TACE Plus Lenvatinib/Pembrolizumab Boosts PFS in Unresectable Liver Cancer

"Based on these data, lenvatinib plus pembrolizumab combined with TACE could be a new treatment option for patients with unresectable, non-metastatic [HCC],” according to the study authors.

Combining transarterial chemoembolization (TACE) with lenvatinib (Lenvima) and pembrolizumab (Keytruda) produced a significant and clinically meaningful progression-free survival (PFS) improvement vs TACE alone in those with unresectable, non-metastatic hepatocellular carcinoma (HCC), according to data from the phase 3 LEAP-012 study (NCT04246177) published in The Lancet.

Based on blinded independent central review (BICR) per RECIST v1.1 criteria, the median PFS was 14.6 months (95% CI, 12.6-16.7) with the lenvatinib/pembrolizumab combination vs 10.0 months (95% CI, 8.1-12.2) with TACE plus placebo (HR, 0.66; 95% CI, 0.51-0.84; P = .0002). Additional findings showed that the PFS benefit in the combination arm was generally comparable across prespecified subgroups.

The overall survival (OS) rate at 24 months was 75% (95% CI, 68%-80%) in the TACE plus lenvatinib/pembrolizumab arm and 69% (95% CI, 62%-74%) in the TACE/placebo arm (HR, 0.80; 95% CI, 0.57-1.11; P = .087). Investigators noted that OS data had not reached maturity at the time of the first interim analysis.

The lenvatinib/pembrolizumab combination yielded an objective response rate (ORR) of 47% (95% CI, 40%-53%) vs 33% (95% CI, 27%-40%) with TACE/placebo, resulting in a difference of 14.6% (95% CI, 5.9%-23.1%; P = .0005) between arms. Additionally, the median duration of response (DOR) was 12.6 months (95% CI, 10.9-16.5) and 10.7 months (95% CI, 8.3-18.4) in each respective arm, and the median time to progression was 16.6 months (95% CI, 14.6-18.7) vs 10.3 months (95% CI, 8.2-12.5), respectively (HR, 0.59; 95% CI, 0.46-0.77; P <.0001).

“At this first interim analysis of LEAP-012, the primary end point was met, with a significant improvement in [PFS] for [patients] who received TACE with lenvatinib plus pembrolizumab compared with placebo, with early separation at the first 9-week imaging that continued beyond 30 months,” Masatoshi Kudo, MD, PhD, a professor and chairman of the Department of Gastroenterology and Hepatology at Kindai University in Osaka, Japan, and coauthors wrote. “Based on these data, lenvatinib plus pembrolizumab combined with TACE could be a new treatment option for patients with unresectable, non-metastatic [HCC].”

In the double-blind LEAP-012 study, 480 patients were randomly assigned 1:1 to receive TACE plus lenvatinib and pembrolizumab (n = 237) or TACE plus dual placebo (n = 243). Investigators administered oral lenvatinib at 12 mg if the patient had a weight of 60 kg or higher or 8 mg if they had a body weight of less than 60 kg once per day. Additionally, patients received pembrolizumab at 400 mg intravenously once every 6 weeks.

The trial’s primary end points were PFS per RECIST v1.1 guidelines and OS. Secondary end points included ORR, DOR, disease control rate, time to progression, PFS per modified RECIST (mRECIST) criteria, and safety.

Patients 18 years and older with confirmed unresectable, non-metastatic HCC and a predicted life expectancy of 3 months or longer were eligible for enrollment on the trial. Additional requirements for study entry included having an ECOG performance status of 0 or 1 and Child-Pugh class A disease within a week of beginning study treatment.

The median age was 65 years in the lenvatinib/pembrolizumab plus TACE arm and 66 years in the placebo/TACE arm. In each respective arm, most patients were male (81% vs 85%), Asian (71% vs 74%), had an ECOG performance status of 0 (91% vs 88%), and had Barcelona Clinic Liver Cancer stage B disease (57% vs 60%).

Based on mRECIST criteria, the median PFS was 14.5 months (95% CI, 12.2-16.8) with lenvatinib/pembrolizumab plus TACE vs 8.5 months (95% CI, 8.1-12.3) with TACE/placebo (HR, 0.64; 95% CI, 0.50-0.83). Additionally, the ORR per mRECIST guidelines in each arm was 71% (95% CI, 65%-77%) vs 50% (95% CI, 43%-56%), and the median DOR was 14.6 months (95% CI, 12.3-18.2) vs 12.5 months (95% CI, 10.3-14.7).

The rates of any-grade adverse effects (AEs) were more than 99% (n = 236/237) of the lenvatinib/pembrolizumab plus TACE arm and 97% (n = 233/241) of the TACE/placebo arm. Additionally, treatment-related AEs (TRAEs) affected 99% (n = 234/237) and 85% (n = 204/241) of each arm, which included hypertension (51% vs 16%) and proteinuria (40% vs 9%). Grade 3 or higher TRAEs were reported in 71% and 32% of patients in each arm, the most common of which included hypertension (24% vs 7%) and platelet count decreased (11% vs 6%).

Clinically significant AEs occurred in 97% (n = 230/237) of the lenvatinib/pembrolizumab plus TACE arm compared with 70% (n = 168/241) in the TACE/placebo arm. The rates of grade 3 or higher clinically significant AEs were 59% and 29%, respectively. Additionally, the most common any-grade clinically significant AEs in each arm included hepatoxicity (71% vs 51%), hypertension (54% vs 21%), and proteinuria (43% vs 10%).

Reference

Kudo M, Ren Z, Guo Y, et al. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet. 2025:S0140-6736(24)02575-3. doi:10.1016/S0140-6736(24)02575-3.