Combination of anti-angiogenic molecular targeted therapy and anti- programmed cell death -1
immune checkpoint inhibitor (ICI) therapy has shown promising antitumor activity in multiple
cancer types, including patients with advanced hepatocellular carcinoma (HCC). The safety
profile and optimal dosage of targeted therapy should be carefully evaluated by clinical
trials. Regorafenib is one of the standard second-line systemic therapy for advanced HCC. The
present study will test the safety and efficacy of combination of regorafenib and
tislelizumab, an anti-programmed cell death-1 ICI. The investigator(s) thus hypothesized that
combination of tislelizumab and regorafenib is a tolerable regimen and may improve treatment
efficacy for patients with advanced HCC. The present study will explore safety and efficacy
of the combination of tislelizumab plus regorafenib as first-line therapy for advanced HCC.
Combination of ICI with anti-angiogenic therapy has been most extensively studies in patients
with renal cell carcinoma, for whom both ICI and anti-angiogenic therapy have proven
anticancer activity as single-agent therapy. Objective response rate of 30-60% was observed,
far exceeding the response rate of single-agent therapy (around 20%). Results from several
early-phase trials of this type of combination also support the potential anti-tumor synergy
between ICI and anti-angiogenic therapy (multi-kinase inhibitors or monoclonal antibody
targeting the vascular endothelial growth factor signaling pathway) in advanced HCC. Further
studies should focus on identifying the optimal targeted agent and its biologically effective
dosage to achieve the best therapeutic window for the treatment of HCC.
Current evidence indicated the following:
Combination of ICI and anti-angiogenic therapy in advanced HCC may have better
anti-tumor efficacy compared with single-agent therapy;
The immune modulatory effects of the multi-kinase inhibitors may be achieved at dosage
lower than recommended for single-agent therapy in the clinic; using this lower dosage
when combined with ICI may lower the treatment-related adverse events.
Objective response of 40% to 50% was recently reported in a phase 1 study of regorafenib
plus nivolumab for patients with advanced gastric or colorectal cancer was reported
recently (Fukuoka S, et al. American Society Of Clinical Oncology 2019, abstract#2522).
Grade 3 or greater treatment-related adverse events were found in 27% of subjects who
received regorafenib 80 mg per day and in 44% of patients who received regorafenib 120
mg per day. Therefore, regorafenib 80 mg/day was defined as the optimal dosage in
combination with nivolumab.
Advanced Hepatocellular Carcinoma
Tislelizumab+regorafenib for part 1;Tislelizumab+regorafenib for group 1 of part 2; Regorafenib for group 2 of part 2.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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