LEAP-002: IO/VEGF Versus IO/IO Versus IO/TKI

Josep M. Llovet, MD, Mount Sinai, and Richard S. Finn, MD, University of California, Los Angeles, consider the available data and how LEAP-002 adds to the debate around IO/VEGF versus IO/IO versus IO/TKI for treatment of advanced hepatocellular carcinoma. Additionally, in the context of lenvatinib plus pembrolizumab, they point to LEAP-012 as having the potential to keep this combination approach “alive.”

Dr. Finn: The other noteworthy aspect is that this was one of the initial placebo-controlled, double-blind studies in many years. Most other studies, in contrast to sorafenib, were open label, introducing different management concepts for investigators. Currently approved frontline treatments include single-agent lenvatinib, single-agent sorafenib, atezolizumab-bevacizumab IO, pure VEGF, durvalumab and tremelimumab (CTLA4 and PD1), and LEAP-002 with lenvatinib and pembrolizumab. Additionally, there is positive data from a study with rivoceranib and cabiralizumab, though not globally approved. How do you approach scientifically the combination of IO and VEGF versus IO/IO and IO and TKI? LEAP-002 shows promise, but the patient response might differ from IO/IO and IO/VEGF. What are your thoughts on this?

Dr. Llovet: This is a complex question. Regimens that incorporate VEGF, such as IMbrave050 and IMbrave150, have shown positive outcomes when combined with IOs. Something synergistic or additive seems to be happening, as indicated by the data. Bevacizumab may act as an immunomodulator, enhancing the checkpoint inhibitor’s effect and exhibiting antitumoral activity. This effect is evident early on in the survival curve.

On the other end, we have durvalumab treatment, where the curves are initially identical and then start separating after the first year. Durvalumab responders show long-lasting responses, with a reported 4-year survival of 25% compared to sorafenib’s 15%. This suggests a unique mechanism, leading to the ESMO5 score.

TKIs fall in between. They enhance IO activity, but capturing this effect, at least with lenvatinib, has been challenging. The combination is impactful, but there’s a mechanistic complexity. Cabozantinib, for instance, showed a counterintuitive decrease in objective response. Three main mechanisms emerge: IO/IO’s impact is seen late with responders, bevacizumab widens the benefit to a broader population, and IO/TKIs enhance activity, though mechanistic understanding is incomplete.

Dr. Finn: Closing the discussion, you mentioned the positive press release showing progression-free survival benefits with durvalumab and bevacizumab in patients receiving TACE. In the context of LEAP-002 and this positive data, what are your thoughts on the ongoing LEAP-012 study, which has a similar design for intermediate patients (TACE plus lenvatinib and pembrolizumab vs. TACE alone or TACE with placebo)? Is this combination still “alive?”

Dr. Llovet: We only have a press release, and bevacizumab is in the mix, emphasizing progression-free survival. In the intermediate setting, where the significance of progression-free survival is less established, the question remains. LEAP-012 shares a single primary endpoint to this trial: progression-free survival. The combination has potential, given LEAP-002’s results and the absence of imatinib in the control arm. However, the small sample size requires a substantial delta and benefit magnitude to demonstrate the advantages convincingly. Despite challenges, I believe it has a chance.

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