Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02-A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC
- PMID: 40749900
- DOI: 10.1016/j.jtho.2025.07.129
Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02-A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC
Erratum in
-
Corrigendum to 'Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02-A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC' [Journal of Thoracic Oncology Volume 20 Issue 12 (2025) 1814-1828].J Thorac Oncol. 2026 Feb 23:103557. doi: 10.1016/j.jtho.2026.103557. Online ahead of print. J Thorac Oncol. 2026. PMID: 41729148 No abstract available.
Abstract
Introduction: Trastuzumab deruxtecan (T-DXd) demonstrated strong and durable responses in patients with previously treated HER2 (ERBB2) mutant (HER2m) metastatic NSCLC (mNSCLC) in the DESTINY-Lung02 primary analysis (December 23, 2022, data cutoff). This final analysis evaluated T-DXd efficacy and safety after 8 additional months of follow-up, including clinically relevant subgroups and patient-reported outcomes.
Methods: DESTINY-Lung02 was a randomized, dose-blinded, multicenter, phase 2 trial. Patients with previously treated HER2m mNSCLC were randomized 2:1 to receive T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. Primary end point was confirmed objective response rate by blinded independent central review.
Results: As of August 25, 2023, 102 and 50 patients had received T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up (Q1-Q3) was 15.8 (8.2-20.7) months and 16.5 (9.4-20.8) months, respectively. Confirmed objective response rate (95% confidence interval) was 50.0% (51/102; 39.9%-60.1%) and 56.0% (28/50; 41.3%-70.0%), respectively. Safety profile was acceptable and generally manageable. Accordingly, median treatment duration (Q1-Q3) was 7.7 (3.7-14.4) months and 8.3 (2.8-13.1) months; drug-related grade 3 or higher treatment-emergent adverse events occurred in 39.6% (40/101) and 60.0% (30/50), with nausea most common (67.3% [68/101], 82.0% [41/50]). Adjudicated drug-related interstitial lung disease occurred in 14.9% (15/101) and 32.0% (16/50), mostly grade 1 or 2 with one grade 5 in each arm. Health-related quality of life was preserved for the duration of T-DXd treatment while sample size was sufficient for analysis, with no adverse effects on health-related quality of life observed at either dose.
Conclusions: T-DXd demonstrated strong and durable responses at both doses, with no clinically significant changes in toxicity. The approved 5.4-mg/kg dose demonstrated a more favorable benefit-risk profile, including lower adjudicated drug-related interstitial lung disease incidence.
Gov identifier: NCT04644237.
Keywords: HER2-directed therapy; HER2-mutant; HER2-targeted; Non–small cell lung cancer; Trastuzumab deruxtecan.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosure Dr. Jänne has received stocks and other ownership interests from Gatekeeper Pharmaceuticals; has a consulting or advisory role for Pfizer, Boehringer Ingelheim, AstraZeneca, Chugai Pharma, Roche/Genentech, Mirati Therapeutics, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Arm, Sanofi, Daiichi Sankyo, Silicon Therapeutics, Nuvalent Inc., Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotech, Duality Biologics, Blueprint Medicines, and Dizal Pharma; has received research grants from AstraZeneca, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, and Revolution Medicines; and is a co-inventor on a DFCI-owned patent on EGFR mutations licensed to Lab Corp and is receiving postmarketing royalties from this invention. Dr. Y. Goto has received payment or honoraria from Boehringer Ingelheim, Lilly, Chugai Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Merck Sharp & Dohme, Pfizer, Bristol Myers Squibb, Novartis, Thermo Fisher Scientific, and Merck; has a consulting or advisory role for Lilly, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Novartis, AstraZeneca, Chugai Pharma, Guardant Health AMEA, Daiichi Sankyo, Ono Pharmaceutical, Bristol Myers Squibb, Illumina, and