Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors.

Abstract

108 Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]