Optimizing Dosing of Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer: A Reminder That More Is Not Always Better
Mené sur 152 patients atteints d'un cancer métastatique non à petites cellules du poumon présentant des mutations au niveau du gène HER2+ (durée médiane de suivi : 11,5 mois), cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du trastuzumab déruxtécan
Human epidermal growth factor receptor 2 (HER2 or ERBB2) mutations (most frequently because of insertions in exon 20) are found in 1%-2% of lung adenocarcinoma and enriched in patients with a never or light smoking history.1,2 Attempts to target HER2-mutant tumors with pan-HER tyrosine kinase inhibitors such as neratinib,3 afatinib,4 dacomitinib,5 or the more selective inhibitor poziotinib6 resulted in limited efficacy and considerable toxicity. The antibody drug conjugate (ADC) trastuzumab emtansine (T-DM1) demonstrated activity in this population, but with relatively short durations of response.7,8 Trastuzumab deruxtecan (T-DXd, DS-8201a) is a newer generation HER2-targeting ADC that, similar to T-DM1, contains a humanized anti-HER2 IgG1 monoclonal antibody, but, in distinction to T-DM1, has a tetrapeptide-based cleavable linker and a novel topoisomerase I inhibitor payload, resulting in distinct pharmacologic features including improved stability in the circulation, higher drug antibody ratio, and potential for bystander effect.9,10 In August 2022, T-DXd received accelerated approval from the US Food and Drug Administration (FDA), to our knowledge as the first drug approved for HER2-mutant non–small-cell lung cancer (NSCLC) and the first ADC approved for NSCLC.
Journal of Clinical Oncology , éditorial en libre accès, 2022