First-in-human, multicenter, open-label, phase I study of ATOR-1017 (evunzekibart), a 4-1BB antibody, in patients with advanced solid malignancies

Abstract

Background: ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death.

Methods: In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective of the study included determination of the maximum tolerated dose (MTD) via assessment of adverse events and dose-limiting toxicities (DLTs). Secondary objectives included determination of the pharmacokinetics, immunogenicity and clinical efficacy assessed with CT scans using immune Response Evaluation Criteria in Solid Tumors. Exploratory objectives included pharmacodynamic (PD) assessment of immune system biomarkers.

Results: Of the 27 patients screened, 25 received treatment with ATOR-1017. The median time on study was 13.1 weeks (range 4.3-92.3). The MTD of ATOR-1017 was not reached. Treatment-related adverse events (TRAEs) were reported in 13 (52%) of 25 patients; most common (≥10%) were fatigue (n=4 (16.0%) patients) and neutropenia (n=3 (12.0%) patients). Five patients experienced a severe (≥ grade 3) TRAE; neutropenia (n=2), febrile neutropenia (n=1), chest pain (n=1), increased liver enzymes (n=1), and leukopenia and thrombocytopenia (n=1). No patients discontinued due to TRAEs and no DLTs were observed. Pharmacokinetic data demonstrated approximate dose-proportional kinetics. Dose-dependent increases in PD biomarkers, including soluble 4-1BB, are indicative of target-mediated biological activity. Best response was stable disease in 13 out of 25 patients (52%), maintained for 6 months or longer in six patients (24%).

Conclusions: Treatment with ATOR-1017 was safe and well tolerated at all dose levels and demonstrated biological activity. Furthermore, almost one-third of patients experienced long-lasting stable disease in this heavily pretreated population. The encouraging safety and preliminary efficacy data warrant further clinical development of ATOR-1017, possibly in combination with other anticancer agents.

Keywords: Antibody; Solid tumor.

Figure 1. Trial profile (Consolidated Standards of Reporting Trials diagram). *Two patients (one in 600 mg dose level cohort, and one in 900 mg dose level cohort) did not start ATOR-1017 treatment due to clinical deterioration. ^†One patient treated at the 900 mg dose level did not meet all eligibility criteria as they did not have their screening serology sample analyzed, and their hepatitis B and hepatitis C status could not be determined. DLT, dose-limiting toxicity.

Figure 2. Swimmer plot for individual patients with cancer with advanced disease (with tumor type) included in the ATOR-1017 study demonstrating the clinical response (iUPD, iCPD and iSD) evaluated according to immune Response Evaluation Criteria in Solid Tumors V.1.1, in relation to ATOR-1017 dose and treatment duration. ATOR-1017 dose escalations are also indicated for individual patients. iCPD, immune-confirmed progressive disease; iSD, immune stable disease; iUSD, immune unconfirmed progressive disease.

Figure 3. Pharmacokinetic profile for ATOR-1017 in individual patients with cancer with advanced disease treated at different antibody doses for cycles 1 and 2. Mean (±SD) serum concentration versus nominal time (0–3 weeks; per cycle). Conc, concentration.

Figure 4. Modulation of peripheral CD8⁺ T cell proliferation and activation (A–C) and soluble 4-1BB (D) in patients with cancer with advanced disease treated with ATOR-1017. Data are presented as maximum fold change from baseline as boxplots at study day 22 (A–C) and study day 8 (D) in cycle 1. Normalized fold change of soluble 4-1BB over time (cycle 1 and at all time points until cycle 2 day one predose) is presented in (E). CD, cluster of differentiation; ICOS, inducible costimulator; ns, not significant. Statistical analysis of PD data was performed using Mann-Whitney, non-parametric, two-tail test (*, p<0.05; **, p<0.01; ***, p<0.001, ****, p<0.0001).