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

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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0679-9) contains supplementary material, which is available to ...

Targeting EphA2 in cancer

“…The maximum tolerated dose was not reached in step 1 and the planned highest dose (20 mg/kg) was used in step 2. A total of 37 cases (22 and 15 in steps 1 and 2, respectively) were included, but all discontinued the study for overt disease progression (20 and 13 in steps 1 and 2, respectively) or adverse events (AEs, the remaining cases) [120]. Similarly, the NCT02004717 trial enrolled 9 patients, who did not complete the study.…”

Antibody Targeting of Eph Receptors in Cancer

“…One gastric cancer patient showed a partial response and 13 patients achieved stable disease, although the latter did not correlate with EphA2 expression in tumor biopsies, suggesting this may not be treatment-related. Consistent with DS-8895a-induced ADCC activity, a decrease in CD16-positive NK cells and a transient increase in serum inflammatory cytokines were observed after treatment [31]. A second trial to investigate imaging and safety of DS-8895a in non-Japanese patients with advanced EphA2+ tumors (NCT02252211) used more limited treatment doses and incorporated PET imaging of 89 Zr trace-labeled antibody at day 1 and 36.…”

“…To date, three anti-Eph antibodies have been tested in clinical trials. The unconjugated anti-EphA2 mAb DS-8895a has been evaluated in a Phase I trial (ClinicalTrials.gov identifier NCT02004717) in Japanese patients with advanced solid tumors [31]. The humanized mAb was afucosylated to enhance ADCC activity, improving antibody binding of the FcγRIIIa receptor (CD16), highly expressed on natural killer (NK) cells.…”

Oncogenic functions and therapeutic targeting of EphA2 in cancer

“…In subsequent clinical trials, tumor uptake of the compound was confirmed in 100% of imaged patients [ 91 ]. Fourteen of thirty-seven patients treated with DS8895a in a phase 1 trial achieved stable disease or partial response with five reports of grade ≥ 3 cytopenia but no thrombotic or hemorrhagic events described, an improvement compared to results with MEDI-547 [ 92 ]. Bicycle Therapeutics has recently described a high-affinity EphA2 targeting peptide-cytotoxin conjugate with low affinity for other Eph proteins which dramatically reduces in vivo tumor volume in an EphA2 expression-dependent manner without hematologic adverse effects [ 93 ].…”