Osimertinib-Associated Cardiotoxicity in EGFR-Mutant Non-Small Cell Lung Cancer: Mechanisms, Phenotypes, and...

Osimertinib, a third-generation EGFR-TKI, is now the standard first-line treatment for EGFR-mutant non-small cell lung cancer and is increasingly given in the adjuvant setting for up to 3 years and in combination with chemotherapy. As exposure has lengthened and shifted toward curative-intent settings, its cardiac effects have acquired greater clinical weight, because patients may remain on therapy for years and survive long enough for cardiovascular outcomes to matter. This review argues that the dominant cardiac phenotype, a decline in left ventricular ejection fraction, with or without clinical heart failure, is best understood as an often reversible functional cardiomyopathy rather than structural myocardial injury. The neuregulin-1/ErbB signaling axis, which maintains adult cardiomyocyte function and whose disruption by trastuzumab causes a comparable reversible dysfunction, provides the lens for this interpretation, and off-target inhibition of ErbB2/ErbB4 has been proposed as a mechanism for osimertinib cardiotoxicity. That account is incomplete: the EGFR-TKIs that inhibit HER2 most potently do not carry the largest clinical signal, and a recently described GATA4-MYLK3-MYL2 contractile pathway offers an alternative, not clearly ErbB-dependent, mechanism. The proximal cause, therefore, remains unresolved, but across the available evidence, the dominant phenotype appears functional, contractile, and often reversible.