Differential T-cell and monocyte responses in hepatocellular carcinoma treated with regorafenib plus nivolumab: an integrated clinical and biomarker analysis of the phase 2 RENOBATE trial

Abstract In this phase 2 REBNOBATE trial, we evaluated regorafenib-nivolumab as front-line treatment for unresectable hepatocellular carcinoma (uHCC). Patients (n = 42) received nivolumab 480 mg every 4 weeks, and regorafenib 80 mg daily (3-weeks on/1-week off schedule). Single-cell RNA sequencing was performed using peripheral blood mononuclear cells from early progressors (progressively increased tumor burden) and long-term responders (response/stable disease for ≥ 10 months). The overall response rate in the study was 31.0%, with a median progression-free survival of 7.4 months and a 1-year overall survival rate of 80.5%. Regorafenib-nivolumab was well-tolerated (no new safety signal). Long-term responders exhibited T-cell receptor repertoire diversification; enrichment of genes representing immunotherapy-responsiveness and cytotoxicity in MKI67+ proliferating CD8+ T cells; and interaction between MKI67+ proliferating CD8+ T cells and classical monocytes through IFN-γ pathways with a higher probability of M1-directed polarization of monocytes. Classical monocytes from early progressors exhibited upregulation of TMEM176A/B coupled with an ineffective inflammasome response. Regorafenib-nivolumab is feasible as front-line treatment for uHCC. Our findings may support the development of biomarkers, or novel immunotherapies to overcome resistance in uHCC.