Dr Akkus on the Second-Line Evidence Gap in Advanced HCC

We know that the TKIs work after sorafenib, and we have multiple first-line, immunotherapy-based options. But what we don't have randomized evidence for is which TKI to use after first-line treatment. Currently, we don't have a second-line randomized controlled trial in HCC at all.

In an interview with OncLive, Erman Akkus, MD, a medical oncologist at Ankara University, discussed the unresolved question of second-line therapy in advanced hepatocellular carcinoma (HCC) and the role of reconstructed patient-level data in informing it.

The first-line landscape now features several immunotherapy-based standards — atezolizumab plus bevacizumab, the STRIDE regimen of tremelimumab plus durvalumab, and, since its April 2025 FDA approval, nivolumab plus ipilimumab. Second-line management is far less settled: agents such as regorafenib, cabozantinib, and ramucirumab were established after sorafenib and have not been prospectively tested after modern immunotherapy combinations, leaving that setting without randomized evidence.

Akkus noted that clinicians nonetheless treat beyond the first line using real-world and single-arm phase 2 data, since no randomized second-line trial exists. He estimated that a substantial share of patients never reach second-line therapy — some are lost during first-line treatment, and others lack the performance status or hepatic reserve to be eligible. Advanced HCC still carries a median overall survival of roughly 19 months, he said.

To interrogate the available data, Akkus's group used reconstructed individual patient data, which reproduces patient-level survival from published Kaplan-Meier curves and allows analyses — including at specific time points — that pooled summary estimates cannot support. In their second-line analysis, lenvatinib appeared to have the highest efficacy and sorafenib the lowest following first-line immunotherapy, though he characterized the findings as exploratory and hypothesis-generating rather than definitive.

Absent a clinical trial, Akkus said he favors lenvatinib where available — often off-label, as it is not approved in this setting in many countries — followed by regorafenib or cabozantinib, with local drug availability frequently the deciding factor.