Trastuzumab Deruxtecan in Patients With HER2-Overexpressing NSCLC

Introduction: HER2-directed treatments for HER2-overexpressing (HER2-OE; immunohistochemistry [IHC] 3+/2+) NSCLC are needed. Methods: DESTINY-Lung03 is an open-label, multi-arm, phase 1b study. Part 1 evaluated trastuzumab deruxtecan (T-DXd, 4.4 or 5.4 mg/kg) plus durvalumab (1120 mg) and cisplatin (60 or 75 mg/m2; Arm 1A)/carboplatin (area under the plasma concentration–time curve [AUC] 4 or 5; Arm 1B) or T-DXd 5.4 mg/kg monotherapy (Arm 1D) in pretreated metastatic HER2-OE NSCLC. Primary end points: dose-limiting toxicities (DLTs) and adverse events (AEs: Arms 1A and 1B). Secondary end points: safety (Arm 1D) and efficacy (all arms). Results: At data cutoff (April 1, 2024), 11, 24, and 36 patients received treatment in Arms 1A, 1B, and 1D, respectively. DLTs reported in Arm 1A: febrile neutropenia (n = 1; grade [G] 5; 4.4 mg/kg/1120 mg/60 mg/m2 doses); decreased platelet count (n = 2; G4 and G5; 5.4 mg/kg/1120 mg/75 mg/m2 doses). DLTs reported in Arm 1B: febrile neutropenia (n = 1; G3; 4.4 mg/kg/1120 mg/AUC 5 doses; n = 1; G4; 4.4 mg/kg/1120 mg/AUC 4 doses); decreased platelet count (n = 1; G4; 5.4 mg/kg/1120 mg/AUC 5 doses). Drug-related serious AEs occurred in 63.6%, 37.5%, and 16.7% of Arms 1A, 1B, and 1D, respectively. Confirmed objective response rate (95% confidence interval) per investigator: 37.5% (18.8–59.4; Arm 1B) and 44.4% (27.9–61.9; Arm 1D). Conclusions: Data confirm the activity of T-DXd monotherapy in pretreated HER2-OE NSCLC but do not support T-DXd plus durvalumab and platinum chemotherapy use in this population. Clinical Trials.gov Identifier: NCT04686305.