A phase 1 dose-escalation with expansion study of the antibody-drug conjugate trastuzumab duocarmazine (SYD985) in locally advanced and metastatic solid tumours and HER2-expressing breast cancer

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 0and#183;3 to 2and#183;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 ClinicalTrials.gov, 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 and#8805; 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 1and#183;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 20and#183;4-48and#183;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 13and#183;8-46and#183;8; nine of 32 patients) and for patients with HER2-low, HR-negative breast cancer 40% (95% CI 16and#183;3-67and#183;6; six of 15 patients). Responses were also observed in one (6%; 95% CI 0and#183;2-30and#183;2) of 16 gastric cancer, four (25%; 95% CI 7and#183;3-52and#183;4) of 16 urothelial cancer, and five (39%; 95% CI 13and#183;9-68and#183;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.