Immunosuppressive monocytes are enriched in hepatocellular carcinoma patients with liver dysfunction in a phase II trial of combination sorafenib and nivolumab [CITE-Seq]

Background and aims: Immune checkpoint inhibition (ICI) and anti-angiogenic therapies are active in hepatocellular carcinoma (HCC), although patients with impaired hepatic function have worse outcomes. Methods: We conducted a multi-center, open-label phase II clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with nivolumab, in patients with advanced or unresectable HCC and varying liver function. In a Part 1 safety lead-in, we investigated the primary endpoint of the maximum-tolerated dose (MTD) of the combination in patients with Child-Pugh A or B7 HCC. In Part 2, we enrolled patients with Child-Pugh B HCC with the primary endpoint of grade >/=3 treatment-related adverse events (TRAE) incidence. Exploratory endpoints included immunologic biomarkers. Results: Overall, 25 patients were consented and 16 eligible patients enrolled. In Part 1, dose-limiting toxicity occurred in 1 of 6 patients in Dose Level -1, and 2 of 5 patients in Dose Level 1; Dose Level -1 was determined to be the MTD. In total, 69% of patients experienced a Grade >/=3 TRAE, with similar distribution for patients with Child-Pugh A and B liver function (70%, 95% CI: 0.35, 0.93 vs 66.7%, 95% CI: 0.22, 0.96). The objective response rate was 6%. We found that patients with Child-Pugh B liver disease harbored more circulating suppressive CD14+ monocytes at baseline. Conclusions: While the combination of sorafenib and nivolumab demonstrated acceptable safety at the MTD in both Child-Pugh subgroups, the objective response rate was below the pre-specified threshold to be declared worthy of further exploration. A distinct immune cell profile in Child-Pugh B patients may define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need