Trastuzumab Deruxtecan in HER2–Low-Expressing, Previously Treated Advanced Breast Cancer

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In a phase Ib study reported in the Journal of Clinical Oncology, Shanu Modi, MD, and colleagues found that the antibody-drug conjugate trastuzumab deruxtecan was active in HER2–low-expressing, previously treated advanced breast cancer.

Shanu Modi, MD

Shanu Modi, MD

The drug component is a topoisomerase I inhibitor. The agent was recently granted accelerated approval for treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting.

Study Details

The dose-escalation and expansion study evaluated trastuzumab deruxtecan in advanced HER2-expressing/mutated solid tumors. The current report presents findings in a cohort of 54 evaluable patients with advanced HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization–negative) breast cancer receiving the recommended doses for expansion of 5.4 or 6.4 mg/kg every 3 weeks. Half the patients were from U.S. sites, and half were from sites in Japan. Patients had received a median of 7.5 prior therapies.

Response Rates

Objective response on independent central review (all partial responses) was observed in 20 patients (37.0%, 95% confidence interval [CI] = 24.3%–51.3%), including 7 (33.3%) of 21 receiving 5.4 mg/kg and 13 (39.4%) of 33 receiving 6.4 mg/kg. Responses were observed in 19 of 47 patients with hormone receptor–positive disease and 1 of 7 with hormone receptor–negative disease.

The median duration of response among all responders was 10.4 months (95% CI = 8.8 months–not evaluable). Among all patients, median progression-free survival was 11.1 months and median overall survival was 29.4 months.


  • Response was observed in 37% of patients.
  • Three patients died from treatment-related interstitial lung disease/pneumonitis.

Adverse Events

Grade ≥ 3 adverse events were observed in 34 patients (63.0%), with those occurring in ≥ 5% of patients consisting of neutrophil count decrease, white blood cell count decrease, anemia, hypokalemia, platelet count decrease, alanine transaminase increase, decreased appetite, febrile neutropenia, cellulitis, and diarrhea. Three patients receiving 6.4 mg/kg had fatal events associated with treatment-related interstitial lung disease/pneumonitis as determined by an independent adjudication committee.

The investigators concluded, “The novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were [gastrointestinal] or hematologic in nature. Interstitial lung disease is an important identified risk and should be monitored closely and proactively managed.”

Dr. Modi, of the Breast Medicine Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Daiichi Sankyo. For full disclosures of the study authors, visit

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