JHEP reports : innovation in hepatology · 2026
MVI-targeted carbon-ion radiotherapy combined with immunotherapy for advanced hepatocellular carcinoma: Phase Ib DEPARTURE trial.
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Ogasawara Sadahisa, Koroki Keisuke, Makishima Hirokazu, Wakatsuki Masaru, Takahashi Asahi, Fujiya Makoto, Yumita Sae, Nakagawa Miyuki, Kanzaki Hiroaki, Kobayashi Kazufumi, Inoue Masanori, Nakamura Masato, Kanogawa Naoya, Kondo Takayuki, Nakamoto Shingo, Kurokawa Tomoya, Ozawa Yoshihito, Inaba Yosuke, Paritala Soumith, Chen Jingxuan, Lee Jeon, Hoshida Yujin, Hanaoka Hideki, Yamada Shigeru, Ishikawa Hitoshi
Аннотация
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.
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.