Multinational phase 2 trial of patritumab deruxtecan in patients with active brain metastases of non-small cell lung cancer

Patritumab deruxtecan (HER3-DXd) is a novel antibody-drug conjugate targeting HER3, which is overexpressed in CNS metastases of NSCLC. Cohort 2 of the multinational phase 2 TUXEDO-3 trial evaluated HER3-DXd in NSCLC patients with newly diagnosed brain metastases (BrM) or BrM progressing after local therapy. The threshold to meet the primary endpoint was at least 15% of patients having an intracranial response. Twenty patients were recruited; 13 patients had BrM progressing after local therapy and seven had untreated BrM; five had activating driver mutations. Median follow-up was 5.3 months (IQR 2.0-8.5). The primary endpoint was met, with six of 20 patients having intracranial responses (ORR 30%; 95% CI 11.9-54.3). The six responders had nonsquamous NSCLC; two with untreated BrM and four with progressing BrM. Treatment-related adverse events occurred in 16 patients (80%). There were no treatment-related deaths, and no new safety signals were identified. The authors conclude that HER3-DXd showed promising clinical activity in patients with NSCLC and active brain metastases.