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BackgroundImmune checkpoint inhibitors (ICIs) are now standard of care for advanced hepatocellular carcinoma (HCC). Early-stage HCC is potentially curable through surgical resection, though recurrence is seen in up to 70%, with an ~55% disease-free survival (DFS) at 2 years with surveillance. Neoadjuvant immunotherapy induces tumor necrosis and may reduce the risk of local and distal recurrences. Addition of stereotactic body radiation therapy (SBRT) before anti-PD1 augmented abscopal responses to ICI in preclinical studies.MethodsIn this Phase 2 open-label trial (NCT03916627), participants with resectable HCC received 2 doses of neoadjuvant cemiplimab 350 mg IV every 3 weeks before surgical resection and 8 cycles of adjuvant cemiplimab. Participants in cohort B2 received additional low-dose SBRT (8 Gy × 3 fractions) immediately before neoadjuvant cemiplimab. The primary endpoint was significant tumor necrosis (STN; >70% necrosis). Secondary endpoints included DFS and incidence of adverse events (AEs). ctDNA (by the Signatera assay) was evaluated as a correlate of response and DFS. As of July 31, 2025 (data cut-off; last patient on study ~24 months [first treatment August 7, 2023]), median follow-up was 41 months (IQR 32-58 months) post-resection.ResultsFrom August 2019 to August 2023, 41 participants received neoadjuvant cemiplimab and 20 patients also received SBRT. Thirty-six completed planned surgery, with one patient experiencing a delay to surgery (defined as surgery >28 days following the end of neoadjuvant immunotherapy). Five did not undergo resection due to subsequent determination of unresectable diseases (n=3) or comorbidity (n=2). Thirty-three received adjuvant cemiplimab (median exposure 23.7 weeks). For patients who underwent resection, rates of tumor necrosis and 1- and 2-year DFS are shown in table 1. Immune-related grade 3/4 adverse events occurred in 4, including grade 3 rash maculo-papular (n=1), hepatitis (n=1), and grade 3 pneumonitis (n=2). ctDNA kinetics in the neoadjuvant period and the prognostic value of minimal residual disease by ctDNA will be included in the full presentation.ConclusionsNeoadjuvant immunotherapy with cemiplimab with or without low-dose SBRT in patients with resectable HCC is potentially feasible with a generally acceptable safety profile consistent with the established profile of cemiplimab. Two-year DFS with neoadjuvant therapy may be favorable compared to historic controls. A larger study is needed to validate the benefits of neoadjuvant immunotherapy and the potential contribution of SBRT to survival outcomes.Trial RegistrationClinicaltrials.gov NCT03916627Ethics ApprovalThe study was approved by BRANY IRB, approval number 19-06-061-05.Abstract 1308 Table 1Disease-free survival for patients with resected tumors treated with and without SBRT.CTN, complete tumor necrosis (100% tumor necrosis); DFS, disease-free survival; IV, intravenous; Q3W, every 3 weeks; SBRT, stereotactic body radiation therapy; STN, significant tumor necrosis (> 70% tumor necrosis).