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Trastuzumab Deruxtecan for ERBB2 -Mutant Metastatic Non–Small Cell Lung Cancer With or Without Brain Metastases: A Secondary Analysis of Randomized Clinical Trials
Open accessAbstract
Importance: Brain metastases reduce overall survival rates of patients with non–small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 ( ERBB2 [formerly HER2 ])–mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2 -directed treatment for previously treated unresectable or metastatic ERBB2- mutant NSCLC. Objective: To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2- mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases. Design, Setting, and Participants: This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2- mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024. Intervention: Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks. Main Outcome and Measure: Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety. Results: This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose. Conclusions and Relevance: In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2- mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population.
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Metadata
- Authors
- Jänne, P. A., Planchard, D., Goto, K., Smit, E. F., de Langen, A. J., Goto, Y., Ninomiya, K., Kubo, T., Pérol, M., Felip, E., Hayashi, H., Nakagawa, K., Shimizu, J., Nagasaka, M., Pereira, K., Taguchi, A., Ali, A., Karnoub, M., Yonemochi, R., Leung, D., & Li, B. T.
- Affiliations
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Institut Gustave Roussy (FR)
- Department of Thoracic Oncology, Nation Cancer Center Hospital East, Kashiwa, Japan
- Leiden University Medical Center (NL)
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
- National Cancer Center Hospital (JP)
- Okayama University Hospital (JP)
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
- Vall d'Hebron Institute of Oncology (ES)
- Kindai University (JP)
- Aichi Cancer Center (JP)
- University of California, Irvine (US)
- Daiichi Sankyo (United States) (US)
- Daiichi-Sankyo (Japan) (JP)
- Daiichi Sankyo (Germany) (DE)
- Memorial Sloan Kettering Cancer Center (US)
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2025-11-12
- Volume
- 8
- Issue
- 11
- Pages
- e2543107
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC12612940
- OpenAlex
- W4416256660
- Cited by
- 27
- References
- 0
- Citations by year
- 2026: 27
- FWCI
- 17.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- JAMA Network Open (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Okayama University Scientific Achievement Repository (Okayama University) (submittedVersion, cc-by-nc-nd)
- Leiden Repository (Leiden University) (submittedVersion, cc-by-nc-nd)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca (DS-8201)
- GlaxoSmithKline
- Sanofi
- Gilead Sciences
- Spectrum Pharmaceuticals
- Celgene
- F. Hoffmann-La Roche
- Medpace
- Memorial Sloan-Kettering Cancer Center
- Takeda Pharmaceutical Company
- Regeneron Pharmaceuticals
- Taiho Pharmaceutical
- Novocure
- Les Laboratories Pierre Fabre
- Mirati Therapeutics
- BeiGene
- Boehringer Ingelheim Japan
- Incyte
- Sysmex Corporation
- Syndax Pharmaceuticals
- Revolution Medicines
- Lunit
- Seagen
- Bayer HealthCare
- Eisai
- Astellas Pharma
- Ono Pharmaceutical
- Grifols
- Genentech
- Novartis Pharma
- Pfizer Japan
- Chugai Pharmaceutical
- Takeda Oncology
- Eli Lilly Japan
- Ignyta
- Bayer Yakuhin
- Loxo Oncology
- National Cancer Institute (P30CA008748)
- Daiichi Sankyo Europe (DS-8201)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Brain Metastases and Treatment
- Keywords
- trastuzumab deruxtecan, HER2-mutant non-small cell lung cancer, brain metastases, metastatic non-small cell lung cancer, HER2-targeted therapy, intracranial response, dose comparison, treatment safety, previously treated patients, central nervous system metastasis
- MeSH terms
- Trastuzumab, Antineoplastic Agents, Immunological, Adult, Aged, Brain Neoplasms, Camptothecin, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Randomized Controlled Trials as Topic, Treatment Outcome, Erb-b2 Receptor Tyrosine Kinases, Immunoconjugates
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