For patients fighting hepatocellular carcinoma (HCC), the current standard first-line treatment is typically immuno-oncology, specifically atezolizumab plus bevacizumab (A+B). But what happens when that treatment fails? The optimal subsequent, or second-line, treatment strategy remains “quite open” and “undefined” in clinical practice.
Now, groundbreaking real-world evidence from the multinational LEVIATHAN study is challenging previous assumptions and offering a solid answer. We recently sat down with Dr. Pasquale Lombardi, a medical oncologist who is completing his PhD at Imperial College, UK, to discuss this vital research in an “Ask the Author” session.
Did you miss the interview? If you are involved in treating advanced HCC, you need to watch the full session. Here is a preview of the revolutionary findings discussed by Dr. Lombardi.
Watch the Full Interview here
The Challenge of Treatment Sequencing
The LEVIATHAN study originated from a prospective maintained international registry, including over 1,000 patients treated with A+B across 26 centers worldwide. Within this framework, LEVIATHAN was designed as an observational cohort study specifically aimed at answering a single, crucial question: What is the optimal second-line therapy after progression on A+B between lenvatinib or sorafenib?
While this was not a randomized trial, the researchers applied propensity score matching—using factors like ECOG, ALBI grade, and response to prior immunotherapy—to minimize imbalances between the two patient groups, providing robust, clinically meaningful data.
The Key Finding: TKIs Are Not Interchangeable
The most important results observed in the study relate to patient survival outcomes. The study compared the efficacy of lenvatinib versus sorafenib after patients progressed on A+B.
The data clearly demonstrated the superiority of lenvatinib:
• Progression-Free Survival (PFS): Lenvatinib showed a median PFS of 5.5 months, compared to 2.6 months in the sorafenib group.
• Overall Survival (OS): The median OS was 11.9 months for the lenvatinib group versus 7.4 months for the sorafenib group.
Crucially, this difference in survival remained statistically significant even after the propensity score matching was applied. For those tracking the entire treatment sequence, the A+B followed by lenvatinib achieved a median OS of 22.4 months, significantly outperforming the A+B followed by sorafenib sequence (14.3 months).
Lenvatinib Works, Even for Resistant Patients
Another major finding discussed by Dr. Lombardi challenges the equivalence of these two TKIs (tyrosine kinase inhibitors). Lenvatinib was found to remain active even in patients who were primarily resistant to the initial immunotherapy (those who never responded to A+B).
In this specific subgroup of patients:
• The disease control rate was around 58% in the lenvatinib group.
• This contrasted sharply with a 29% disease control rate for the sorafenib group.
Guiding Clinical Practice Today
As Dr. Lombardi highlighted in the interview, LEVIATHAN provides what is “probably the most comprehensive real world evidence” comparing these two particular TKIs in the post-immunotherapy setting.
The key message is simple: TKIs are not interchangeable.
Based on these results, lenvatinib should be considered the preferred second-line option after atezolizumab plus bevacizumab over sorafenib, given its superiority in terms of efficacy and disease control rate. While we await results from prospective randomized trials, LEVIATHAN offers a “solid and clinically meaningful rationale” to guide day-to-day clinical practice immediately.
This study is critically important because, as noted during the discussion, a Phase III randomized clinical trial on this specific sequence may never materialize, making this observational data highly valuable.
Watch the full “Ask the Author” session with Dr. Pasquale Lombardi to understand the full design of the LEVIATHAN study, the implications of the survival data, and how these powerful findings are already guiding advanced HCC treatment sequencing.
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Join the Conversation
We invite oncologists, hepatologists, and all specialists in liver cancer management to watch this insightful interview and share your perspectives.