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Cited by 2,006HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsAdvanced Breast Cancer Therapies

Trastuzumab deruxtecan in previously treated HER2-positive breast cancer

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Modi, Shanu, Saura, Cristina, Yamashita, Toshinari, Park, Yeon Hee, Kim, Sung-Bae, Tamura, Kenji, Andre, Fabrice, Iwata, Hiroji +17 more·2020·New England Journal of Medicine
DOI 10.1056/nejmoa1914510PMC PMC7458671
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Abstract

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS: In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS: Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS: Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).

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Crossref · 10.1056/nejmoa1914510

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  • Trastuzumab deruxtecan carried a 13.6% risk of ILD/pneumonitis, fatal in 2.2% of cases.

    “Trastuzumab deruxtecan was associated with a 13.6% risk of interstitial lung disease (ILD)/pneumonitis, fatal in 2.2% of cases, which needed appropriate and rapid diagnosis and treatment.”

    From 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020) · cites this paper as [64]

    The Results > Safety passage reports ILD in 25 patients (13.6%) and four ILD-attributed deaths (2.2% of all treated patients). The claim's “fatal in 2.2% of cases” is imprecise: if “cases” means patients who developed ILD, the fatal proportion was four of 25, not 2.2%. The Discussion supports early detection and prompt intervention. (LLM, conf=0.86)

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  • Trastuzumab deruxtecan produced a 60.6% response rate (95% CI 53.4-68.0) and median PFS of 16.4 months (95% CI 12.7-not reached) in heavily pretreated patients (median six lines; range 2-27; including trastuzumab and T-DM1).

    “Trastuzumab deruxtecan (DS-8201), an ADC composed of trastuzumab, a cleavable tetrapeptide-based linker and a cytotoxic topoisomerase I inhibitor, demonstrated a response rate of 60.6% (95% CI 53.4-68.0) and an unprecedented median PFS of 16.4 months (95% CI 12.7—not reached) in a phase II study of heavily pretreated patients (median six lines, range 2-27 lines, including trastuzumab and T-DM1).64”

    From 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020) · cites this paper as [64]

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Research works printed but not linked: 1

  1. [19]Modi S, Tsurutani J, Takahashi S, Safety and efficacy results from a phase 1 study of trastuzumab deruxtecan (DS-8201a) in subjects with HER2 expressing metastatic breast cancers. Presented at the 2017 San Antonio Breast Cancer Symposium, San Antonio, TX, December 5–9, 2017.

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Authors
Modi, S., Saura, C., Yamashita, T., Park, Y. H., Kim, S.-B., Tamura, K., Andre, F., Iwata, H., Ito, Y., Tsurutani, J., Sohn, J., Denduluri, N., Perrin, C., Aogi, K., Tokunaga, E., Im, S.-A., Lee, K. S., Hurvitz, S. A., Cortes, J., Lee, C., Chen, S., Zhang, L., Shahidi, J., Yver, A., & Krop, I.
Affiliations
  • SHOWA Medical University (JP)
  • From Memorial Sloan Kettering Cancer Center, New York (S.M.); Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona (C.S., J.C.), and IOB Institute of Oncology, Quiron Group, Barcelona and Madrid (J.C.); Kanagawa Cancer Center, Yokohama (T.Y.), National Cancer Center Hospital (K.T.), the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (Y.I.), and the Advanced Cancer Translational Research Institute, Showa University (J.T.), Tokyo, Aichi Cancer...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2020-02-13
Volume
382
Issue
7
Pages
610-621
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1914510
PMC
PMC7458671
OpenAlex
W2996630100
Cited by
2,006
References
40
Citations by year
2026: 234 · 2025: 266 · 2024: 317 · 2023: 355 · 2022: 345 · 2021: 312 · 2020: 174
FWCI
86.91
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
Daiichi-Sankyo
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
Keywords
trastuzumab deruxtecan, HER2-positive breast cancer, metastatic breast cancer, trastuzumab emtansine, antibody-drug conjugates, previously treated patients, objective response rate, progression-free survival, neutropenia, dose escalation, topoisomerase I inhibitor, HER2-targeted therapy, treatment efficacy and safety
MeSH terms
Trastuzumab, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Camptothecin, Female, Humans, Middle Aged, Lung Diseases, Interstitial, Erb-b2 Receptor Tyrosine Kinases, Immunoconjugates, Kaplan-Meier Estimate, Intention to Treat Analysis, Consolidation Chemotherapy, Antibodies, Monoclonal, Humanized

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