The combination of the VEGF tyrosine kinase inhibitor lenvatinib, the PD-1 inhibitor pembrolizumab, and transarterial chemoembolization (TACE) significantly improved progression-free survival in patients with intermediate-stage hepatocellular carcinoma (HCC) compared with TACE alone, according to data presented at the European Society for Medical Oncology (ESMO) Congress 2024.1
The results of the phase III LEAP-012 study demonstrated a median progression-free survival of 14.6 months for patients receiving the combination therapy compared with 10 months for those receiving placebo plus TACE, representing a 34% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.66, P = .0002). Trial investigators emphasized that these findings may potentially change the standard of care for this patient population.
Josep Llovet, MD, PhD
“The LEAP-012 study showed a clinically meaningful and statistically significant improvement in the primary endpoint of progression-free survival for patients with intermediate-stage HCC who received lenvatinib plus pembrolizumab plus TACE vs dual placebo plus TACE,” said Josep Llovet, MD, PhD, Director of the Liver Cancer Program and Professor of Medicine at the Icahn School of Medicine at Mount Sinai, New York; Professor of Medicine–Hepatic Oncology, University of Barcelona; and Professor of Research-ICREA in the Liver Unit at IDIBAPS-Hospital Clínic of Barcelona. “Treatment with lenvatinib, pembrolizumab, and TACE may be a new option for patients with intermediate-stage HCC, potentially improving outcomes in this challenging disease.”
As Dr. Llovet explained, hepatocellular carcinoma is the most common type of primary liver cancer, with TACE being the standard of care for intermediate-stage disease for the past 20 years. Recent studies have shown median progression-free survival with TACE alone to be approximately 7 to 8 months, with a median overall survival of 26 to 30 months. The combination approach tested in LEAP-012 aims to improve these outcomes by leveraging the synergistic effects of targeted therapy (lenvatinib), immunotherapy (pembrolizumab), and local treatment (TACE).
Study Design
The LEAP-012 study was a randomized, double-blind, placebo-controlled trial that enrolled 480 patients with confirmed HCC confined to the liver, without portal vein thrombosis or extrahepatic disease spread. Patients had Child-Pugh A liver function and an Eastern Cooperative Oncology Group performance status of 0 or 1 and were randomly assigned 1:1 to receive either lenvatinib plus pembrolizumab plus TACE or dual placebo plus TACE for up to 2 years.
The primary endpoints of the study were progression-free survival and overall survival.
Key Outcomes and Safety
At the first interim analysis, with a median follow-up of 25.6 months, the study met its primary progression-free survival endpoint. The progression-free survival benefit was consistent across prespecified subgroups.
Although overall survival data were not mature at the time of this analysis, there was a favorable trend observed in the combination arm, according to Dr. Llovet, with a 2-year survival probability of 74.6% vs 68.6% in the placebo arm (HR = 0.8, P = .086).
The objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was significantly higher in the combination arm (46.8% vs 33.3%, P = .0005). Using modified RECIST, the objective response rate in the combination arm reached 71.3%, with a complete response rate of 56.1%.
Regarding safety, grade 3 and 4 treatment-related adverse events occurred in 71% of patients in the combination arm compared with 31% in the placebo arm. The most common adverse events included hypertension, proteinuria, elevated liver enzymes, hypothyroidism, and postembolization syndrome. Treatment discontinuation as a result of adverse events occurred in 8.4% of patients in the combination arm, with a 1.7% rate of grade 5 toxicity.
“The safety profile of lenvatinib plus pembrolizumab in combination with TACE was manageable and consistent with the known safety profiles of lenvatinib, pembrolizumab, and TACE,” said Dr. Llovet, who noted that no new safety signals were identified.
Overall survival data will be analyzed in future analyses as per the statistical plan, said Dr. Llovet. Further studies may explore this combination in different stages of HCC or in with other treatment modalities, he added.
EXPERT POINT OF VIEW
Angela Lamarca, MD, PhD, MSc
Invited discussant of the LEAP-012 trial was Angela Lamarca, MD, PhD, MSc, of the Department of Medical Oncology, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, in Spain. She called the trial of the combination of lenvatinib and pembrolizumab with transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) a “significant step forward in addressing an area of unmet need in HCC.” Although the results of the study are promising and may lead to a new treatment option, Dr. Lamarca underscored the complexity of HCC management and the need for continued research to optimize patient outcomes.
The LEAP-012 trial demonstrated efficacy in its primary endpoint, showing a statistically significant improvement in progression-free survival (hazard ratio = 0.66). According to Dr. Lamarca, the progression-free survival benefit was consistent across various subgroups, including different etiologies and tumor burden scores. Overall survival data are still immature, she noted, but there is a “promising trend that warrants further follow-up.”
Of note, Dr. Lamarca addressed the question of whether a progression-free survival benefit alone, without a confirmed overall survival benefit, is sufficient to change clinical practice. In the context of intermediate-stage HCC, which is highly heterogeneous, she argued that “a progression-free survival benefit could be clinically meaningful and potentially practice-changing.”
The safety profile of the combination therapy appears manageable, according to Dr. Lamarca, with toxicities consistent with the known profiles of lenvatinib and pembrolizumab. However, she noted, it is important to understand the details of treatment discontinuations, which occurred in 8.4% of patients in the experimental arm.
Dangers of Cross-Trial Comparisons
In comparing LEAP-012 with the recent EMERALD-1 trial (durvalumab plus bevacizumab with TACE), Dr. Lamarca highlighted that both studies have shown positive progression-free survival outcomes in intermediate-stage HCC, which is “encouraging for the field.” However, cross-trial comparisons should be interpreted cautiously, she noted. The LEAP-012 data appear “more robust, with earlier separation of progression-free survival curves and a slightly lower hazard ratio.”
Dr. Lamarca concluded: “The LEAP-012 results support the combination of lenvatinib, pembrolizumab, and TACE as a potential new option for patients with intermediate-stage HCC. The oncology community eagerly awaits mature overall survival data and further studies to address remaining questions in this challenging disease setting.”
DISCLOSURE: Dr. Llovet reported financial relationships with Eisai, Merck Sharp & Dohme, Bristol Myers Squibb, AbbVie, AstraZeneca, Bayer Pharmaceuticals, Exelixis, Genentech, Glycotest, Moderna, Roche, and Sanofi. Dr. Lamarca reported financial relationships with Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath Advanz Pharma, Merck, Incyte, QED, Servier, AstraZeneca, Eisai, Roche, MSD, Nutricia, Boston Scientific, Albireo Pharma, Boehringer Ingelheim, GENFIT, TransThera Biosciences, and Taiho.
REFERENCE
1. Llovet JM, Finn RS, Ren Z, et al: Transarterial chemoembolization with or without lenvatinib + pembrolizumab for intermediate-stage hepatocellular carcinoma: Phase III LEAP-012 study. ESMO Congress 2024. Abstract LBA3. Presented September 14, 2024.
