Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer.

HER3 is expressed in the majority of EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase 1, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated NSCLC with prior EGFR TKI therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg IV Q3W, the confirmed ORR by BICR (RECIST v1.1) was 39% (95% CI, 26.0-52.4), and median PFS was 8.2 (4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade {greater than or equal to}3 TEAE were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treating a broad range of drug-resistant cancers.