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Background Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker-drug containing duocarmycin. Preclinical studies showed impressive antitumour activity in various models. In this first-in-human study we evaluated the safety and activity in patients with solid tumours. Methods In the dose-escalation part, patients aged 18 years or older with locally advanced or metastatic solid tumours with variable HER2 status and refractory to standard therapy were enrolled. The expansion cohorts included patients with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to RECIST. Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle at doses of 0·3 to 2·4 mg/kg until disease progression or unacceptable toxicity. A 3+3 design was used in the dose-escalation part and the primary endpoint was to evaluate safety and determine the recommended phase 2 dose. The primary endpoint of the expansion part was the proportion of patients who achieved an objective response. This ongoing study is registered with, number NCT02277717, and is fully recruited. Findings Between October 30, 2014 and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation part and 146 patients in the expansion part of the study. One dose-limiting toxicity (fatal pneumonitis) occurred at the highest administered dose. Grade ≥ 3 treatment-related adverse events reported more than once were keratitis (three patients) and fatigue (two patients). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In de expansion part of the study, treatment-related serious adverse events were reported in 16 (11%) of 146 patients. The most common treatment-related adverse events were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). The majority of patients had one or more ocular adverse events, with grade 3 events in 10 (7%) of 146 patients. In the breast cancer expansion cohorts, 16 (33%, 95% CI 20·4-48·4) of 48 evaluable patients with HER2-positive breast cancer achieved an objective response. The proportion of patients with HER2-low, HR-positive breast cancer who achieved an objective response was 28% (95% CI 13·8-46·8; nine of 32 patients) and for patients with HER2-low, HR-negative breast cancer 40% (95% CI 16·3-67·6; six of 15 patients). Responses were also observed in one (6%; 95% CI 0·2-30·2) of 16 gastric cancer, four (25%; 95% CI 7·3-52·4) of 16 urothelial cancer, and five (39%; 95% CI 13·9-68·4) of 13 endometrial cancer patients. Interpretation Trastuzumab duocarmazine has shown important clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile.


Journal article


The Lancet Oncology




Udai Banerji, Institute of Cancer Research, London, United Kingdom, Carla ML van Herpen, Radboud University Medical Center, Nijmegen, Netherlands, Cristina Saura, Vall d’Hebrón University Hospital, Vall d’Hebrón Institute of Oncology (VHIO), Barcelona, Spain, Fiona Thistlethwaite, University of Manchester, Manchester, United Kingdom, Simon Lord, University of Oxford, Oxford, United Kingdom, Victor Moreno, START Madrid-FJD, Madrid, Spain, Iain R Macpherson, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom, Valentina Boni, START-Madrid-CIOCC, Madrid, Spain, Christian Rolfo, Antwerp University Hospital, Antwerp, Belgium, Elisabeth GE de Vries, University Medical Center Groningen, Groningen, Netherlands, Sylvie Rottey, Ghent University Hospital, Ghent, Belgium, Jill Geenen, The Netherlands Cancer Institute, Amsterdam, Netherlands, Ferry Eskens, Erasmus University Medical Center, Rotterdam, Netherlands, Marta Gil-Martin, Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain, Ellen C Mommers, Synthon (Netherlands), Nijmegen, Netherlands, Philippe Aftimos, Université Libre de Bruxelles, Brussels, Belgium