Updated Results of Phase I Study of Trastuzumab Deruxtecan (Ds-8201A) in HER2-expressing Advanced Colorectal Cancer

Background: DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed a broad antitumor activity in a wide range of tumors, including colorectal cancer (CRC) regardless of KRAS status. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects (sbj) with advanced breast cancer, gastric cancer, and other HER2-expressing/mutated solid tumors. Here, we present updated results for HER2-expressing CRC. Methods: Sbj with advanced HER2-expressing (defined as IHC ≥1+) CRC were eligible to enroll. HER2 expression was assessed using archival tissue. Objective response rate (ORR), disease control rate (DCR; CR + PR + SD), duration of response (DOR), and adverse events (AEs) were assessed. Results: As of Apr 18, 2018, 19 HER2-expressing CRC sbj received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 59 y with median of 4 prior regimens (range: 1 to 8). Sixteen of 19 sbj had prior treatment (tx) with irinotecan, another topoisomerase -I inhibitor. At the data cutoff, 7 of 19 (36.8%) sbj remain on treatment. Median duration of tx was 2.76 months (range 0.69, 15.44). Two sbj were known to have KRAS mutations. Overall, confirmed ORR and DCR in the efficacy evaluable sbj was 3 of 12 (25.0%) and 10 of 12 (83.3%), respectively. All responses were observed in KRAS wildtype sbj. One sbj with a KRAS mutation had SD with reduction in tumor markers. Median DOR has not been reached (NR, range 2.76, 5.52+ mo). Nine of 15 (60.0%) sbj with ≥1 post baseline scan experienced tumor shrinkage. Major reason for tx discontinuation was progressive disease (9/12; 75.0%). As for the safety outcomes, 12/19 (63.2%) experienced a grade ≥3 AE. Common AEs included nausea 57.9% (0.0% grade ≥3), platelet count decreased 52.6% (26.3% grade ≥3), anemia 47.4% (26.3% grade ≥3), vomiting 42.1% (0% grade ≥3), and diarrhea 42.1% (0% grade ≥3). Conclusions: DS-8201a demonstrated antitumor activity with manageable safety profile in heavily pretreated subjects with HER2-expressing CRC and warrants further investigation in a phase 2 trial. Clinical trial identification: NCT02564900. Editorial acknowledgement: Editorial and submission support was provided by Stefan Kolata, PhD of AlphaBioCom, LLC (King of Prussia, PA USA). Legal entity responsible for the study: Daiichi Sankyo Co,. Ltd. Funding: Daiichi Sankyo Co,. Ltd. Disclosure: T. Yoshino: Grants: MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., GlaxoSmithKline K.K., Nippon Boehringer Ingelheim Co., Ltd; Grants and personal fees: Sanofi K.K., Chugai Pharmaceutical Co., Ltd.; Personal fees: Eli Lilly Japan K.K, Merck Serono Co., Ltd. H. Iwata: Dr. Iwata Grants and personal fees: Daiichi Sankyo, during the conduct of the study; Grants and personal fees: Chugai, AstraZeneca, Pfizer; Personal fees: Eisai; Grants from MSD, Kyowahakou Kirin, GSK, Lilly, Novartis, Bayer. S. Takahashi: Grants and personal fees: Daichi-Sankyo, during the conduct of the study; Grants and personal fees: Daiichi-Sankyo, outside the submitted work. T. Doi: Grants: Daiichi Sankyo during the conduct of the study; Grants and personal fees: Lilly, Chugai Pharma, Kyowa Hakko Kirin, MSD, Daiichi Sankyo; Personal fees: Amgen; Grants from Taiho, Novartis, Merck Serono, Astellas Pharma, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Sumitomo Group, Celegene, Bristol Myers Squibb, Abbvie, Quintiles. H. Kawakami: Grants: Diaiichi Sankyo; Personal fees: Eli Lilly, Ono Pharmaceutical, Co., Ltd., Chugai Pharmaceutical, Co., Ltd., Taiho Pharmaceutical, Co., Ltd., MSD Pharmaceutical, Co., Ltd., Merck Serono, Takeda Pharmaceutical, Co., Ltd., Astra Zeneca K.K., Yakult Pharmaceutical industry, Co., Ltd. H. Taniguchi: Grants and personal fees: Takeda; Personal fees: Taiho, Chugai. K. Yamaguchi: Research grants: MSD, Ono Pharmaceuticals, Dainppon-Sumitomo, Taiho Pharmaceuticals, Daiichi-Sankyo, Eli Lilly, Giriad, Yakurt Honsha; Consultation fees: Daiichi Sankyo Bristol-Myers Squibb; Speakers' bureau: Taiho Chugai, Merck, Tkeda, Yakurt Honsha, Bayer, Ono Pharmaceuticals, Sanofi, Eli Lilly. B. Li: Grants: Daiichi Sankyo, during the conduct of the study; Personal fees: Genentech. K. Saito, Y. Fujisaki, M. Sugihara: Full-time employee: Daiichi Sankyo Co., Ltd. J. Tsurutani: Grants: Daiichi-Sankyo, during the conduct of the study; Personal fees: Daiichi-Sankyo, outside the submitted work. All other authors have declared no conflicts of interest.