Discussion
tumor, fatigue, unresectable HCC, constipation, dizziness, HCC, epistaxis
TUMOR, REMISSIONS, SOLID TUMORS, EPISTAXIS, EVENTS
On the basis of evidence showing the potential of antiangiogenic agents plus immunotherapy, we conducted the first, multicenter, single-arm, phase 1b/2 study to determine the recommended phase 2 dose of GT90001 when combined with nivolumab, as well as to prospectively investigate the efficacy and safety of this combination at the recommended dose in patients with advanced HCC. In this phase 1b/2 study, we found that this combination regimen is well-tolerated and has promising anti-tumor activity with durable remissions and objective responses in this population.The safety profiles of GT90001 plus nivolumab are generally acceptable and manageable in our patients. The most common events were platelet count decreased, fatigue, epistaxis, dizziness, and constipation but these events of grade 3 or more were infrequent, which was consistent with the historical data for solid tumors [Anti-PD1/anti-PDL1 plus anti-angiogenic agents or anti-CTLA4 regimens are now the standard of care as first-line systemic therapy for unresectable HCC based on the survival benefit, compared with single-agent multi-kinase inhibitor (MKI) therapy, demonstrated by randomized controlled trials [GT90001 may modulate the tumor immune microenvironment through its TGF-β-inhibiting and anti-vascular effects. While single-agent GT90001 therapy had only limited antitumor efficacy in advanced solid tumors (ORR of 0–6.8%, median PFS shorter than 2 months [An obvious limitation of this study is its small sample size and non-randomized design, which make comparison of treatment efficacy of GT90001 plus nivolumab with other ICI or MKI-based regimens difficult. This study did not prospectively collect tumor or blood samples for biomarker studies, which is critical for mechanistic exploration. Finally, all of our subjects received first-line MKI therapy (sorafenib or lenvatinib). Application of results from this study will be limited because the standard first-line systemic therapy for unresectable HCC now is ICI-based combination therapy. This change will also impact on design of confirmatory clinical trials of new regimens in the second-line setting. Despite all these limitations, future studies for mechanistic clarification and structure optimization of ALK-1 inhibitor are warranted to identify novel immune modulatory agents for the treatment of HCC.