Lenvatinib, Pembrolizumab, and TACE Demonstrate Significant Progression-Free Survival in Intermediate-Stage Hepatocellular Carcinoma

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A combined treatment regimen of lenvatinib (Lenvima), pembrolizumab (Keytruda), and transarterial chemoembolization (TACE) significantly outperformed dual placebo and TACE in improving progression-free survival (PFS) for patients with intermediate-stage hepatocellular carcinoma (HCC). These findings are based on data from the phase 3 LEAP-012 clinical study (NCT04246177) that were presented at the 2024 ESMO Congress^1.

At a data cutoff date of January 30, 2024, the median PFS per RECIST v1.1 by blinded independent central review (BICR) was 14.6 months (95% CI, 12.6-16.7) and 10.0 months (95% CI, 8.1-12.2) in the lenvatinib/pembrolizumab/TACE and dual placebo/TACE arms, respectively. In the respective arms, events occurred in 132 (55.7%) and 154 (63.4%) patients.

At 12 months, the PFS was 62.2% and 43.4% in the lenvatinib/pembrolizumab/TACE and dual placebo/TACE arms, respectively. At 18 months, the PFS was 39.1% and 27.9% in the respective arms (HR, 0.66; 95% CI, 0.51-0.84; P = .0002).

“The first interim analysis is the final analysis for PFS. The initial one-sided alpha of 0.25 allocated to PFS passed to OS if progression-free survival is statistically significant,” Josep M. Llovet, MD, PhD, director of the Liver Cancer Program and professor of Medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai in New York, said during the presentation.

The phase 3, double-blinded, active-controlled, multicenter, randomized study included 480 patients with intermediate-stage HCC to randomized to receive lenvatinib/pembrolizumab/TACE (n = 237) or dual placebo/TACE (n = 243). Of the two respective arms, 237 and 241 patients were treated.

Patients in the lenvatinib/pembrolizumab/TACE arm received 12 mg (body weight [BW] ≥ 60 kg) or 8 mg (BW < 60 g) of lenvatinib orally once daily, 400 mg of intravenous pembrolizumab on an every 6 weeks dosing schedule for up to 2 years, and TACE for 2 to 4 weeks after the start of systemic therapy with a maximum of 2 treatments per tumor and no more than 1 treatment per month.

Patients in the dual placebo plus TACE arm received placebo intravenously on an every 6 weeks dosing schedule for up to 2 years, placebo orally once per day, and TACE for 2 to 4 weeks after the start of systemic therapy with a maximum of 2 treatments per tumor and no more than 1 treatment per month.

Key eligibility criteria included confirmed HCC not amenable to curative treatment, at least 1 measurable HCC lesion per RECIST v1.1, all lesions treatable with TACE in 1 or 2 sessions, no portal vein thrombosis or extrahepatic disease, Child-Pugh liver class A, and an ECOG performance status of 0 or 1. Stratification factors included study site, alpha fetoprotein (≤ 400 ng/mL vs > 400 ng/mL), ALBI grade 1 vs 2 or 3, tumor burden score (≤ 6 vs > 6 but ≤ 12 vs > 12), and an ECOG status of 0 or 1.

Dual primary end points were PFS and overall survival (OS); secondary end points were objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to progression (TTP), PFS per mRECIST by BICR, and safety.

At the data cutoff, the OS at 12 months was 89.0% and 83.1% in the lenvatinib/pembrolizumab/TACE and dual placebo/TACE arms, respectively; at 24 months, the OS was 74.6% and 68.6% in the respective arms. Events occurred in 29.1% (n = 69) and 33.7% (n = 82) of patients from the respective arms (HR, 0.80; 95% CI, 0.57-1.11; P = .0867).

The ORR per RECIST v1.1 by BICR was 46.8% (95% CI, 40.3%-53.4%) and 33.3% (95% CI, 27.4%-39.6%) in the lenvatinib/pembrolizumab/TACE and dual placebo/TACE arms, respectively (difference = 14.6%; 95% CI, 5.9%-23.1%; nominal P = .0005). In the lenvatinib/pembrolizumab/TACE arm, the complete response, partial response, stable disease, and progressive disease rates were 3.4% (95% CI, 1.5%-6.5%), 43.5% (95% CI, 37.1%-50.0%), 42.6% (95% CI, 36.2%-49.2%), and 6.8% (95% CI, 3.9%-10.7%), respectively. In the dual placebo/TACE arm, the complete response, partial response, stable disease, and progressive disease rates were 4.1% (95% CI, 2.0%-7.4%), 29.2% (95% CI, 23.6%-35.4%), 48.1% (95% CI, 41.7%-54.6%), and 14.8% (95% CI, 10.6%-19.9%), respectively.

The median DOR was 12.6 months (range, 1.3+ to 39.1+ months) and 10.7 months (range, 2.0+ to 39.5+ months) in the lenvatinib/pembrolizumab/TACE and dual placebo/TACE arms, respectively. The DCR was 89.5% (95% CI, 84.8%-93.1%) and 81.5% (95% CI, 76.0%-86.2%), respectively.

Regarding safety, treatment-related adverse events (TRAEs) occurred in 98.7% (n = 234) and 84.6% (n = 204) of patients in the lenvatinib/pembrolizumab/TACE and dual placebo/TACE arms, respectively; grade 3 or 4 TRAEs occurred in 71.3% (n = 169) and 31.1% (n = 75). Serious AEs occurred in 33.3% (n = 79) and 12.4% (n = 30) of patients, with AEs leading to treatment discontinuation in 8.4% (n = 20) and 1.2% (n = 3). Grade 5 AEs occurred in 1.7% (n = 4) and 0.4% (n = 1). The most common TRAEs were hypertension, proteinuria, increased ALT, increased ALT, decreased platelet count, hypothyroidism, increased blood bilirubin, decreased appetite, PPE, diarrhea, decreased weight, fatigue, dysphonia, and post-embolization syndrome.

“The safety profile of lenvatinib plus pembrolizumab was manageable and consistent with the known safety profiles of lenvatinib, pembrolizumab and TACE. No new safety concerns were identified,” Llovet concluded. “Overall, treatment with lenvatinib, pembrolizumab and TACE may be a new option for patients with intermediate-stage hepatocellular carcinoma.”

REFERENCE:

Llovet J, Finn R, Ren ZG, et al. LEAP-012: A Phase 3 Study of Lenvatinib Plus Pembrolizumab Plus Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA3.