First-in-human phase 1 study of RO7119929, an oral TLR7 agonist prodrug, in patients with advanced primary or metastatic liver cancers.

[BACKGROUND] The orally available toll-like receptor 7 (TLR7) agonist prodrug RO7119929 is converted to active drug predominantly in the liver, where it is hypothesized to reprogram the local immune microenvironment. We aimed to explore the safety, pharmacokinetics (PK), and preliminary antitumor activity and obtain the proof-of-mechanism for RO7119929 in patients with liver cancer.

[METHODS] RO7119929 was investigated in mouse tumors and liver tissue from cynomolgus monkeys. In the first-in-human, open-label, dose-escalation and expansion study, patients with histologically confirmed advanced or metastatic primary liver cancers or solid tumors with predominant liver involvement received RO7119929 weekly in 3-week cycles either on a flat-dose (FD) or step-up dose (SUD) schedule.

[RESULTS] Preclinical results demonstrated antitumor activity and the proinflammatory proof-of-mechanism in mouse liver tumors and cynomolgus monkey liver tissue. The subsequent first-in-human study enrolled 27 patients in five FD dose-escalation cohorts, 18 patients in a FD dose-expansion cohort, and 9 patients in two SUD dose-escalation cohorts. The most common primary tumor type at study entry was hepatocellular carcinoma (HCC) (31%). PK data showed fast conversion of RO7119929 to the active TLR7 agonist. Treatment-related adverse events (TRAEs) were observed in 50 (91%) patients across all treated patients; the most commonly reported TRAE was cytokine release syndrome (CRS) in 48 (81%) patients. CRS was also identified as a dose-limiting safety risk and had a dose-dependent incidence and severity. Grade 3 CRS occurred in six (13%) patients receiving FD RO7119929, while no grade 3 CRS was reported in SUD patients at comparable target dose levels. TLR7-related transient, dose-dependent gene expression and cytokine induction was observed both with FD and SUD treatment and corresponded with treatment-induced local inflammation of the tumor microenvironment induced by reprogramming of the myeloid cells. Among 17 patients with HCC, one durable complete response was observed, and 10 (59%) patients had stable disease.

[CONCLUSIONS] SUD appears to reduce the risk of CRS while maintaining mode-of-action-relevant pharmacodynamic effects. The clinical activity of RO7119929 as a single agent was limited, suggesting that combination therapy with a checkpoint inhibitor may be needed to leverage the proinflammatory potential of RO7119929 and further increase antitumor activity.

[TRIAL REGISTRATION NUMBER] NCT04338685.