Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer

N Engl J Med. 2024 Dec 5;391(22):2110-2122. doi: 10.1056/NEJMoa2407086. Epub 2024 Sep 15.

Abstract

Background: Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy.

Methods: We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety.

Results: Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively.

Conclusions: Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Clinical Trial, Phase III
  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal* / administration & dosage
  • Antineoplastic Agents, Hormonal* / adverse effects
  • Antineoplastic Agents, Immunological* / administration & dosage
  • Antineoplastic Agents, Immunological* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / mortality
  • Breast Neoplasms* / pathology
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives
  • Female
  • Humans
  • Immunoconjugates* / administration & dosage
  • Immunoconjugates* / adverse effects
  • Kaplan-Meier Estimate
  • Middle Aged
  • Progression-Free Survival
  • Receptor, ErbB-2* / analysis
  • Receptor, ErbB-2* / metabolism
  • Receptors, Estrogen / analysis
  • Receptors, Estrogen / metabolism
  • Trastuzumab* / administration & dosage
  • Trastuzumab* / adverse effects
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Hormonal
  • Antineoplastic Agents, Immunological
  • Camptothecin
  • ERBB2 protein, human
  • Immunoconjugates
  • Receptor, ErbB-2
  • Receptors, Estrogen
  • Trastuzumab
  • trastuzumab deruxtecan

Associated data

  • ClinicalTrials.gov/NCT04494425