Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial

Regorafenib has anti-tumor activity in hepatocellular carcinoma (HCC) with potential immunomodulatory effects, suggesting its combination with immune checkpoint inhibitor may have clinically meaningful benefits in unresectable HCC patients. The multicenter single-arm phase 2 RENOBATE trial tested regorafenib-nivolumab as front-line treatment for unresectable HCC. Forty-two patients received nivolumab 480 mg/4 weeks, and regorafenib 80 mg/daily (3-weeks on/1-week off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). ORR per RECIST v1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were hand-foot skin reaction (33.3%), alopecia (26.2%), and skin rash (21.4%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, while the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells show thatlong-term responders exhibited T-cell-receptor repertoire diversification; enrichment of genes representing immunotherapy-responsiveness in MKI67+ proliferating CD8+ T cells; and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib-nivolumab combination as front-line treatment for unresectable HCC and provide preliminary insights on immune biomarkers of response ClinicalTrials.gov identifier: NCT04310709.