Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors

Kohei Shitara, Taroh Satoh, Satoru Iwasa, Kensei Yamaguchi, Kei Muro, Yoshito Komatsu, Tomohiro Nishina, Taito Esaki, Jun Hasegawa, Yasuyuki Kakurai, Emi Kamiyama, Tomoko Nakata, Kota Nakamura, Hayato Sakaki, Ichinosuke Hyodo, Kohei Shitara, Taroh Satoh, Satoru Iwasa, Kensei Yamaguchi, Kei Muro, Yoshito Komatsu, Tomohiro Nishina, Taito Esaki, Jun Hasegawa, Yasuyuki Kakurai, Emi Kamiyama, Tomoko Nakata, Kota Nakamura, Hayato Sakaki, Ichinosuke Hyodo

Abstract

Background: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.

Methods: Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.

Results: Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3.

Conclusions: Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells.

Trial registration: Phase 1 Study of DS-8895a in patients with advanced solid tumors ( NCT02004717 ; 7 November 2013 to 2 February 2017); retrospectively registered on 9 December 2013.

Keywords: Advanced solid tumors; Antibody-dependent cellular cytotoxicity; DS-8895a; Erythropoietin-producing hepatocellular receptor A2; Esophageal cancer; Gastric cancer; Phase I study.

Conflict of interest statement

Kohei Shitara has received consultation fees from Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda Pharmaceutical, Pfizer, and Ono Pharmaceutical; honoraria from Novartis, Abbvie, and Yakult Honsha; and research funding from Dainippon Sumitomo Pharma, Eli Lilly, MSD, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, and Ono Pharmaceutical.

Taroh Satoh has received consultation fees from Bayer Yakuhin, Ltd., Eli Lilly, Ono Pharmaceutical, Takara Bio, and Merck Serono; honoraria from Chugai Pharmaceutical, Merck Serono, Bristol-Myers Squibb, Takeda Pharmaceutical, Yakult Honsha, Eli Lilly, Bayer Yakuhin, Ono Pharmaceutical, Merck, and Astellas Pharma; and research funding from Yakult Honsha, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Eli Lilly, Daiichi Sankyo, Merck, Merck Serono, Gilead Sciences, and Dainippon Sumitomo Pharma.

Satoru Iwasa has received honoraria from Taiho Pharmaceutical, Lilly Japan and Chugai Pharma; and research funding from Daiichi Sankyo, Chugai Pharma, Bristol-Myers Squibb, Lilly Japan, Eisai, Novartis, Merck Serono, Otsuka and Bayer.

Kensei Yamaguchi has received consultation fees from Bristol-Myers Squibb Japan and Daiichi Sankyo; speaker’s bureau funds from Chugai Pharma, Merck Serono, Bristol-Myers Squibb Japan, Takeda, Taiho Pharmaceutical, Lilly, Yakult Honsha, Ono Pharmaceutical and Sanofi; and research funding from MSD Oncology, Ono Pharmaceutical, Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Lilly, Gilead Sciences and Yakult Honsha.

Kei Muro has received honoraria from Chugai Pharma, Merck Serono, Takeda, Taiho Pharmaceutical, Lilly, Yakult Honsha, Ono Pharmaceutical and Bayer; and research funding from Ono Pharmaceutical, MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Merck Serono, Pfizer and Sanofi.

Yoshito Komatsu has received speaker’s bureau funds from Taiho Pharmaceutical, Lilly, Chugai Pharma, Merck Serono, Novartis, Pfizer, Bayer, Ono Pharmaceutical, Yakult Honsha, Takeda, Sanofi, Bristol-Myers Squibb Japan, Daiichi Sankyo, TOWA and Nipro Corporation; honoraria from Novartis, Pfizer and Bayer; and research funding from Taiho Pharmaceutical, Lilly, MSD, Ono Pharmaceutical, Novartis, Bayer, Chugai Pharma, Yakult, Takeda, Dainippon Sumitomo Pharma, Boehringer Ingelheim, Sysmex, Sanofi, Astellas Pharma and Eisai.

Tomohiro Nishina has received honoraria from Taiho Pharmaceutical, Chugai Pharma, Lilly, Merck Serono and Takeda; and research funding from Taiho Pharmaceutical, Chugai Pharma, Dainippon Sumitomo Pharma, Lilly Japan, Merck Serono, MSD, Daiichi Sankyo, and Ono Pharmaceutical.

Taito Esaki has received consultation fees from Chugai Pharma; speakers’ bureau funds from Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Lilly, Eisai, Daiichi Sankyo, Merck Serono, Chugai Pharma, Ono Pharmaceutical and Takeda; honoraria from Lilly and Kyowa Hakko Kirin; and research funding from Daiichi Sankyo, Merck Serono, Taiho Pharmaceutical, MSD, Novartis, Dainippon Sumitomo Pharma and Ono Pharmaceutical.

Jun Hasegawa, Yasuyuki Kakurai, Emi Kamiyama, Tomoko Nakata, Kota Nakamura and Hayato Sakaki are employees of Daiichi Sankyo.

Ichinosuke Hyodo has received honoraria from Chugai Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Lilly, Ono Pharmaceutical and Bristol-Myers Squibb; and research funding from Bristol-Myers Squibb Japan, Chugai Pharma, Kyowa Hakko Kirin, Takeda, Merck Serono, Yakult Honsha, Taiho Pharmaceutical, Sanofi, Daiichi Sankyo and Ono Pharmaceutical.

Figures

Fig. 1
Fig. 1
Best (minimum) percent change from baseline in sum of diameters (%) of target lesions. Baseline is defined as the last measurement prior to administration of the first dose of DS-8895a. Each vertical bar represents the best (minimum) percent change from baseline for an individual patient
Fig. 2
Fig. 2
Changes in CD16-positive natural killer (NK) cells. Time-course of circulating CD16-positive NK cells (CD3−CD56+CD16+) after DS-8895a treatment in a) Cycle 1 of Step 1 and b) Cycle 1 of Step 2, and c) the ratio of CD3−CD56+CD137+ cells to CD3−CD56+CD16+ cells in Cycle 1 of Step 2

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Source: PubMed

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