| Abstract: |
Background: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. Patients and methods: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. Results: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. Conclusions: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy. © 2024 The Authors |
| Keywords: |
adult; cancer survival; controlled study; aged; aged, 80 and over; middle aged; survival analysis; survival rate; gene mutation; major clinical study; overall survival; frameshift mutation; genetics; mutation; clinical trial; mortality; neutropenia; dose response; drug dose reduction; drug efficacy; drug safety; drug withdrawal; treatment duration; outcome assessment; gene; progression free survival; multiple cycle treatment; gene expression; thrombocytopenia; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; camptothecin; cohort analysis; lung cancer; gene function; pathology; mutational analysis; cancer resistance; monoclonal antibody; drug dose escalation; pneumonia; lung tumor; drug fatality; survival time; antibodies, monoclonal; adverse outcome; multicenter study; drug response; sepsis; phase 1 clinical trial; egfr gene; epidermal growth factor receptor 3; predictive value; egfr protein, human; non small cell lung cancer; antibody conjugate; immunoconjugates; receptor, erbb-3; erbb receptors; antibodies, monoclonal, humanized; very elderly; humans; human; male; female; article; broadly neutralizing antibody; broadly neutralizing antibodies; antibody–drug conjugate; patritumab deruxtecan; erbb3 protein, human; patritumab; erbb3 gene; top1 gene
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