MVI-targeted carbon-ion radiotherapy combined with immunotherapy for advanced hepatocellular carcinoma: Phase Ib DEPARTURE trial

BACKGROUND & AIMS: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) carries an extremely poor prognosis, necessitating novel therapeutic strategies. This phase Ib trial evaluated the safety and preliminary efficacy of combining carbon-ion radiotherapy (C-ion RT) with immune checkpoint inhibitors (ICIs) in patients with advanced HCC with MVI. METHODS: Fifteen patients with MVI-positive advanced HCC were enrolled (Cohort A: durvalumab monotherapy, n = 3; Cohort B: durvalumab plus tremelimumab, n = 12). C-ion RT (60 Gy, four fractions) was delivered to the MVI-containing primary tumor, while systemic therapy with durvalumab (+tremelimumab) was administered concurrently. The primary endpoints included dose-limiting toxicities and adverse events. Secondary endpoints included progression-free survival and overall survival. RESULTS: No dose-limiting toxicities were observed, and the combination exhibited a manageable safety profile. The most common adverse events were pyrexia, rash, and elevated lipase levels. Grade 3-4 adverse events occurred in 53.3%, including cytokine release syndrome and meningitis. Median progression-free survival and overall survival were 4.7 and 10.4 months, respectively. Although C-ion RT achieved effective local control of irradiated lesions, non-irradiated lesions showed limited systemic immune responses. CONCLUSIONS: The combination of MVI-targeted C-ion RT and immune checkpoint inhibitors demonstrated safe and effective local tumor control in advanced HCC. This novel approach of selective irradiation to MVI-containing tumors, combined with systemic immunotherapy, warrants further investigation to optimize the synergistic effects and enhance systemic efficacy in this poor-prognosis group. IMPACT AND IMPLICATIONS: Advanced hepatocellular carcinoma with macrovascular invasion (MVI) has a poor prognosis, highlighting the need for new therapeutic strategies. Our phase Ib study suggests that carbon-ion radiotherapy targeting MVI combined with immune checkpoint inhibitors is feasible and achieves sustained local tumor control. RNA-sequencing revealed that immune activation pathways were enriched in responders, while resistance was associated with mesenchymal and angiogenesis signatures. These results reinforce the potential of MVI-targeted irradiation combined with immune checkpoint inhibitors as a promising treatment strategy for these high-risk patients, warranting further investigation to improve systemic tumor control. CLINICAL TRIALS REGISTRATION: jRCT2031210046.