A randomized phase 2, multicenter, open-label study of trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing gastric cancer.

TPS4133 Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer who progressed on trastuzumab-based therapy. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker (deruxtecan), and with a high drug-to-antibody ratio of 7 to 8. In the ongoing phase 1 DS8201-A-J101 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in salvage-line subjects with gastric cancer who previously received trastuzumab (confirmed objective response rate [ORR] of 45.5% at Oct 16, 2017 data cutoff) (Iwasa et al, ASCO-GI 2018). Methods: The randomized, phase 2, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of DS-8201a in HER2-expressing gastric cancer subjects. The primary cohort, HER2-positive (IHC 3+ or IHC 2+/ISH+) subjects who progressed after ≥2 prior regimens and previously received trastuzumab, will be randomized (2:1) to DS-8201a (6.4 mg/kg dose; once every 3 weeks) or physician’s choice (irinotecan or paclitaxel). Two nonrandomized exploratory cohorts will assess the efficacy and safety of DS-8201a in subjects with HER2-low gastric cancer (IHC 2+/ISH- and IHC 1+, respectively) who are treatment-naïve to HER2-targeted therapies. The primary endpoint is ORR assessed by an independent central review; secondary endpoints include overall survival (OS), progression-free survival, duration of response, disease control rate, pharmacokinetics, and safety (as shown in ClinicalTrials.gov). The primary analyses for ORR and interim OS analysis will occur after all subjects complete tumor assessments on week 18 and when approximately 108 OS events are observed, whichever comes later. The primary cohort will enroll 180 subjects; providing 92.9% power to detect a difference between the ORR of 40% for DS-8201a vs 15% for physician’s choice. Each exploratory cohort will enroll a maximum of 20 subjects. Enrollment began in October 2017. As of Feb 13, 2018, 12 of 180 subjects have been enrolled. Clinical trial information: NCT03329690.