Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer (GC) who progressed on trastuzumab-based therapy. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, topoisomerase I inhibitor payload, cleavable peptide-based linker, and high drug-to-antibody ratio of approximately 8. In an ongoing phase I trial, [fam-] trastuzumab deruxtecan showed an acceptable safety profile and promising antitumor activity in salvage-line subjects with HER2+ GC who previously received trastuzumab (confirmed objective response rate [ORR] of 43.2% [19/44]; Iwata et al, ASCO 2018). Methods: The randomized, phase II, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in HER2-expressing GC. The primary cohort, HER2+ (IHC 3+ or IHC 2+/ISH+) GC subjects who progressed after ≥ 2 prior regimens and previously received trastuzumab, will be randomized (2:1) to [fam-] trastuzumab deruxtecan (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 [fam-] trastuzumab deruxtecan in subjects with HER2-low GC (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 analysis 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 [fam-] trastuzumab deruxtecan 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