HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy

Yu, HA; Goto, Y; Hayashi, H; Felip, E; Yang, JCH; Reck, M; Yoh, K; Lee, SH; Paz-Ares, L; Besse, B; Bironzo, P; Kim, DW; Johnson, ML; Wu, YL; John, T; Kao, S; Kozuki, T; Massarelli, E; Patel, J; Smit, E; Reckamp, KL; Dong, Q; Shrestha, P; Fan, PD; Patel, P; Sporchia, A; Sternberg, DW; Sellami, D; J&#228;nne, PA

Author(s): Yu, HA; Goto, Y; Hayashi, H; Felip, E; Yang, JCH; Reck, M; Yoh, K; Lee, SH; Paz-Ares, L; Besse, B; Bironzo, P; Kim, DW; Johnson, ML; Wu, YL; John, T; Kao, S; Kozuki, T; Massarelli, E; Patel, J; Smit, E; Reckamp, KL; Dong, Q; Shrestha, P; Fan, PD; Patel, P; Sporchia, A; Sternberg, DW; Sellami, D; Jänne, PA;
Details: Publication Year 2023-12-10,Volume 41,Issue #35,Page 5363-5375
Journal Title: Journal of Clinical Oncology
Publication Type: Research article
Abstract: PURPOSE: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). METHODS: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR-mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data. RESULTS: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations. CONCLUSION: After tumor progression with EGFR TKI therapy and PBC in patients with EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).
Publisher: American Society of Clinical Oncology
Keywords: Humans; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism; *Lung Neoplasms/drug therapy/genetics/metabolism; Platinum/therapeutic use; ErbB Receptors/genetics; Mutation; Protein Kinase Inhibitors/adverse effects
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1200/jco.23.01476
Open Access at Publisher's Site: https://doi.org/10.1200/jco.23.01476
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-01-23 04:00:47

Last Modified: 2024-01-23 04:01:24