BACKGROUND: Antibody-drug conjugates have emerged as a powerful strategy in 
cancer therapy and combine the ability of monoclonal antibodies to specifically 
target tumour cells with the highly potent killing activity of drugs with 
payloads too toxic for systemic administration. Trastuzumab deruxtecan (also 
known as DS-8201) is an antibody-drug conjugate comprised of a humanised 
antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I 
inhibitor payload. We assessed its safety and tolerability in patients with 
advanced breast and gastric or gastro-oesophageal tumours.
METHODS: This was an open-label, dose-escalation phase 1 trial done at two study 
sites in Japan. Eligible patients were at least 20 years old with breast or 
gastric or gastro-oesophageal carcinomas refractory to standard therapy 
regardless of HER2 status. Participants received initial intravenous doses of 
trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were 
assessed over a 21-day cycle; thereafter, dose reductions were implemented as 
needed and patients were treated once every 3 weeks until they had unacceptable 
toxic effects or their disease progressed. Primary endpoints included 
identification of safety and the maximum tolerated dose or recommended phase 2 
dosing and were analysed in all participants who received at least one dose of 
study drug. The dose-escalation study is the first part of a two-part study with 
the second dose-expansion part ongoing and enrolling patients as of July 8, 
2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, 
number NCT02564900.
FINDINGS: Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and 
received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg 
doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 
2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, 
or deaths occurred. One patient was removed from the activity analysis because 
they had insufficient target lesions for analysis. The most common grade 3 
adverse events were decreased lymphocyte (n=3) and decreased neutrophil count 
(n=2); and grade 4 anaemia was reported by one patient. Three serious adverse 
events-febrile neutropenia, intestinal perforation, and cholangitis-were 
reported by one patient each. Overall, in 23 evaluable patients, including six 
patients with low HER2-expressing tumours, ten patients achieved an objective 
response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% 
CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 
4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or 
greater.
INTERPRETATION: The maximum tolerated dose of trastuzumab deruxtecan was not 
reached. In this small, heavily pretreated study population, trastuzumab 
deruxtecan showed antitumour activity, even in low HER2-expressing tumours. 
Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 
or 6·4 mg/kg.
FUNDING: Daiichi Sankyo Co, Ltd.