Doi T, et al. - Researchers here investigated safety and tolerability of trastuzumab deruxtecan (DS-8201) in patients with advanced breast and gastric or gastro-oesophageal tumours. In this study, the maximum tolerated dose of trastuzumab deruxtecan was not reached. Trastuzumab deruxtecan demonstrated antitumour activity, even in low HER2-expressing tumours in the present small, heavily pretreated study population. In accordance with the safety and activity, the most likely recommended phase 2 dosing seemed 5.4 or 6.4 mg/kg.

Methods

• An open-label, dose-escalation phase 1 trial was undertaken at two study sites in Japan.
• Patients who were at least 20 years old had breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status were eligible.
• Participants were administered initial intravenous doses of trastuzumab deruxtecan from 0.8 to 8.0 mg/kg.
• Dose-limiting toxicities were assessed over a 21-day cycle.
• Thereafter, researchers implemented dose reductions as needed and treated patients once every 3 weeks until they had unacceptable toxic effects or their disease progressed.
• For this study, primary endpoints were identification of safety and the maximum tolerated dose or recommended phase 2 dosing; these were analysed in all participants who received at least one dose of study drug.

Results

• From Aug 28, 2015, to Aug 26, 2016, researchers enrolled 24 patients and administered trastuzumab deruxtecan to them (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).
• There appeared no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths up to the study cutoff date of Feb 1, 2017.
• Because of insufficient target lesions for analysis, 1 patient was removed from the activity analysis.
• In the study population, 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.
• Febrile neutropenia, intestinal perforation, and cholangitis were the three serious adverse events which were reported by one patient each.
• Overall, 23 patients were evaluable, these included six patients with low HER2-expressing tumours; ten patients out of those achieved an objective response (43%, 95% CI 23.2–65.5).
• Researchers achieved disease control 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.