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

Abstract

<p class="first" id="d5818962e392">In a phase I dose escalation/expansion study, use of the HER3-DXd antibody drug conjugate showed clinical activity in EGFR TKI-resistant, <i>EGFR</i>-mutant non–small cell lung cancer, presenting a future option for drug-resistant cancers. </p><p id="d5818962e400">Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most <i>EGFR</i>-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 I, dose escalation/expansion study included patients with locally advanced or metastatic <i>EGFR</i>-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 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 ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. </p><div class="section"> <a class="named-anchor" id="d5818962e408"> <!-- named anchor --> </a> <h5 class="section-title" id="d5818962e409">Significance:</h5> <p id="d5818962e411">In metastatic <i>EGFR</i>-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. </p> <p id="d5818962e416"> <i>See related commentary by Lim et al., <span class="generated">[Related article:]</span>p. 16 </i>. </p> <p id="d5818962e423"> <i>This article is highlighted in the In This Issue feature, <span class="generated">[Related article:]</span>p. 1 </i> </p> </div>