Exposure–Response Relationships in Patients with Non‐Small‐Cell Lung Cancer and Other Solid Tumors Treated with Patritumab Deruxtecan (HER3‐DXd)

Patritumab deruxtecan (HER3‐DXd, also known as MK‐1022), an antibody‐drug conjugate consisting of a human epidermal growth factor receptor 3 (HER3) antibody attached to a topoisomerase I inhibitor payload (DXd), has demonstrated efficacy in patients with metastatic breast cancer and non‐small cell lung cancer (NSCLC). Exposure–efficacy was assessed in 446 patients with EGFR ‐mutated NSCLC; exposure–safety was assessed in 715 patients with NSCLC, breast cancer, or colorectal cancer. A range of HER3‐DXd dosing regimens was evaluated, including fixed‐dosing regimens (1.6–8 mg/kg every 3 weeks [Q3W]; 3.2–6.4 mg/kg Q3W), an up‐titration dosing regimen, and an alternative Q2W/Q3W dosing regimen. Logistic regression or time‐to‐event models were used to test the relationships of each endpoint with pharmacokinetic analytes (anti‐HER3‐ac‐DXd and DXd). Anti‐HER3‐ac‐DXd exposure was positively associated with objective response rate, and bone metastasis was identified as a significant covariate. DXd exposure showed a stronger correlation with most safety endpoints compared with anti‐HER3‐ac‐DXd exposure, except for grade ≥ 2 nausea/vomiting and any grade adjudicated drug‐related interstitial lung disease (ILD). Dose response predictions verified a manageable safety profile for the 5.6 mg/kg Q3W regimen. This observation was supported by low predicted rates of adjudicated drug‐related ILD and adverse events leading to treatment discontinuation with the 5.6 mg/kg Q3W regimen. Overall, these results support the selection of HER3‐DXd 5.6 mg/kg Q3W as the recommended dosing regimen for patients with NSCLC, and these data inform the optimal dosing regimen for other tumor types.