Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer | NEJM

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List of authors.
  • Bob T. Li, M.D., Ph.D., M.P.H.,
  • Egbert F. Smit, M.D., Ph.D.,
  • Yasushi Goto, M.D., Ph.D.,
  • Kazuhiko Nakagawa, M.D.,
  • Hibiki Udagawa, M.D.,
  • Julien Mazières, M.D.,
  • Misako Nagasaka, M.D., Ph.D.,
  • Lyudmila Bazhenova, M.D.,
  • Andreas N. Saltos, M.D.,
  • Enriqueta Felip, M.D., Ph.D.,
  • Jose M. Pacheco, M.D.,
  • Maurice Pérol, M.D.,
  • Luis Paz-Ares, M.D.,
  • Kapil Saxena, M.D.,
  • Ryota Shiga, B.Sc.,
  • Yingkai Cheng, M.D., Ph.D.,
  • Suddhasatta Acharyya, Ph.D.,
  • Patrik Vitazka, M.D., Ph.D.,
  • Javad Shahidi, M.D.,
  • David Planchard, M.D., Ph.D.,
  • and Pasi A. Jänne, M.D., Ph.D.
  • for the DESTINY-Lung01 Trial Investigators*

Human epidermal growth factor receptor 2 (HER2)–targeted therapies have not been approved for patients with non–small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody–drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.


We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.


A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.


Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 number, NCT03505710.)

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Supported by Daiichi Sankyo and AstraZeneca. Dr. Li was also supported by grants from the National Institutes of Health (P30 CA008748 and 1R01CA249666-01A1) to the Memorial Sloan Kettering Cancer Center.

Disclosure forms provided by the authors are available with the full text of this article at

Drs. Li and Smit contributed equally to this article.

This article was published on September 18, 2021, at

A data sharing statement provided by the authors is available with the full text of this article at

We thank the patients who participated in this study, as well as their families and caregivers; the staff and investigators at all the study sites; Wenqin Feng, Ph.D., of Daiichi Sankyo, for assistance with biomarker assessment; and Eileen L. McIver, Ph.D., Cindy M. Rigby, Ph.D., and Charlene Rivera, Ph.D., of ApotheCom, for assistance with medical writing and editorial support for an earlier version of the manuscript.

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.), and the National Cancer Center East, Kashiwa (H.U.) — all in Japan; Centre Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif (D.P.) — all in France; Karmanos Cancer Institute, Detroit (M.N.); the University of California, San Diego, Moores Cancer Center, San Diego (L.B.); Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado, Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O–Centro Nacional de Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ (K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana–Farber Cancer Institute and the Belfer Center for Applied Cancer Science, Boston (P.A.J.).

Address reprint requests to Dr. Li at the Thoracic Oncology and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, 530 E. 74th St., New York, NY 10021, or at [email protected].

A list of the DESTINY-Lung01 Trial principal investigators is provided in the Supplementary Appendix, available at

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