LAUSR

Background Agonists for TLR7, a major regulator of the innate immune response, have been tested in oncology across several nonclinical and clinical investigations due to their ability to stimulate T-cell mediated cancer cell killing. The orally available TLR7 agonist prodrug RO7119929 is converted to active drug predominantly in the liver. It was hypothesized to effectively reprogram the local immune microenvironment and thus enhance anti-tumor activity in liver tumors. Methods In this phase 1, first-in-human, open-label, dose-escalation study (NCT04338685), eligible pts had histologically confirmed advanced or metastatic primary liver cancers or solid tumors with predominant liver involvement. Pts received oral RO7119929 weekly in 3-week cycles in Part A (dose-escalation: Flat dosing [FD][A1], step-up dosing [SUD][A2] or FD with tocilizumab pre-treatment [A3]) and Part B (FD dose expansion with paired biopsies). Participants received treatment until disease progression, unacceptable toxicity or withdrawal. Primary endpoints were maximum tolerated dose (MTD) and/or optimal biologic dose and safety. Results At data cut-off (22 April 2022), 55 pts were enrolled (A1: n=27; A2: n=9; A3: n=1; B1: n=18). Median age: 58 years; 76% male; 51% Asian; 52% received ≥3 prior lines of therapy; 31% HCC as primary tumor type. Most pts discontinued treatment due to disease progression (75%). Among 17 HCC pts, a durable complete response was observed in one pt and 10 (59%) pts had stable disease. Treatment-related AEs were reported in 91% of pts, most common event was CRS (87%). Fever following drug administration was generally reported as CRS, and most CRS events were Grade 1 (fever). With FD, Grade 2 CRS occurred in 20 (44%) pts and Grade 3 CRS in 6 (13%) pts. With SUD, Grade 2 CRS occurred in one (11%) pt and no Grade 3 CRS was reported. The incidence and severity of CRS events was dose-dependent. Events generally had a predictable onset within 12h post-dosing. All events resolved, the majority within 1-2 days. CRS events of Grade 2/3 commonly occurred in Cycle 1, with later events rarely exceeding Grade 1. Increases in the TLR7-related peripheral pharmacodynamic (PD) biomarkers IFNα, ISG15 and IL6 were associated with higher doses, with particularly IL6 correlating with CRS severity. With SUD, high levels of IFNα and ISG15 levels were maintained while IL6 levels were reduced compared with FD. Pharmacokinetics (PK) of the active TLR7 agonist drug appeared linear (Cmax, AUC) and time-independent with a short effective t1/2 of approximately 5h on average. PK, PD and safety modeling-informed dose decisions. Conclusion CRS was identified as a dose-limiting safety risk, the incidence and severity of CRS appeared dose-dependent, and events were predictable and manageable. SUD reduced the risk of CRS whilst maintaining mode of action relevant PD effects. Combination therapy with a checkpoint inhibitor may be needed to leverage the pro-inflammatory potential of RO7119929 and further increase anti-tumor activity. Citation Format: Changhoon Yoo, Helena Verdaguer, Chia-Chi Lin, Camilla Qvortrup, Thomas Yau, Do-Youn Oh, Felix Lichtenegger, Izolda Franjkovic, Nicole Kratochwil, Juliana Bessa, Eva Rossmann, Elia Hall, Congqi Dai, Oliver Krieter, Audrey Yeo Te-Ying, Michael Cannarile, Christina Schiff, Bruno Sangro. Phase 1 study of RO7119929 (TLR7 agonist prodrug) in patients (pts) with advanced primary or metastatic liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT096.