Exposure-Response Relationships in Patients with Non-Small-Cell Lung Cancer and Other Solid Tumors Treated with...

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.