Photon radiotherapy

Tremelimumab plus durvalumab (the STRIDE regimen) is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC); however, it demonstrates limited efficacy, with an objective response rate (ORR) of only 20.1%. Radiation therapy (RT) is highly effective in controlling localized solid tumors and has become an integral component of the treatment algorithm for unresectable HCC. Preclinical studies have shown that combining RT with PD-L1/PD-1 blockade promotes immunogenic cell death and enhances antigen presentation by dendritic cells, thereby boosting systemic T cell-mediated antitumor responses in mouse models. The addition of CTLA-4 inhibition further enhances antigen cross-priming following RT. Recent retrospective data also indicate that combining RT with immune-oncology agents is associated with improved overall survival and prolonged time to progression compared to RT or immunotherapy alone. However, the clinical benefit and immunologic impact of combining RT with tremelimumab and durvalumab have not yet been evaluated in prospective clinical trials for unresectable HCC. This phase II, single-arm clinical trial aims to assess the safety, efficacy, and immunologic effects of combining proton RT with tremelimumab and durvalumab in patients with unresectable HCC.

Atezolizumab (anti-programmed death-ligand 1; anti-PD-L1) in conjunction with bevacizumab (anti-vascular endothelial growth factor; anti-VEGF) has become the established standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Despite an improved objective response rate (ORR) of 27%, the majority of patients face HCC progression and liver failure \[Finn et al., N Engl J Med 2020\]. Developing a new combined treatment strategy to overcome resistance to anti-PD-L1 and anti-VEGF is essential to improve patient outcomes. Radiation treatment (RT) is highly efficacious in controlling localized solid tumors and has become an integral component of the treatment algorithm for unresectable HCC. Importantly, a recent retrospective cohort described that RT combined with atezolizumab plus bevacizumab was associated with favorable median overall survival of 16.1 months (Manzar et al, Cancers 2022). Our preclinical study (Hsieh et al., Science Immunology 2022) revealed that RT combined with PD-L1/PD-1 blockade induces immunogenic cell death and tumor antigen cross-presentation in antigen-presenting cells, thereby potentiating the systemic antitumor T cell responses in murine tumor models. However, whether the combinatorial therapy with RT, atezolizumab, and bevacizumab can trigger synergistic antitumor effects and systemic immune mobilization has not yet been validated in clinical trials for unresectable HCC. Both atezolizumab/bevacizumab and X-ray RT are approved treatment methods for unresectable HCC by the U.S. and Taiwan Food and Drug Administration (FDA). The present phase II non-randomized trial aims to prospectively document the therapeutic efficacy, safety, and immunological responses in patients with unresectable HCC treated with atezolizumab/bevacizumab combined with conventional photon radiotherapy.