LBA4000 Background: TACE, a global standard of care (SoC) for unresectable eeHCC, induces a tumor immune response. STRIDE (Single Tremelimumab T Regular Interval Durvalumab D) has shown OS benefit at 6-year follow-up and is a SoC for unresectable advanced HCC. We report preplanned analyses from EMERALD-3 (NCT05301842), which combined STRIDE ± lenvatinib (L) with TACE. Methods: Eligible pts (≥18 yr) with confirmed eeHCC were randomized 1:1:1 to STRIDE (T 300 mg + D 1500 mg on Day 1 then D 1500 mg Q4W) + L (8 or 12 mg QD) + TACE; STRIDE + TACE; or TACE until reaching 175 pts/arm. Randomization continued 1:1 until STRIDE + L + TACE and TACE reached 275 pts/arm. D and L continued for ≤36 months (mo), until disease progression, unacceptable toxicity, or withdrawn consent. Pts were stratified by region, any prior palliative embolization, and baseline tumor burden by the Up-To-Seven criteria. The primary endpoint was PFS for STRIDE + L + TACE vs TACE by a stratified Cox proportional hazards model and stratified log-rank test. Key secondary endpoints were OS (STRIDE + L + TACE vs TACE), and PFS plus OS (STRIDE + TACE vs TACE). Results: As of Feb 23, 2026, 293 pts were randomized to STRIDE + L + TACE, 175 to STRIDE + TACE, and 292 to TACE. Baseline characteristics were broadly balanced across arms. STRIDE + L + TACE showed a statistically significant improvement in PFS vs TACE (HR, 0.70; 95% CI, 0.57–0.86; p=0.0007), and a positive OS trend (HR, 0.84; 95% CI, 0.65–1.09; p=0.1814). STRIDE + TACE also improved PFS (HR, 0.71; 95% CI, 0.56–0.91) and OS (HR, 0.70; 95% CI, 0.51–0.95) vs TACE. STRIDE ± L + TACE showed higher 24-mo OS rate vs TACE (Table). The incidence of treatment-related AEs of maximum grade 3/4 was 62.7% for STRIDE + L + TACE, 48.6% for STRIDE + TACE, and 18.6% for TACE. Conclusions: STRIDE + L + TACE significantly improved PFS vs TACE. At interim analysis, with ≤45% maturity, a positive trend for OS with STRIDE ± L + TACE vs TACE was observed. STRIDE + TACE also improved PFS vs TACE. AEs were aligned with known safety profiles of individual therapies. The EMERALD-3 results support STRIDE ± L + TACE as potential new treatment option in unresectable eeHCC. Clinical trial information: NCT05301842 . STRIDE + L + TACE(n=293) TACE(n=292) STRIDE + L + TACE(n=first 175) STRIDE + TACE(n=175) TACE (n=first 175) PFS (95% CI) HR 0.70 (0.57–0.86)p = 0.0007* 0.71 (0.56–0.91) † Maturity 64%* 75% † Median, mo 13.0 (12.2–16.7)* 9.8 (8.0–11.4)* 13.1 (11.0–17.7) † 12.9 (10.2–15.9) † 8.1 (6.5–10.2) † OS (95% CI) HR 0.84 (0.65–1.09) p = 0.1814 † 0.70 (0.51–0.95) † Maturity 40% † 45% † Median, mo 39.5 (34.1–NC) † 34.7 (28.8–NC) † 39.5 (32.6–NC) †
Abou-Alfa et al. (Wed,) studied this question.