A phase Ib, multicenter, open-label study of the antibody-drug conjugate trastuzumab deruxtecan (DS-8201a) combination with nivolumab for advanced HER2-expressing breast or urothelial cancer

Abstract

Background: DS-8201a is a novel antibody-drug conjugate comprised of a humanized HER2 antibody attached by a cleavable peptide-based linker to a topoisomerase I inhibitor; characterized by a high drug-to-antibody ratio of about 8. In an ongoing phase 1 trial, DS-8201a showed high and durable responses across multiple tumors, with a confirmed objective response rate (ORR) of 61.4% in previously T-DM1-treated HER2- positive (IHC 3+ or IHC2+and ISH+) breast cancer (BC) and 31.6% in HER2 lowexpressing (IHC 2+/1+ and ISH-) BC (Oct 2017 cutoff; Modi et al, SABCS 2017). Nivolumab, an anti-PD-1 antibody, is FDA-approved for metastatic urothelial carcinoma (UC) after platinum failure. A xenograft model of HER2-expressing cancer showed significantly increased survival with the combination of DS-8201a with an anti-PD-1 antibody vs either treatment alone (Iwata et al, ASCO 2017). Trial design: This phase 1b, multicenter, open-label study will assess the combination of DS-8201a with nivolumab in previously chemotherapy-treated HER2-expressing advanced BC or UC. Previous treatment with anti-PD-1/PD-L1 therapy is an exclusion criterion. A dose escalation (part 1) will identify the recommended dose for expansion (RDE), and dose expansion (part 2) will evaluate efficacy and safety/tolerability of the DS-8201a RDE combination with nivolumab (360 mg IV; q3wk). Part 1 is a 3+3+3 design with 3 dose cohorts of DS-8201a (3.2, 5.4, and 6.4 mg/kg q3wk); enrollment will start at 3.2 mg/kg. Following RDE determination, enrollment in part 2 will open (Table); estimated total enrollment is 99-117. ORR is the primary efficacy endpoint; secondary endpoints include overall survival, disease control rate, duration of response, progression-free survival, time to response based on central review, and safety/tolerability. The study is open for enrollment as of May 2018. (Table Presented).