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Activity and Safety of Regorafenib Plus Nivolumab in First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma

Findings from the RENOBATE study
22 Feb 2024
Targeted Therapy;  Immunotherapy
Hepatobiliary Cancers

In a phase II study, the RENOBATE team investigated the clinical outcomes and dynamic immune landscapes associated with regorafenib plus nivolumab as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). The primary endpoint was met, with an objective response rate (ORR) of 31.0% and a median progression-free survival (PFS) of 7.38 months. Overall, regorafenib plus nivolumab was well tolerated.

Combination regimens with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents are now considered standard first-line therapy, and the present data may provide insights into the biological or immunological implications of such combination treatment in patients with unresectable HCC according to Dr. Changhoon Yoo of the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine in Seoul, Republic of Korea, and colleagues who published the findings on 19 February 2024 in the Nature Medicine.

The authors explained in the background that discrepancies observed in phase III trials have not yet been explained, but the results suggest that clinical efficacy of first-line combination with ICI plus anti-angiogenic treatment may partly depend on differences in the detailed molecular and/or immunological mechanisms underlying the effects of the combination partners.

Regorafenib has antitumour activity in patients with unresectable HCC with potential immunomodulatory effects, suggesting that its combination with ICI may have clinically meaningful benefits. Several biomarkers are reportedly associated with clinical outcomes among patients with unresectable HCC treated with ICI. However, none has yet been firmly established as predictive for ICI response. Thus, there remains a need to further investigate the detailed mechanisms underlying response or resistance to ICI-based treatments.

The RENOBATE is a multicentre phase II study evaluating the efficacy and safety of the regorafenib plus nivolumab combination, in the first-line setting, in patients with unresectable HCC. In the article, published in the Nature Medicine, the authors present the results in terms of clinical outcomes and a comprehensive biomarker study, including analyses of circulating tumour DNA, single-cell RNA sequencing, single-cell T cell receptor (TCR) repertoire and multicolour flow cytometry with serially collected peripheral blood mononuclear cells (PBMCs).

In total, 42 patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily in 3-weeks-on/1-week-off schedule. The primary endpoint was the investigator-assessed ORR per RECIST v1.1. The secondary endpoints included safety, PFS and overall survival (OS). ORR was 31.0%, meeting the primary endpoint. Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached.  

The safety profiles were in line with those described in a previous phase I study of other types of gastrointestinal cancers, and no new safety profile was noted for either regorafenib or nivolumab. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%).

Exploratory single-cell RNA sequencing analyses of PBMCs showed that long-term responders exhibited TCR repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67-positive proliferating CD8-positive T cells and a higher probability of M1-directed monocyte polarisation.

The authors concluded that regorafenib plus nivolumab has clinical activity and is a well-tolerated first-line treatment for patients with unresectable HCC. Exploratory biomarker analyses provide insights that may help to understand the clinically relevant immune responses in this therapeutic context and identify potential targets to overcome resistance to ICI-based treatments. Regorafenib plus anti-PD1/L1 should be further investigated for use in patients with unresectable HCC.


Kim H-D, Jung S, Lim HY, et al. Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial. Nature Medicine; Published online 19 February 2024. DOI: https://doi.org/10.1038/s41591-024-02824-y



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