Merck Sharp & Dohme; has participated with leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for Cancer Net Japan, JAMT; and has received research grants from AbbVie, Lilly Japan, Pfizer, Ono Pharmaceutical, Daiichi Sankyo, Bristol Myers Squibb Japan, Novartis, Preferred Network, and Kyorin. Dr. Kubo has nothing to declare. Dr. Ninomiya has received payment or honoraria from Nippon Kayaku, Chugai Pharma, Kyowa Kirin, AstraZeneca, Ono Pharmaceutical, Pfizer, MSD K.K., Takeda, Lilly Japan, Bristol Myers Squibb, Taiho Pharmaceutical, Boehringer Ingelheim, Electa K.K., Daiichi Sankyo, Amgen K.K., and Janssen Pharma. Dr. S-W Kim has a consulting or advisory role for Amgen, AstraZeneca, Janssen, Yuhan, and Takeda; is a speakers’ bureau member for Amgen, Boehringer Ingelheim, and Takeda; and has received research grants from Yuhan. Dr. Planchard has a consulting or advisory role for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, Janssen, Merck, Novartis, Peer CME, Pfizer, prIME Oncology, and Roche; has received support for attending meetings and/or travel from AstraZeneca, Novartis, Pfizer, prIME Oncology, and Roche; and has other financial interests with AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Janssen, Medimmune, Merck, Novartis, Novocure, Pfizer, Roche, Sanofi Aventis, and Taiho Pharmaceutical Co. Dr. Ahn has received payment or honoraria from AstraZeneca, Roche, Lilly, Merck Sharp & Dohme, Takeda, Amgen, Merck, Yuhan, Ono Pharmaceutical, and Novartis; has a consulting or advisory role for AstraZeneca, Roche, Lilly, Merck Sharp & Dohme, Merck, Takeda, Ono Pharmaceutical, Novartis, Alpha Pharmaceutical, Amgen, and Yuhan; and has received research grants from Yuhan. Dr. Smit has received payment or honoraria from Daiichi Sankyo and Boehringer Ingelheim; has a consulting or advisory role for Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Takeda, Daiichi Sankyo, Janssen, Merck Sharp & Dohme, and Sanofi; and has participated on a data safety monitoring board or advisory board for DSI DSMB. Dr. Johannes de Langen has a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, MSD Oncology, Roche, Boehringer Ingelheim, Pfizer, Lilly, and Blueprint Medicines; and has received research grants from AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD Oncology, Roche, and Merus. Dr. Pérol has received payment or honoraria from AstraZeneca, Pfizer, Merck Sharp & Dohme, Bristol Myers Squibb, Takeda, Sanofi, Janssen, and AnHeart Therapeutics; has a consulting or advisory role for Lilly, Roche, Pfizer, AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Takeda, GlaxoSmithKline, Daiichi Sankyo, Janssen, Ipsen, Eisai, and Novocure; has received payment for expert testimony from AstraZeneca, Bristol Myers Squibb, Janssen, and Roche; has received support for attending meetings and/or travel from AstraZeneca, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Takeda; and has participated on a data safety monitoring board or advisory board for Roche and Pharmamar. Dr. Pons-Tostivint has received support for attending meetings and/or travel from AstraZeneca and Pfizer; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bristol Myers Squibb, Sanofi, and Takeda. Dr. Novello has a consulting or advisory role for Bristol Myers Squibb, Eli Lilly, Takeda, Roche, Pfizer, AstraZeneca, BI, Merck Sharp & Dohme, AbbVie, Pharmamar, and Beigene; has received payment or honoraria from Bristol Myers Squibb, Eli Lilly, Takeda, Roche, Pfizer, AstraZeneca, BI, Merck Sharp & Dohme, AbbVie, Pharmamar, and Beigene; has received support for attending meetings and/or travel from Sanofi; has participated on a data safety monitoring board or advisory board for Daiichi Sankyo, AstraZeneca, and GlaxoSmithKline; and has participated with leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Women Against Lung Cancer in Europe patients association (President of WALCE). Dr. Hayashi has received payment or honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Lilly Japan, Nippon Boehringer Ingelheim, AstraZeneca