Phase I trial of high-dose SBRT combined with atezolizumab and bevacizumab in advanced hepatocellular carcinoma.

560 Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. In the pivotal IMbrave150 trial, atezolizumab plus bevacizumab achieved a complete response (CR) rate of only 5.5%, with an objective response rate (ORR) of 27.3%. Preclinical and clinical evidence suggest that stereotactic body radiotherapy (SBRT) can enhance the efficacy of immunotherapy. We therefore conducted a phase I trial to evaluate the safety, feasibility, and immunologic effects of high-dose SBRT combined with atezolizumab and bevacizumab in patients with advanced HCC. Methods: This single-center, open-label, dose-escalation study (NCT05488522) enrolled patients with multifocal unresectable and/or metastatic, systemic-therapy naïve HCC. All received atezolizumab 1200 mg and bevacizumab 15 mg/kg every 21 days. SBRT (17 Gy/fraction) was delivered to one or more lesions on 1 to 3 occasions (depending on assigned dose level), 4 weeks apart using a Rolling 6 design. The first SBRT fraction was administered one week after the start of systemic therapy. The primary endpoint was dose-limiting toxicity (DLT) defined as Grade ≥3 events attributable to SBRT. Secondary endpoints included objective response rate by RECIST 1.1, overall and disease-free survival, and immune correlates from peripheral blood mononuclear cells (PBMCs). Results: Thirteen patients were treated (5 with one fraction, 6 with two fractions, and 2 with three fractions). Median age was 66 years; 77% were Child-Pugh A; 69% ECOG 0. Across all three cohorts, no radiation-related ≥Grade 3 DLTs were observed; the maximum tolerated dose was not reached. The ORR was 53.9% (7/13), and the best responses included 5 complete responses (38.5%) and 2 partial responses (15.4%); none of the patients with a complete response experienced recurrence. The median disease-free survival was 14.1 months, and the overall survival was 25.8 months. Immune profiling of PBMCs demonstrated that responders exhibited an increased frequency of CD8+ T cells expressing high levels of PD-1, along with proliferative (Ki-67) and activation (HLA-DR) markers, consistent with an “intermediate exhausted” but functionally active phenotype. Responders also displayed enhanced CD4+ Th1 activation, including upregulation of interferon-I signaling and ISG15, indicating a coordinated Th1-polarized immune response. Conclusions: High-dose SBRT combined with atezolizumab/bevacizumab in advanced HCC was feasible, safe, and yielded durable CRs in ~40% of patients. Median DFS and OS exceeded historical benchmarks. These results suggest that SBRT, when combined with atezolizumab and bevacizumab, may stimulate systemic immune activation and reinvigorate both CD8⁺ and CD4⁺ T-cell compartments in patients who experience prolonged clinical benefit. Clinical trial information: NCT05488522 .