A phase 1b study of andecaliximab in combination with S-1 plus platinum in Japanese patients with gastric adenocarcinoma

Abstract

Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, MMP9 inhibitors have been shown to enhance the cytotoxic effects of chemotherapeutic agents and to suppress distant metastasis. In this phase Ib, multicenter study, the safety and efficacy of ADX combined with S-1 plus cisplatin (SP) or S-1 plus oxaliplatin (SOX) as a first-line treatment were evaluated in Japanese patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. ADX was administrated at a dose of 800 mg every 2 weeks for the SP cohort and 1200 mg every three weeks for the SOX cohort. As of December 2019, 16 patients were enrolled (six patients in the SP cohort and 10 patients in the SOX cohort). Peripheral sensory neuropathy (69%), anorexia (63%), nausea (56%), and decreased neutrophil counts (44%) were the most common adverse events (AEs). The grade 3 or higher AEs attributed to ADX were stomatitis and abnormal hepatic function (each one patient) in the SP cohort and decreased neutrophil counts (two patients) in the SOX cohort. The objective response rate in 11 patients with measurable target lesions was 73% (8/11), based on the investigator's evaluation. Median progression-free survival was11.9 months (90% confidence interval, 5.6-16.6), and median overall survival was not reached. In conclusion, ADX combined with S-1 plus platinum demonstrated a manageable safety profile and promising clinical activity in the first-line treatment of patients with advanced gastric or GEJ adenocarcinoma.Clinical Trial Registration information: ClinicalTrials.gov Identifier: NCT02862535 (11/08/2016) and protocol ID: GS-US-296-1884.

Conflict of interest statement

KY received speaker honoraria from Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb, Merck Serono, Taiho Pharmaceutical Co., Takeda, and Eli Lilly; a consultant fee from Takeda Pharmaceutical Co. Ltd.; honoraria from Tsumura Co. Ltd., Nihon Kayaku Co. Ltd., and Chugai Pharmaceutical Co. Ltd; research grants from Sumitomo Dainippon Pharma, Gilead Sciences, MSD, and Boehringer Ingelheim, Daiichi Sankyo, and Chugai Pharmaceutical Co. Ltd; Speaker honoraria, research grants, and scholarship grant from Ono Pharmaceutical, Yakult Honsha Co., Ltd., and Sanofi. AO received speaker honoraria from Merck Serono, Chugai, Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co., Bristol Myers-Squib, Daiichi Sankyo, and Ono Pharmaceutical. TS belonged to Endosed Department of Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Ono pharmaceutical Co., Ltd.received speaker honoraria from Chugai Pharmaceutical Co. Ltd.Daiichi Sankyo Ono Pharmaceutical. Bristol-Myers Squibb, Merck Serono and Elli Lilly, a consultant fee from Takara Bio. TK research fund from Chugai Pharmaceutical Co. Ltd. Daiichi Sankyo Ono Pharmaceutical. Bristol-Myers Squibb, Parexell, Hutchmed, Giliad, BeiGene and Elli Lilly. NB has received research grant from Ono pharmaceutical company and Takeda pharmaceutical company, and honorarium from Ono pharmaceutical company, Taiho, ONO Pharmaceutical. Co. Ltd and Bristol Myers Squibb. KM received grants (to his institution and himself) from Astellas, Amgen, Daiichi Sankyo, Merck Sharp & Dohme Corp., Merck Serono, Ono Pharmaceutical Co., Ltd, Parexel International, Pfizer, Sanofi, Solasia Pharma, and Taiho Pharmaceutical Co; consulting fees from Amgen, AstraZeneca, and Ono Pharmaceutical Co., Ltd; honoraria from Bayer, Bristol-Myers Squibb, Chugai, Eli Lilly, Ono Pharmaceutical Co., Ltd, Sanofi, Taiho Pharmaceutical Co, and Takeda. SK received honoraria for lectures from Eli Lilly, Taiho Pharmaceutical Co., ONO Pharmaceutical. Co. Ltd, Bristol Myers-Squib, Chugai Pharmaceutical Co. Ltd, Bayer, Merck Serono, Eisai, and Daiichi-Sankyo; departmental research grants from Taiho Pharmaceutical Co., Eli Lilly, MSD, Chugai Pharmaceutical Co. Ltd, Nobelpharma, Daiichi Sankyo, ONO Pharmaceutical. Co. Ltd, and Yansen. AT received personal fees from Eli Lilly, Taiho Pharmaceutical, Chugai Pharma, and Merck Serono; grants from Merck Sharp & Dohme, Eisai, Bayer Yakuhin, Bristol-Myers Squibb, and BeiGene Japan; grants and personal fees from Ono Pharmaceutical and Takeda. TK belonged to a donated fund laboratory of Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Ono pharmaceutical Co., Ltd. SM received speaker honoraria from Taiho Pharmaceutical Co., Takeda Pharmaceutical Co., and Ono Pharmaceutical Co, and grants from Taiho Pharmaceutical Co. SK received personal fees from Astra Zeneca, Pfizer, Taiho, Novartis, Sumitomo Dainippon Pharma, Bristol-Myers Squibb, AYUMI Pharmaceutical Corporation, Rakuten Medical, GSK, ImmuniT Research Inc., and PMDA(Pharmaceuticals and Medical Devices Agency) outside the submitted work; grants and personal fees from Gilead Sciences, Chugai, Boehringer Ingelheim, MSD, Eisai, Ono Pharmaceutical Co., Ltd, REGENERON, and Daiichi Sankyo; grants from Astellas, PACT Pharma, Takara Bio Inc., grants from AMED (Japan Agency for Medical Research and Development), and JSPS (Japan Society for the Promotion of Science).

© 2022. The Author(s).

Figures

Figure 1

Kaplan–Meier curve of PFS when cohorts 2 and 3 were combined. Kaplan–Meier curve was estimated from cut-off data of December 2018. The median PFS was 12.5 months (90% CI 5.6–14.7). After follow up at the data cut-off date (December, 2019), the median PFS was 11.9 months (90% CI 5.6–16.6).

Figure 2

Kaplan–Meier curve of OS when cohorts 2 and 3 were combined.