Safety, efficacy, and outcomes of 90-yttrium radioembolization in combination with immune checkpoint inhibitors as a definitive first-line treatment approach in non-surgical hepatocellular carcinoma.
Authors: Grahovac Alexandre , Sandow Tyler , Mizrahi Jonathan , Du Lingling , Vallejo-Calzada Ricardo , Gimenez Juan , Cohen Ari , Nunez Kelley , Thevenot Paul 
Published: January 2025

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Background:
Immune checkpoint inhibitors (ICI) have emerged as first line therapy for advanced-stage hepatocellular carcinoma (HCC). However, response rates remain modest (<20%). Combination treatments offer potential to improve initial response rates while extending duration of response. While early studies of
90
Yttrium transarterial radioembolization (
90
Y)-ICI showed fewer adverse events (AE) and improved objective responses (OR) (30-40%), there were no improvements in time to progression (TTP) and overall survival (OS). This study evaluates safety, efficacy, and outcomes of first line
90
Y-ICI while evaluating the role of ICI regimen and treatment sequencing.
Methods:
A retrospective, multi-center study was conducted in BCLC A-C stage HCC patients (ECOG 0-1) receiving first line
90
Y-ICI with atezolizumab/bevacizumab (A+B) or tremelimumab/durvalumab (STRIDE). Treatment response was recorded at
90
Y follow-up. TTP, progression-free survival (PFS), and OS were primary endpoints, with AE and safety as secondary outcomes.
Results:
The study included 40 patients receiving
90
Y-ICI from 2021–2024, with a median follow-up of 12 months. The cohort was predominantly Child-Pugh A (96%) with HCV-related cirrhosis (76%), BCLC-C stage (51%), and a median target HCC size of 7.7 cm (IQR, 6-11 cm). Grade 3-4 AEs occurred in 15 patients (37%), leading to steroid use (12, 29%), treatment delays (13, 31%), or discontinuation (4, 10%). The first cycle target OR rate was 82% (32/39), with a 51% (20/39) complete response (CR) rate. The first cycle overall OR was 59% (23/39), with a 41% (16/39) CR rate. No significant differences were found in adverse events, delays, or discontinuations based on sequencing or regimen. Sequencing had no significant effect on target or overall OR with no downstream effect on TTP (P = 0.968) or PFS (P = 0.906). Similarly, there was no effect of ICI regimen on OR, TTP (P = 0.813) or PFS (P = 0.904), although the data trended toward higher response rates with the STRIDE regimen. Log-rank analysis revealed target CR was associated with improved TTP (P = 0.004) and PFS (P = 0.009), but not OS (P = 0.237). Achieving an overall CR was associated with further improvements in TTP (P < 0.001) and PFS (P < 0.001). The cohort 2-year OS was 55% with median OS not yet reached.
Conclusions:
First line
90
Y-ICI therapy in BCLC A-C stage HCC is an effective treatment strategy with AEs in the expected range of systemic therapy and low rates of treatment discontinuation. Sequencing and ICI regimen did not significantly impact AEs or treatment outcomes. However, patients achieving CR showed significantly improved TTP and PFS. Although follow-up is limited, these findings suggest achieving CR is key to optimal long-term outcomes. We anticipate long-term follow-up will demonstrate an OS benefit linked to first line CR rate.