LAUSR

4095 Background: LEAP-002 was a randomized, double-blind, phase 3 study (NCT03713593) that was conducted to evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab versus lenvatinib plus placebo in participants with advanced hepatocellular carcinoma (HCC). The study did not meet its primary end points of OS at final analysis and PFS at interim analysis. After a median study follow-up of 43.6 months, OS, PFS, and ORR remained consistent with the primary efficacy analysis (OS: HR, 0.84 [95% CI, 0.71-0.98]; PFS: HR, 0.81 [95% CI, 0.69-0.95]; ORR, 26.3% vs 17.5%); no new safety signals were observed. Here, we present results based on an additional 15 months of follow-up. Methods: Eligible participants with advanced HCC were randomly assigned 1:1 to receive lenvatinib (8 mg/day if bodyweight [BW] < 60 kg; 12 mg/day if BW ≥60 kg) plus pembrolizumab (200 mg IV Q3W) or lenvatinib plus placebo. Dual primary end points were OS and PFS (per RECIST v1.1 by BICR). Secondary end points included ORR and DOR, both per RECIST v1.1 by BICR, and safety. The database cutoff was September 24, 2024. Results: 794 participants were randomly assigned to receive lenvatinib plus pembrolizumab (n = 395) or lenvatinib plus placebo (n = 399). Median study follow-up was 59.2 mo (range, 52.9-68.3). The HR for OS was 0.80 (95% CI, 0.69-0.94; median, 21.1 months with lenvatinib plus pembrolizumab vs 19.0 months with lenvatinib plus placebo). 60-month OS rates were 19.7% with lenvatinib plus pembrolizumab versus 10.7% with lenvatinib plus placebo. Grade 3-5 treatment-related adverse event (AE) rates were 62.8% with lenvatinib plus pembrolizumab and 58.0% with lenvatinib plus placebo. No additional deaths due to treatment-related AEs were reported since the final analysis (database cutoff, June 21, 2022). Overall, 47.3% of participants treated with lenvatinib plus pembrolizumab versus 56.1% of participants treated with lenvatinib plus placebo received subsequent systemic therapy (TKI/VEGF, 38.5% vs 42.6%; immunotherapy, 17.2% vs 26.8%; chemotherapy, 5.3% vs 4.0%); 21.5% versus 25.6% received subsequent liver-directed therapy (locoregional therapy, 20.0% vs 23.8%; surgery, 2.8% vs 2.8%). Conclusions: The LEAP-002 study did not meet its primary end points; however, with a long-term follow-up of 5 years, almost twice as many participants randomly assigned to receive lenvatinib plus pembrolizumab versus lenvatinib plus placebo were alive at database cutoff; no new safety signals were observed. Clinical trial information: NCT03713593 .