Yttrium-90 SIRT followed by lenvatinib plus sintilimab for unresectable intermediate-to-advanced hepatocellular carcinoma: Phase II SIRLENS-90 trial.

Abstract

4149 Background: Selective internal radiation therapy (SIRT) with yttrium-90 microspheres is an established locoregional therapy for unresectable hepatocellular carcinoma (HCC) and may induce immunogenic modulation, providing a rationale for PD-(L)1 blockade combinations. However, outcomes with SIRT–PD-(L)1 doublets suggest room for improvement. Lenvatinib has biological plausibility to augment radiation- and immunotherapy-mediated effects via VEGFR/FGFR pathway inhibition. We evaluated the efficacy and safety of sequential SIRT followed by lenvatinib plus sintilimab and explored serum protein biomarkers for outcome stratification. Methods: SIRLENS-90 (NCT05992584) is a single-center, open-label, single-arm phase II trial in unresectable BCLC B/C HCC (ECOG 0–1, Child–Pugh 5–7) suitable for SIRT after mapping and 99m Tc-MAA simulation. Patients received yttrium-90 resin SIRT (partition-model dosimetry) followed 3–7 days later by lenvatinib (8/12 mg daily) plus sintilimab (200 mg IV Q3W). Primary endpoint: PFS by mRECIST. Secondary endpoints: PFS by RECIST v1.1, OS, ORR, DCR, and safety (CTCAE v5.0). Exploratory Olink proteomics and LASSO-penalized Cox modeling derived a baseline risk score. Results: Thirty patients were treated (mean age 57 years [(SD 9.9], 93% male, 87% HBV-related; 43% BCLC B, 57% BCLC C; 43% macrovascular invasion; 53% bilobar disease; 37% extrahepatic metastases; mean max tumor diameter 9.6 cm [SD 3.8; range 3.2–16.1]). Median follow-up was 23.4 months. Median PFS was 15.8 mo (95% CI 8.3–20.7) by mRECIST (6-, 12-, and 18-mo rates: 77%, 53%, 40%) and 17.0 mo (95% CI 8.3–20.7) by RECIST v1.1. Median OS was not reached (12-, 18-, and 24-mo OS rates: 83%, 73%, 68%). ORR was 83% (95% CI 65–94) by mRECIST and 60% (95% CI 41–77) by RECIST v1.1; DCR was 90% (95% CI 74–98) by both. Intrahepatic ORR was 93% (95% CI 78–99) by mRECIST. Grade 3–4 treatment-related AEs occurred in 47%, with treatment-related SAEs in 10% and no treatment-related deaths. A baseline risk score incorporating IL-5 (protective), CXCL11 (adverse), extrahepatic metastasis, and bilobar disease stratified PFS (log-rank P = 0.001) and OS ( P = 0.02), with optimism-corrected C-index 0.758 (for PFS). Conclusions: Yttrium-90 SIRT followed by lenvatinib plus sintilimab demonstrated encouraging activity with manageable toxicity in unresectable intermediate-to-advanced HCC. The cytokine-integrated baseline risk score is hypothesis-generating and warrants external validation. Clinical trial information: NCT05992584 .