Antibody-drug conjugates offer wider therapeutic window by efficient and specific drug delivery to target expressing tumor cells. DS-8201a is a HER2-targeting ADC of high drug-to-antibody-ratio (DAR 7 to 8) with a novel topoisomerase I inhibitor. Compelling preclinical evidence exists that the HER2 targeting is highly specific. In preclinical models, DS-8201a showed a much broader antitumor spectrum than T-DM1, including efficacy against T-DM1 resistant and HER2 low-expressing tumors. A 2-part Phase 1 trial is underway, with a dose escalation (Part 1) and expansion (Part 2), focusing on HER2+ breast cancer (BC), gastric cancer (GC), and other HER2 expressing tumors.
Part 1 used a modified continuous reassessment method in BC and GC pts. DS-8201a was administered IV tri-weekly and escalated in cohorts starting at 0.8 mg/kg. Adverse events (AEs), pharmacokinetics (PKs), objective response rate (ORR) RECIST v1.1, and durability of responses were assessed. The primary objectives were safety and PK, determine the maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D).
During Part 1, 22 pts (including 13 BC pts previously treated with T-DM1), were administered 0.8 mg/kg to 8.0 mg/kg of DS-8201a. There were no dose limiting toxicities, and the MTD was not reached. Three pts (14%) experienced Gr3 AEs. The most common AEs were Gr1-2 gastrointestinal and hematological toxicities. The PK profile was favorable, and all pts at 6.4 mg/kg reached the target exposure based on preclinical data. The ORR and disease control rate (DCR: CR + PR + SD) were 35% and 90%, respectively, in 20 efficacy evaluable pts, including 5 pts with HER2 low expression. Especially, for 12 BC pts previously treated with T-DM1, 92% DCR was achieved, including 5 PRs (4 HER2 IHC3 + , 1 IHC1+). Five of the 22 pts have discontinued the treatment due to PD, and of the 17 remaining, 5 of the first evaluable 10 pts have been under active treatment (0.8 ∼ 6.4 mg/kg) for more than 24 weeks.
DS-8201a was well tolerated and remarkably active in pts previously treated with T-DM1, or in HER2 low-expressing BC pts. The dose of 6.4 mg/kg tri-weekly was preliminarily selected as the RP2D.
Clinical trial identification
Legal entity responsible for the study
Daiichi Sankyo Co Ltd JP
Daiichi Sankyo Co Ltd JP
K. Tamura: Direct research support to the responsible project lead (eg Principal Investigator). K. Shitara: Novartis Chugai both Euro500-20,000; Consulting and advisory services, speaking or writing engagements, public presentations. Y. Naito: Eisai, Taiho, Chugai, Lilly, Novartis, Bayer; all Eur500-20,000 Consulting and advisory services, speaking or writing engagements, public presentations. Y. Fujiwara: DaiichiSankyo EUR500-20,000 Consulting and advisory services, speaking or writing engagements, public presentations. Y. Kuboki: Tayo Bayer All EUR500-20,000; Consulting and advisory services, speaking or writing engagements, public presentations. N. Matsubara: AstraZeneca, Eisai, Sanofi, Janssen, Takeda, Chugai, Novartis EUR500-20,000 All Consulting and advisory services, speaking or writing engagements, public presentations. T. Jikoh, Y. Fujisaki, A. Yver: Company leadership role, employment relationship or ownership interest. T. Doi: MSD, Pfizer, Kyowa Kirin, Novartis, Lilly, Chugai, Taiho all EUR500-20,000 pa Consulting and advisory services, speaking or writing engagements, public presentations. All other authors have declared no conflicts of interest.