Abstract 7172: Pharmacokinetic/biomarker (PK/BMx) analysis of the toll-like receptor 7 and 8 (TLR7/8) agonist EIK1001 in phase 1 studies in participants (Pts) with solid tumors
Authors: Rasco Drew , Patel Manish , Johnson Melissa , Tolcher Anthony , Sommerhalder David , Hamid Omid , Alistar Angela , Kochan Jarema , Kurland Etah , Wang Meihua , Cho Carolyn , Rebello Sam 
Published: March 2024

Abstract
Introduction: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a TLR7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs.
Methods: Adults with advanced solid tumors received a range of doses of EIK1001 (QW IV) alone and in combination with pembrolizumab (200 mg Q3W; NCT03486301) or atezolizumab (1200 mg Q3W; NCT04196530) in Phase 1 studies (n=128). PK samples were collected on Cycle 1 Day 1 (C1D1) and C1D8 predose and at 0.5, 1, 2, 4, 6, 8, 12, and 24 hrs postdose, with sparse sampling thereafter. Matched cytokine BMx samples were collected.
The PK analysis population comprised pts with at least one measurable EIK1001 concentration (1563 observations from 94 pts). PK data were analyzed using non-linear mixed effects in Phoenix (v8.3). Covariate effects of the combination drugs were tested using a stepwise approach with a significance level of 0.05 for forward addition. All other covariates were evaluated using exploratory plots and formally tested using a full matrix approach. Empirical Bayes estimates were used to generate individual steady-state concentration-time profiles and calculate post-hoc PK parameters. Exploratory analyses of exposure-safety and exposure-efficacy were conducted.
Results: EIK1001 PK was linear and dose-proportional over the doses studied. Tmax ranged from 4-12 hrs with no accumulation. Pop-PK analysis indicated that body size influenced clearance, but intrinsic factors of age, gender, tumor type, ECOG status, or hepatic/renal impairment (mild/moderate) did not. Combination drugs did not influence clearance. These attributes support BSA-based dosing and inform inclusion/exclusion criteria for future studies.
On C1D1, time-dependent increases in IL-6, IL-8, IFNγ, and IP-10 returned to baseline within 24 hrs. An earlier IL-8 increase (Tmax 3-5 hr) is consistent with TLR8 activation on various cells including neutrophils, whereas the delayed increase of IFNγ/IP-10 (Tmax 5-8 hr) suggests a downstream effect. Dose-dependent increases in cytokines were observed, with median peak changes from baseline of 1.13- to 7.97-fold for IFNγ and 0.63- to 12.1-fold for IP-10. The 2 highest doses provided evidence of robust target engagement alone or in combination.
Conclusion: The linear, dose-proportional PK of EIK1001 is well described by the Pop-PK model. Increases in IFNγ and IP-10 were consistent with the anticipated mechanism of action, with doses representing target engagement identified. Further development of EIK1001 is underway.
Citation Format: Drew Rasco, Manish Patel, Melissa Johnson, Anthony Tolcher, David Sommerhalder, Omid Hamid, Angela Alistar, Jarema Kochan, Etah Kurland, Meihua Wang, Carolyn Cho, Sam Rebello. Pharmacokinetic/biomarker (PK/BMx) analysis of the toll-like receptor 7 and 8 (TLR7/8) agonist EIK1001 in phase 1 studies in participants (Pts) with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7172.