Lenvatinib plus pembrolizumab versus lenvatinib alone as first-line therapy for advanced hepatocellular carcinoma: Longer-term efficacy and safety results from the phase 3 LEAP-002 study.
Authors: Finn Richard S. , Kudo Masatoshi , Merle Philippe , Meyer Tim , Qin Shukui , Ikeda Masafumi , Xu Ruocai , Edeline Julien , Ryoo Baek-Yeol , Ren Zhenggang , Cheng Ann-Lii , Galle Peter R. , Kaneko Shuichi , Kumada Hiromitsu , Wang Anran , Mody Kalgi , Dubrovsky Leonid , Siegel Abby B. , Llovet Josep M 
Published: January 2024

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Background: The randomized, double-blind, phase 3 LEAP-002 study (NCT03713593) was conducted to evaluate the efficacy and safety of first-line (1L) lenvatinib (len) + pembrolizumab (pembro) vs len + placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (HCC). After a median follow-up (randomization to data cutoff) of 32.1 mo, LEAP-002 did not meet its primary end points of OS at final analysis (median, 21.2 vs 19.0 mo; HR, 0.840; 95% CI, 0.708-0.997) and PFS at interim analysis 1 (IA1; median, 8.2 vs 8.0 mo; HR, 0.867; 95% CI, 0.734-1.024). However, the study highlighted the activity of len + pembro and, given the late separation of Kaplan-Meier survival curves for OS and PFS between treatment arms from 12 mo onwards, outcomes with extended follow-up are of interest. We report results after 12 mo of additional follow-up (median 43.6 mo). Methods: Eligible pts with advanced HCC were randomized 1:1 to len (8 mg/day if bodyweight [BW] <60 kg; 12 mg/day if BW ≥60 kg) + pembro (200 mg IV Q3W) or len + pbo. 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. Data cutoff was June 6, 2023. Results: 794 pts were randomly assigned to receive len + pembro (n = 395) or len + pbo (n = 399). Median follow-up was 43.6 mo (range, 37.3-52.6), and treatment was ongoing in 25 (3.2%) pts. Median OS was 21.1 mo with len + pembro vs 19.0 mo with len + pbo (HR, 0.836; 95% CI, 0.713-0.981). OS rates for len + pembro vs len + pbo were 43.4% vs 40.0% at 24 mo, 32.7% vs 24.3% at 36 mo, and 22.4% vs 15.3% at 48 mo. Median PFS was 8.2 mo with len + pembro vs 8.1 mo with len + pbo (HR, 0.810; 95% CI, 0.692-0.949). PFS rates for len + pembro vs len + pbo were 16.4% vs 9.7% at 24 mo and 14.1% vs 3.3% at 36 mo. ORR was 26.3% for len + pembro vs 17.5% for len + pbo. Median DOR was 16.6 mo (range, 2.0+ to 45.3+) for len + pembro vs 10.4 mo (range, 1.9 to 37.0+) for len + pbo. Grade 3-5 treatment-related adverse event (TRAE) rates were 62.8% in the len + pembro arm and 58.0% in the len + pbo arm. No additional deaths due to TRAEs were reported. The most common TRAEs of any grade in the len + pembro vs len + pbo arms were hypertension (43.8% vs 46.8%), diarrhea (40.8% vs 34.2%), and hypothyroidism (40.0% vs 35.9%). Overall, 46.6% vs 55.4% of pts received ≥1 poststudy systemic anticancer treatment. Conclusions: With an additional 12 mo of follow-up, the LEAP-002 primary end points of OS and PFS for len + pembro vs len + pbo remained consistent with the primary efficacy analyses; no new safety signals were observed. The median OS of 19.0 mo with len monotherapy continues to support its role as a standard-of-care treatment in 1L advanced HCC. The activity of len + pembro for pts with advanced HCC observed in this study supports the evaluation of TACE ± len + pembro for intermediate-stage HCC in the ongoing phase 3 LEAP-012 study (NCT04246177). Clinical trial information: NCT03713593 .