PURPOSE: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human 
epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) 
with a topoisomerase I inhibitor payload. A dose escalation and expansion phase 
I study evaluated the safety and activity of T-DXd in patients with advanced 
HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended 
doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 
1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov 
identifier: NCT02564900) are reported.
PATIENTS AND METHODS: Eligible patients had advanced/metastatic 
HER2-low-expressing breast cancer refractory to standard therapies. The RDE of 
5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until 
withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor 
activity and safety were assessed.
RESULTS: Between August 2016 and August 2018, 54 patients were enrolled and 
received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated 
(median, 7.5 prior therapies). The confirmed objective response rate by 
independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median 
duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most 
patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; 
grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in 
neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; 
decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered 
fatal events associated with T-DXd-induced interstitial lung disease 
(ILD)/pneumonitis as determined by an independent adjudication committee.
CONCLUSION: The novel HER2-targeted ADC, T-DXd, demonstrated promising 
preliminary antitumor activity in patients with HER2-low breast cancer. Most 
toxicities were GI or hematologic in nature. ILD is an important identified risk 
and should be monitored closely and proactively managed.