Background: TIS is a monoclonal antibody with high affinity and specificity for programmed cell death protein 1. In the phase 3 RATIONALE-301 trial (NCT03412773), TIS demonstrated non-inferior OS versus sorafenib (SOR) as 1L monotherapy for unresectable HCC (median [m] OS 15.9 [TIS] vs 14.1 [SOR] months [mo]; hazard ratio [HR] 0.85), with a favorable safety profile. Certain biomarkers are potential prognostic factors and may impact OS in 1L treatment of unresectable HCC; this exploratory analysis examined the effect of albumin-bilirubin (ALBI) grade, platelet count, platelet-lymphocyte ratio (PLR), and neutrophil-lymphocyte ratio (NLR) as predictors of OS in RATIONALE-301. Methods: Systemic therapy-naïve adults with histologically confirmed HCC (Barcelona Clinic Liver Cancer Stage C or Stage B that was not amenable to or progressed after loco-regional therapy; Child-Pugh A), with ≥1 measurable lesion per RECIST v1.1, and an ECOG performance status ≤1 were randomized 1:1 to receive TIS (200 mg IV Q3W) or SOR (400 mg orally BID) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS. Results: Overall, 674 pts were randomized (TIS n=342; SOR n=332). At data cutoff (July 11, 2022), minimum study follow-up was 33 mo. Demographic and baseline characteristics for biomarkers were generally balanced across arms. Numerically longer (≥2 mo) mOS was observed in biomarker subgroups ALBI grade 1 vs 2 and NLR ≤3 vs >3 with TIS or SOR, and PLR ≤141 vs >141 with TIS. Both platelet count threshold subgroups were accompanied by a smaller difference (<2 mo) in mOS between biomarker cutoffs, which may indicate limited prognostic value for this biomarker. TIS also demonstrated numerically longer OS versus SOR in the same subgroup categories: ALBI grade 1, PLR ≤141, and NLR ≤3. Conclusions: This analysis suggests that ALBI grade, PLR, and NLR could have prognostic value for OS, irrespective of treatment. TIS demonstrated numerically improved mOS compared with SOR for PLR ≤141 and NLR ≤3, suggesting higher benefit for pts with a more favorable balance between systemic inflammation and immunity. Clinical trial information: NCT03412773.

No., number. Intent-to-treat analysis set. *Threshold used in RATIONALE-208.