Loss of Payload Sensitivity and Other Mechanisms of Resistance to T-DXd in HER2-Mutant NSCLC: Implications for Subsequent Responsiveness to HER2 TKIs

INTRODUCTION: Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed. METHODS: Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches. RESULTS: We determined that acquired resistance to T-DXd could occur through multiple mechanisms including payload resistance which could be mediated by SFLN11 loss and copy number gains in the efflux pump ABCC1/MRP1. Moreover, T-DXd resistance could be mediated by secondary HER2 extracellular mutations in domain IV, the trastuzumab binding site. Tumor cells with acquired payload resistance or domain IV mutations maintained HER2 signaling and remained sensitive to HER2 TKIs, including zongertinib or poziotinib. Likewise, patients with HER2-mutant NSCLC treated with poziotinib demonstrated similar response rates regardless of prior T-DXd. CONCLUSIONS: In patients with HER2-mutant NSCLC, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.