LEAP-002: Lenvatinib Plus Pembrolizumab for First-Line Advanced HCC?

Josep M. Llovet, MD, Mount Sinai, and Richard S. Finn, MD, University of California, Los Angeles, provide a high-level understanding of the LEAP-002 study looking at lenvatinib plus pembrolizumab in the first-line setting for advanced hepatocellular carcinoma. Why were the results disappointing, and was study design a contributing factor?

Dr. Finn: Hi Dr. Llovet, thank you for joining me today to discuss the LEAP-002 study, which evaluated lenvatinib and pembrolizumab versus lenvatinib and placebo in advanced liver cancer patients. The primary endpoint was to improve overall survival in Child-Pugh A patients. Can you provide more background on the study and its design or selection criteria?

Dr. Llovet: This is a frontline trial for advanced HCC, where the majority of patients have advanced disease, including portal vein invasion, lymph node involvement, metastasis, or ECOG 0-10. About 20% of patients at the intermediate stage progress to local regional therapies.

The trial was randomized (1:1), with patients receiving pembrolizumab for 3 weeks plus lenvatinib based on body weight (8 or 12 milligrams) versus lenvatinib with placebo in a double-blind fashion. Stratification included certification factors like high FP, geographical region eco, and others.

In summary, lenvatinib plus pembrolizumab showed a positive outcome with a 21.2-month median survival. Surprisingly, lenvatinib alone had a median survival of 19 months, higher than the expected 13 months. The trial had two co-primary endpoints: overall survival and progression-free survival. However, due to a split alpha, the trial was negative with a P-value of .023.

Dr. Finn: This is a disappointing outcome, especially considering the promising phase 1B that led to this study. LEAP-002 results, despite a high objective response rate and similar survival over 20 months, were negative due to statistical reasons. Also, the study did not include patients with main portal vein invasion, a factor present in some studies. Looking back, would you design the study differently?

Dr. Llovet: Yes, as you mentioned, there are reasons for this negative outcome. The choice of sorafenib as the control arm might be a factor, as it has a consistent 15-15.5 month median survival in frontline therapy. Lenvatinib, in comparison, had a 19-month median survival.

Another issue was the split alpha, impacting the trial’s interpretation. For future trials, I would stick to overall survival as the primary endpoint.

Additionally, lenvatinib’s exposure time was 9 months, possibly due to physicians’ familiarity with the drug, unlike in the REFLECT trial, where it was first introduced for HCC. These factors, along with slight differences in vascular invasion and population characteristics, contributed to the trial’s negative results.

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