Updated results of phase 1 study of DS-8201a in patients with HER2 expressing non-breast, non-gastric malignancies

Abstract

Background: DS-8201a is a HER2 targeting antibody-drug conjugate of high drug to antibody ratio (7 to 8) with a novel linker and topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broad antitumor spectrum, including efficacy against low HER2 expressing breast cancer (BC) and HER2 expressing non-gastric and non-breast cancers. The current phase 1 trial includes dose escalation (Part 1) and expansion (Part 2) including BC, gastric cancer (GC) and other HER2 expressing solid tumors. Methods: Part 1 used a mCRM to identify the recommended dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: HER2 positive BC, HER2 positive GC, low HER2 expressing BC, and other solid tumors expressing HER2. HER2 expression was determined by IHC, FISH, NGS or other platforms. Adverse events (AEs), objective response rate (ORR), and disease control rate (DCR: CR + PR+ SD) were assessed. Results: Twenty four pts in Part 1 and 113 pts in Part 2 were enrolled. 24 of 113 pts were HER2 expressing solid tumors other than BC and GC. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose level of 6.4 mg/kg IV every 3 weeks was chosen. DLTs were not observed in the study. In the updated Part 1 results, confirmed ORR was 35%, DCR was 91% (BC: 88%, GC: 100%), and the median duration of treatment was ≥32 weeks in heavily pretreated BC and GC pts. Non-BC and non-GC cohort consists of 11 CRC, 5 NSCLC, 4 salivary gland, 2 Paget's disease, 1 cholangiocarcinoma and 1 esophageal cancer. ORR including under confirmation and DCR were 33% and 91%, respectively in evaluable 12 pts. Two out of 5 evaluable pts with CRC and 2 out of 4 evaluable pts with salivary gland achieved PRs. Of all pts in this phase 1 study, the most common AEs of any grades were nausea (≥Gr1 60%; ≥Gr 3 2%), decreased appetite (≥Gr 1 55%; ≥Gr 3 4%), vomiting (≥Gr 1 30%; ≥Gr 3 0%) and platelet count decreased (≥Gr 1 30%; ≥Gr 3 9%). Updated phase 1 results will be presented. Conclusions: DS-8201a was well tolerated and is remarkably active in pts with heavily pretreated HER2 expressing BC and GC with durable disease control. Promising efficacy in HER2 expressing other tumors was observed and warrants further investigation.