Pilot Study of Ipilimumab and Nivolumab With Response-adapted Stereotactic Body Radiotherapy Followed by Definitive Resection for Patients With Locally Advanced Hepatocellular Cancer
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, with Native Hawaiian and Pacific Islander (NHPI) populations experiencing significantly higher mortality rates compared to other groups in Hawaii. This disparity is influenced by factors such as higher prevalence of chronic hepatitis B, non-alcoholic fatty liver disease, limited access to early detection, and delayed diagnoses. NHPI patients are also underrepresented in clinical trials, limiting the relevance of treatment advances for this population. The standard treatment for HCC is surgical resection; however, many NHPI patients present with unresectable disease. Recent advances with immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, have shown promise in treating advanced HCC and improving survival in previously untreatable cases. Additionally, stereotactic body radiotherapy (SBRT) has been shown to enhance survival and local control when combined with systemic therapies like ICIs. However, without surgery, outcomes remain suboptimal, with response rates for ICIs alone at 20-30%, and combination ICI-SBRT treatment showing slightly better results but still a high risk of progression. Despite improvements in HCC treatment, significant gaps remain in managing borderline resectable disease, especially in NHPI patients. This study aims to evaluate the safety and efficacy of combining ICIs and SBRT with curative surgery for patients with borderline resectable HCC, focusing on NHPI populations. The study will also explore the use of biomarkers such as cell-free DNA (cfDNA), CD8+ T-cell infiltration, and serum cytokine markers to guide personalized treatment strategies. Preliminary findings suggest that this multimodal approach may improve outcomes and enable surgical resection for patients previously considered inoperable. This study seeks to address the unmet need for effective treatment strategies in borderline resectable HCC and to improve survival outcomes for underserved NHPI populations.
⁃ Histologically or cytologically confirmed hepatocellular cancer
• Locally advanced/borderline resectable HCC as defined by:
∙ Solitary tumor \>5 cm, OR
‣ Unilobar multifocal disease either with \>3 tumors or one tumor \>3 cm, OR
‣ Bilobar disease with adequate future liver remnant, still technically resectable, OR
‣ High risk disease features (tumor \>3 cm with macrovascular invasion or tumor \>3 cm with AFP\>400).
• No extrahepatic spread, no nodal disease, no bilateral left and right branch portal vein involvement, no hepatic vein / IVC involvement. Unilateral hepatic vein involvement is not exclusionary.
• Measurable disease per RECIST 1.1 as determined by the investigator
• Age ≥ 18 years old on the day of consent
• ECOG performance status ≤1 (Appendix XX)
• Adequate organ and marrow function, as defined below. Criteria a, b, c, and f cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose.
∙ Hemoglobin ≥9 g/dL
‣ Absolute neutrophil count ≥1000/μL
‣ Platelet count ≥90,000/μL
‣ Total bilirubin (TBL) \<2.0 mg/dL
‣ ASTandALT≤5×ULN
‣ Albumin≥2.8g/dL
‣ International normalized ratio(INR)≤2xULN
‣ Calculated creatinine clearance ≥ 40 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance