osimertinib + patritumab deruxtecan

The combination of osimertinib and patritumab deruxtecan is being investigated for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). This combination pairs osimertinib, an established EGFR tyrosine kinase inhibitor, with patritumab deruxtecan, a HER3-directed antibody-drug conjugate. ## Drug Information Patritumab deruxtecan (also known as HER3-DXd or U3-1402) is a specifically engineered HER3-directed antibody-drug conjugate consisting of a human IgG1 monoclonal antibody against HER3 (patritumab) covalently linked to a topoisomerase I inhibitor payload (DXd, an exatecan derivative) via a tetrapeptide-based cleavable linker[1][8]. After binding to HER3, the drug is internalized and the linker is cleaved by lysosomal enzymes, releasing the cytotoxic payload which enters the nucleus and causes cell death[6][8]. The payload is membrane-permeable, enabling a bystander antitumor effect that can eliminate both target and surrounding tumor cells[6]. Osimertinib is an EGFR tyrosine kinase inhibitor that targets EGFR mutations and has been approved by regulatory authorities for treating advanced NSCLC with specific EGFR mutations[4]. ## Clinical Development The combination is being studied in a Phase 1 open-label trial (NCT04676477) evaluating patritumab deruxtecan in combination with osimertinib in patients with locally advanced or metastatic EGFR-mutated NSCLC[1][4]. The study has two parts: 1. **Dose Escalation**: Enrolling patients with locally advanced/metastatic NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who experienced progression during or after osimertinib therapy. Patients receive patritumab deruxtecan at various doses (1.6, 3.2, 4.8, or 5.6 mg/kg) intravenously every 3 weeks in combination with osimertinib (40 or 80 mg) orally once daily[1]. 2. **Dose Expansion**: Patients are randomized to receive either the combination at the recommended combination dose or patritumab deruxtecan monotherapy[1]. The primary objectives include assessing safety, tolerability, and identifying a recommended combination dose, as well as evaluating efficacy compared to monotherapy[1]. As of the search results, this is the first time patritumab deruxtecan is being used in combination with osimertinib in humans[4]. ## Development Status While patritumab deruxtecan as a monotherapy has shown promising results in the HERTHENA-Lung02 Phase 3 trial, demonstrating statistically significant improvement in progression-free survival versus doublet chemotherapy in patients with EGFR-mutated NSCLC who received prior EGFR TKI treatment[9], the combination with osimertinib is still in earlier clinical development. In May 2025, Daiichi Sankyo and Merck voluntarily withdrew a Biologics License Application for patritumab deruxtecan monotherapy for previously treated locally advanced or metastatic EGFR-mutated NSCLC, despite positive progression-free survival results in the HERTHENA-Lung02 trial[2]. The companies indicated they would conduct further biomarker analyses to better identify patients who may benefit from patritumab deruxtecan[2].

Brand names

HERTHENATagrisso

Other names

patritumab deruxtecan + osimertinib