Radio-immunotherapy for advanced HCC: A pilot study of irradiation dose

426 Background: Preclinically, radiation therapy for tumors was well known to reverse the immunosuppressive state by reprograming the tumor microenvironment. The combination of radiotherapy and immune checkpoint inhibitors (radio-immunotherapy) has renewed interest in clinical practice, and different irradiation dose may contribute diversely to immune response and abscopal effect. This pilot study aimed to assess the antitumour activity of the anti-PD-1 inhibitor Camrelizumab combined with different irradiation dose in patients with advanced hepatocellular carcinoma (HCC). Methods: Between April 2020 and January 2021, 20 patients with advanced HCC were prospectively enrolled in this pilot study. Five patients were treatment-naive and 15 patients were diagnosis as progressive diseases after previous treatment. For each patient, one to 3 intrahepatic and/or extrahepatic lesions were selected to irradiate. Camrelizumab was concurrently administered with 200mg on the first day of radiation and then every 3 weeks until disease progression, or unacceptable toxicity. Eligible patients were randomly assigned to receive 3 irradiation doses: low-dose group of 30Gy/10 fractions(3Gy/fx), intermediate-dose group of 40Gy/10 fractions (4Gy/fx), and high-dose group of 50Gy/10 fractions (5Gy/fx). Results: Nine patients had intrahepatic lesions (8 of macrovascular invasion) and 11 had extrahepatic metastases. The median number of treatment lines receiving immunotherapy of Camrelizumab was 2 (range 1-5). Enrolment to the 30Gy group was halted after 2 patients due to the poor clinical response. Finally, 2, 11, and 7 patients received the irradiation dose of 30, 40, and 50Gy, respectively. Twenty-eight selected lesions were irradiated (partial lesions in 12 patients and all lesions in 8 patients). Grade 3 treatment-related adverse events were observed in 4 patients, including 2 thrombocytopenia and 1 anaemia in the 40Gy group, and 1 anaemia in the 50Gy group. The median follow-up time was 12 months (range 7.0–18.0 months). There was a significant difference in PFS, but no difference in OS between the three groups. The median, 6- and 12-months PFS for the 30, 40, and 50 Gy groups were 1.7 months, 0% and 0% vs. 4.0 months (95%CI 1.7-6.3 months), 27.3% and 18.2% vs. 7.8 months (95%CI 4.1-11.5 months), 57.1% and 38.1%, respectively (P = 0.027). The median, 12-months OS were 11.4 months and 50% vs. 11.8 months and 34.6% vs. not reached and 66.7%, respectively (P = 0.229). The disease control rates were statistically different between the 30, 40, and 50Gy groups (50% vs. 54.5% vs. 100%, P = 0.039), whereas objective response rates were not significant different (0% vs. 45.5% vs. 71.4%, P = 0.123). Conclusions: Higher irradiation dose with 50 Gy in 10 fractions plus Camrelizumab may augment the radio-immunotherapy activity in advanced HCC with favorable PFS. The present study offers guidance for the dose selection of subsequent clinical trials. Clinical trial information: ChiCTR2000032375.