumab deruxtecan, an antibody–drug conjugate targeting human epidermal growth factor receptor 3 (HER3) linked to exatecan derivatives, for treating EGFR-mutant NSCLC. By incorporating EGFR TKIs to upregulate surface HER3 expression, the antitumor efficacy of patritumab deruxtecan was augmented in various preclinical models. In parallel, Jänne and colleagues reported the clinical activity of patrimumab deruxtecan in patients with EGFR-mutant NSCLC with prior EGFR TKI treatment. These two studies provide the grounds for hopeful anticipation for a novel strategy that concurrently targets compensatory feedback loops in addition to oncogenic signaling pathways.

See related article by Haikala et al., p. 130

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