K.K., Chugai Pharmaceutical, Pfizer Japan, MSD K.K., Novartis, Merck Biopharma, Amgen, Daiichi Sankyo, Takeda Pharmaceutical, 3H Clinical Trial, and Sysmex Corporation; has received research grants from IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku, MSD K.K., Amgen, Janssen Pharmaceutical K.K., CMIC, Labcorp Development Japan K.K., Kobayashi Pharmaceutical, EP-CRSU, Shionogi & Co., Nippon Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Ascent Development Services, Bayer Yakuhin, Astellas Pharma, Bristol Myers Squibb, Eisai, EPS Associates Co. Ltd., GlaxoSmithKline K.K., Otsuka Pharmaceutical, Pfizer Japan, Pfizer R&D Japan G.K., Taiho Pharmaceutical, Takeda Pharmaceutical, and Chugai Pharmaceutical; and has been part of a patent or has received royalties or licenses from Sysmex. Dr. Shimizu has received payment or honoraria from Ono Pharmaceutical, MSD Oncology, Novartis, AstraZeneca, Taiho Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Takeda, Merck, and Amgen. Dr. D-W Kim has received payment or honoraria from Amgen, Boehringer Ingelheim, BridgeBio Therapeutics, Bristol Myers Squibb, Chong Keun Dang, GlaxoSmithKline, Pfizer, Merck Sharp & Dohme, Merck, Merus, Novartis, Roche, Takeda, Yuhan, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society, and Asian Thoracic Oncology Research Group; has received research grants from Alpha Biopharma, Hanmi, Janssen, Merus, Mirati, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Chong Kun Dang Pharmaceutical, BridgeBio Therapeutics, GlaxoSmithKline, Merck InnoN, and Bristol Myers Squibb; has received support for attending meetings and/or travel from International Association for the Study of Lung Cancer, Asian Thoracic Oncology Research Group, and Taiwan Lung Cancer Society; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bristol Myers Squibb/ONO Pharmaceuticals, Daiichi Sankyo, GlaxoSmithKline, Janssen, Merck, Merck Sharp & Dohme, Pfizer, SK Biopharm, and Takeda; and has participated with leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, and Korean Society of Medical Oncology; and has other financial or nonfinancial interests from Health Insurance Review and Assessment Service, Republic of Korea. Dr. Pereira is an employee of Daiichi Sankyo. Dr. F-C Cheng is an employee of Daiichi Sankyo and has received employee benefits (stocks or other financial or nonfinancial interests) from Daiichi Sankyo. Dr. Taguchi is an employee of Daiichi Sankyo and has received employee benefits (stocks or other financial or nonfinancial interests) from Daiichi Sankyo. Dr Y Cheng is an employee of Daiichi Sankyo and has received employee benefits (stocks or other financial or non-financial interests) from Daiichi Sankyo. Mr. Dunton is an employee of Daiichi Sankyo. Dr. Ali is an employee of Daiichi Sankyo and has received support for attending meetings and/or travel from Daiichi Sankyo. Dr. K Goto has received payment or honoraria from Amgen, Amoy Diagnostics, Bayer, Boehringer Ingelheim Japan, Bristol Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Lilly Japan, Guardant Health, Janssen Pharmaceutical K.K., Merck Biopharma, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Thermo Fisher Scientific K.K.; has participated on a data safety monitoring board or advisory board for Amgen, Amgen K.K., Lilly Japan, HaiHe Biopharma, and Janssen Pharmaceutical K.K.; and has received research grants from Medical & Biological Laboratories, Kyowa Kirin, Kissei Pharmaceutical, Merck Biopharma, Merus, Spectrum Pharmaceuticals, HaiHe Biopharma, MSD K.K., Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim Japan, Ono Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, Eisai, Lilly Japan, Pfizer Japan, Pfizer R&D Japan, Bristol Myers Squibb K.K., Ignyta, Janssen Pharmaceutical K.K., Loxo Oncology, Sysmex, Amgen, Turning Point Therapeutics, Novartis, Bayer Yakuhin, Amgen Astellas BioPharma, Amgen K.K., Craif, Xcoo Inc., RIKEN GENESIS, Precision Medicine Asia, and LSI Medience Corporation.
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous
