Phase II trial with nivolumab and sorafenib in HCC identified enrichment of immunosuppressive monocytes in patients with Child-Pugh B liver dysfunction.

[BACKGROUND & 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 an open-label phase II clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with nivolumab, in patients with advanced HCC and varying liver function. In a Part 1 safety lead-in, we investigated the maximum-tolerated dose (MTD) of the combination in patients with Child-Pugh A or B7. In Part 2, we enrolled patients with Child-Pugh B7-9 HCC with the primary endpoint of grade ≥3 treatment-related adverse event (TRAE) incidence. Exploratory endpoints included immunological biomarkers.

[RESULTS] Overall, 25 patients were consented and 16 eligible patients enrolled. In Part 1, dose-limiting toxicity occurred in one of six patients in Dose Level -1, and two of five 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 (70%, 95% CI: 0.35-0.93 vs. 66.7%, 95% CI: 0.22-0.96). The objective response rate was 6% and median overall survival was 12.99 months (Child-Pugh A: 15.26 and Child-Pugh B: 10.41). We found that patients with Child-Pugh B liver disease harbored more circulating suppressive CD14 monocytes at baseline compared with those with Child-Pugh A disease.

[CONCLUSIONS] Although combination sorafenib and nivolumab demonstrated acceptable safety at the MTD in both Child-Pugh subgroups, the objective response rate was below the prespecified threshold to be declared worthy of further exploration. A distinct immune cell profile in patients with Child-Pugh B disease might define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need.

[IMPACT AND IMPLICATIONS] This study addresses the crucial need for effective therapies for patients with advanced HCC and compromised liver function, a population historically excluded from many clinical trials. The findings suggest that, although the combination of sorafenib and nivolumab demonstrated acceptable safety across different liver function subgroups, there was a low response rate overall. Importantly, the discovery of distinct immune profiles, particularly an increase in suppressive immune cells in patients with worse liver function, provides insights into potential mechanisms of resistance to immunotherapy. These results are crucial for understanding how we can improve the treatment of advanced HCC, especially in patients with impaired liver function.

[CLINICAL TRIAL] NCT03439891.