Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors

Abstract

E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg. The most frequent treatment-related treatment-emergent adverse events were chills (50.0%; 85.7%), fever (40.0%; 85.7%), and fatigue (30.0%; 35.7%) in patients who received non-visceral and visceral injections, respectively. Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-α, IFN-β, IFN-γ, TNF-α, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.

Keywords: Biomarker; Immunotherapy; Solid tumor.

Figure 1. Tumor response in a patient with gastro-esophageal cancer (A, B)^a; percentage change in the first injected lesion diameter (C^b,c,d); sum of non-injected target lesion (D^c,d,e), and all target lesion (E^d) diameters from baseline to postbaseline nadir by dose level; and baseline STING expression^f by maximal tumor growth of the first injected lesion (F^g). ^aPhotographs depict the response of injected tumor of a patient with gastro-esophageal cancer: injected with E7766 at 75 µg (first row) and an adjacent non-injected tumor lesion (second row); ^bY/N on top of each bar indicate the presence (Y) or absence (N) of previous immunotherapy history; ^cby investigator assessment, per modified RECIST version 1.1; ^dinclude patients with both baseline and ≥1 postbaseline measure of target lesion diameters; ^epatients who received E7766 at 300 µg did not have non-injected target lesions; ^fbaseline STING RNA expression was evaluated by measuring the expression of TMEM173; ^gpatients were divided into two groups based on the size of the first injected lesion: injected lesion progressed if the maximum tumor growth of the first injected lesion was ≥20%, and injected lesion stabilized if the maximum tumor growth of the first injected lesion was <20%. C#D#, cycle # day #; PD, progressive disease; N, no; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; STING, stimulator of interferon genes; TPM, transcripts per kilobase million; Y, yes.

Figure 2. Changes from baseline in plasma levels of different biomarkers in all dosing cohorts of patients receiving E7766. C#D#, cycle # day #; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant; TNF, tumor necrosis factor.