Neoadjuvant Cemiplimab Plus SBRT Improves 2-Year Disease-Free Survival in Resectable Hepatocellular Carcinoma
Key Insights
A phase II study demonstrated that combining stereotactic body radiotherapy (SBRT) with neoadjuvant cemiplimab significantly improved 2-year disease-free survival to 88% compared to 62% with cemiplimab alone in resectable hepatocellular carcinoma (search) patients.
The combination therapy maintained an acceptable safety profile despite increased treatment-related adverse events, with no grade 3 or higher toxicities observed during adjuvant treatment in the combination arm.
Minimal residual disease status emerged as a powerful prognostic indicator, with MRD-negative patients showing markedly lower recurrence risk compared to MRD-positive patients (HR 0.18; p = 0.002).
A phase II clinical trial has shown that adding stereotactic body radiotherapy (SBRT) to neoadjuvant cemiplimab significantly improves long-term outcomes in patients with resectable hepatocellular carcinoma (search) (HCC (search)), with 2-year disease-free survival reaching 88% compared to 62% with cemiplimab monotherapy.
The study, presented at the Society for Immunotherapy of Cancer 2025 Annual Meeting, enrolled 42 patients with resectable HCC (search) who were evenly randomized to receive either cemiplimab alone or cemiplimab combined with SBRT before surgical resection.
Study Design and Treatment Protocol
Patients in the cemiplimab monotherapy arm received 350 mg every three weeks for two cycles before surgery. The combination arm received SBRT delivered as 8 Gy × 3 fractions over one week, along with cemiplimab 350 mg every three weeks for three cycles. Following neoadjuvant therapy and surgical resection, all patients received eight additional cycles of adjuvant cemiplimab every three weeks.
The primary endpoint was significant tumor necrosis (STN) rate in resected specimens, with secondary endpoints including disease-free survival and treatment-related safety. The analysis was conducted after a median post-resection follow-up of 41 months.
Superior Disease-Free Survival Outcomes
The combination therapy demonstrated substantial improvements in disease-free survival at both time points. At one year, DFS rates were 79% (95% CI, 53%-92%) for cemiplimab alone versus 88% (95% CI, 59%-97%) for the combination. The difference became more pronounced at two years, with DFS rates of 62% (95% CI, 36%-80%) versus 88% (95% CI, 59%-97%), respectively.
Despite similar pathologic response rates between arms—with STN occurring in 20% of cemiplimab-only patients versus 19% in the combination arm—the superior DFS outcomes suggest that radiotherapy may enhance immune-mediated systemic control of micrometastatic disease.
Biomarker Insights
Circulating tumor DNA (ctDNA) analysis revealed a strong correlation between ctDNA levels and baseline tumor size (r = 0.84; p < 0.001). A ≥50% reduction in ctDNA before surgery was associated with a trend toward improved disease-free survival (HR 0.55), indicating that early molecular response may reflect treatment sensitivity.
Postoperative minimal residual disease (MRD) status emerged as one of the most powerful prognostic indicators. Patients who were MRD-negative after resection had a markedly lower risk of recurrence compared with those who were MRD-positive (HR 0.18; p = 0.002).
Safety Profile
While the addition of SBRT increased the overall rate of treatment-related adverse events, the combination remained manageable. Neoadjuvant treatment-related adverse events occurred in 29% of patients receiving cemiplimab alone compared with 55% in the combination arm. During adjuvant therapy, adverse events were observed in 39% versus 67% of patients, respectively.
Importantly, high-grade toxicities were uncommon. Grade ≥3 treatment-related adverse events occurred in 9.5% of patients in the cemiplimab-only group during neoadjuvant therapy, whereas no grade ≥3 events were reported in the combination arm. During adjuvant therapy, grade ≥3 events were observed in 17% of cemiplimab-alone patients and none in the combination arm.
Clinical Implications
"Two-year DFS with neoadjuvant therapy is favorable compared with historic controls. Patients who received cemiplimab plus SBRT have favorable relapse-free survival compared with patients who received cemiplimab alone," noted Dan Feng, MD, assistant professor of Medicine, Hematology, and Oncology at Mount Sinai Ichan School of Medicine (search), and co-authors.
The study population was representative of typical HCC (search) patients, with 61% aged 65 years or older, 83% male, and 58% having tumors larger than 5 cm. The results suggest that neoadjuvant cemiplimab plus SBRT produces clinically meaningful improvements in disease-free survival without compromising surgical feasibility, offering a promising perioperative strategy for resectable HCC patients.