Lenvatinib Plus Pembrolizumab in Hepatocellular Carcinoma: LEAP-002 Fails to Meet Co-primary Endpoints

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The highly anticipated final analysis of the phase III LEAP-002 trial failed to meet expectations, as first-line treatment with lenvatinib plus pembrolizumab did not significantly improve outcomes in unresectable advanced hepatocellular carcinoma. Both progression-free survival and overall survival were numerically improved with the combination, vs lenvatinib alone, but the statistical thresholds for these co-primary endpoints were not met. The LEAP-002 investigators reported these results at the European Society for Medical Oncology (ESMO) Congress 2022.1

“This study did not meet its prespecified statistical significance for overall or progression-free survival. Lenvatinib and pembrolizumab achieved a median overall survival of 21.2 months, consistent with the phase Ib study [Study 116/KEYNOTE-524],2” said Richard S. Finn, MD, Professor of Medicine at the Geffen School of Medicine at the University of California, Los Angeles. “However, median survival with lenvatinib alone was 19.0 months, significantly longer than the 13.6 months we saw in REFLECT.3 This supports the role of lenvatinib monotherapy as a standard front-line treatment in advanced liver cancer.”

Richard S. Finn, MD

Richard S. Finn, MD

The REFLECT trial showed lenvatinib to be noninferior to sorafenib for overall survival in the first-line setting, leading to its approval in this setting. Although in LEAP-002 the combination did not yield a significant difference vs lenvatinib alone, single-agent lenvatinib achieved the longest survival yet with a tyrosine kinase inhibitor in this cancer, the authors pointed out.

About LEAP-002

Based on preclinical data suggesting a synergistic effect in combining a multikinase inhibitor such as lenvatinib with an immunotherapeutic, the LEAP-002 study was designed for patients with previously untreated advanced hepatocellular carcinoma. The study randomly assigned 790 patients to receive first-line lenvatinib (8 or 12 mg/d depending on body weight) plus pembrolizumab (200 mg intravenously every 3 weeks) or lenvatinib plus placebo. Lenvatinib was administered until progressive disease or unacceptable toxicity, whereas pembrolizumab and placebo were given for up to 35 cycles.

All patients had no prior systemic therapy for advanced disease, and tumors were not amenable to curative therapy. In addition, study patients had Child-Pugh class A disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no main portal vein invasion. Patients underwent an esophagogastroduodenoscopy within 3 months of randomization.

Favorable Trends Observed 

In the final analysis, after a median follow-up of 17.6 months, median progression-free survival was 8.2 months with lenvatinib plus pembrolizumab vs 8.0 months with lenvatinib plus placebo (hazard ratio [HR] = 0.867; P = .0466), which missed the statistical threshold for progression-free survival of P = .002. At 12 months, 34.1% and 29.3%, respectively, were free of disease progression, as were 16.7% and 9.3%, respectively, at 24 months.

After a median follow-up of 32.1 months, median overall survival was 21.2 months vs 19.0 months, respectively (HR = 0.840; P = .0227), also missing the statistical threshold of P = .0185. At 24 months, the overall survival rate was 43.7% vs 40.0%, respectively, for the combination vs the lenvatinib plus placebo, Dr. Finn reported.

Subgroup analysis showed the combination regimen was universally favored. The trend was especially strong for patients with high-risk features, such as macrovascular invasion or extrahepatic spread (HR = 0.78) and elevated alpha-fetoprotein levels (HR = 0.67).

Response was determined by blinded independent central review. By Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, the combination induced an overall response rate of 26.1%, compared with 17.5% with lenvatinib plus placebo, and a disease control rate of 81.3% vs 78.4%, respectively. By modified RECIST v1.1, the response rate was 40.8% vs 34.1%, respectively, and the disease control rates were 84.3% and 83.2%. Complete responses were observed in 1.5% of each arm. Median duration of response in this final analysis was 16.1 vs 10.4 months, respectively, by RECIST v1.1 and 11.2 vs 8.5 months, respectively, by modified RECIST.

Dr. Finn noted that subsequent treatment may have impacted overall survival: “The treatment landscape has changed significantly for advanced liver cancer in the past several years, and, therefore, there may be an impact of treatment post disease progression,” he said. Patients in both arms received some systemic treatment after disease progression [174 on the combination and 208 on the control arm], mostly with a tyrosine kinase inhibitor or an anti-VEGF–focused agent. After disease progression, 23% of the control arm and 14% of the experimental arm received some type of immunotherapy.


  • The phase III LEAP-002 trial evaluated lenvatinib plus pembrolizumab vs lenvatinib plus placebo in previously untreated, unresectable advanced hepatocellular carcinoma.
  • The combination did not improve progression-free or overall survival significantly, thus the co-primary endpoints were not met.
  • The control arm performed well, however, yielding a median overall survival of 19 months, and favorable trends were observed with the combination.
  • The benefit of single-agent lenvatinib as a first-line treatment was confirmed in this final analysis.

Safety Profile

“The toxicity was consistent with what we know about this combination as well as the single agent,” he said. Grade 3–5 adverse events occurred in 62.5% of patients receiving lenvatinib plus pembrolizumab and 57.5% of patients receiving lenvatinib plus placebo. The most common immune-mediated toxicity in both arms was hypothyroidism (42.3% vs 39.5%, respectively). Discontinuation of any treatment was noted for 18.0% of the combination arm compared with 10.6% of the control arm. 

DISCLOSURE: Dr. Finn reported financial relationships with AstraZeneca, Bayer, Bristol Myers Squibb, CStone, Eisai, Exelixis, Merck Sharp & Dohme, Eli Lilly, Roche/Genentech, and Pfizer.


1. Finn RS, Kudo M, Merle P, et al: Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line therapy for advanced hepatocellular carcinoma. ESMO Congress 2022. Abstract LBA34. Presented September 10, 2022.

2. Finn RS, Ikeda M, Zhu AX, et al: Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol 38:2960-2970, 2020.

3. Kudo M, Finn RS, Qin S, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 391:1163-1173, 2018.


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