The latest first-line treatments for advanced liver cancer center on immunotherapy combinations that have replaced older targeted drugs as the standard of care. The most recent FDA approval came in April 2025, when nivolumab with ipilimumab was approved for first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC). This joins two other immunotherapy-based regimens that have reshaped how liver cancer is treated over the past few years.
How Treatment Depends on Stage
Liver cancer treatment isn’t one-size-fits-all. The approach depends heavily on tumor size, how many tumors are present, whether the cancer has spread, and how well the liver itself is functioning. For people with a single small tumor and healthy liver function, surgery to remove the tumor remains the first choice. Recurrence after surgery is common, though: 50 to 70% of patients see their cancer return within five years.
Liver transplantation is considered when surgery isn’t feasible due to poor liver function, portal hypertension (high blood pressure in the liver’s blood vessels), or multiple tumors. For people with very early-stage disease who aren’t transplant candidates, ablation (destroying the tumor with heat or cold) is an alternative to surgery.
When cancer is more advanced but still confined to the liver, locoregional therapies that target the tumor directly through the blood supply are the main option. Once cancer spreads beyond the liver or invades major blood vessels, systemic therapies (drugs that treat the whole body) become the focus. And for patients whose liver function has significantly declined, the priority shifts to supportive care regardless of tumor stage.
First-Line Immunotherapy Combinations
Three immunotherapy-based regimens now form the front line for advanced liver cancer that can’t be surgically removed.
The combination of atezolizumab plus bevacizumab was the first to prove superior to sorafenib, the older drug that had been the standard for over a decade. In the landmark IMbrave150 trial, this combination reduced the risk of death by 42% compared to sorafenib. At one year, 67.2% of patients on the combination were alive versus 54.6% on sorafenib. Median progression-free survival was 6.8 months compared to 4.3 months. This pairing works by combining an immune checkpoint inhibitor (which helps the immune system recognize cancer cells) with a drug that cuts off blood supply to tumors.
The STRIDE regimen pairs two immune checkpoint inhibitors: a single dose of tremelimumab followed by ongoing durvalumab. In the HIMALAYA trial, this combination achieved a median overall survival of 16.43 months and reduced the risk of death by 22% compared to sorafenib. At three years, 30.7% of patients were still alive. This regimen is particularly notable because it doesn’t include a blood-vessel-targeting drug, making it an option for patients who can’t safely receive those medications, such as people at high risk of bleeding from esophageal varices.
The newest addition, approved in April 2025, is nivolumab combined with ipilimumab for first-line use. This dual checkpoint inhibitor combination targets two different braking mechanisms on immune cells simultaneously. It had previously been approved only for patients who had already tried other treatments.
What Happens After First-Line Treatment Fails
When cancer progresses despite first-line immunotherapy, several targeted drugs are available as second-line options. These are tyrosine kinase inhibitors, which block signals that tumors use to grow and build blood vessels.
Recent data from the LEVIATHAN study found that lenvatinib performed better than sorafenib when used after the atezolizumab-bevacizumab combination. Patients who received lenvatinib as their second treatment had a median progression-free survival of 5.5 months compared to 2.6 months with sorafenib. When measured from the start of first-line therapy, the full treatment sequence with lenvatinib achieved a median overall survival of 22.4 months versus 14.3 months with sorafenib.
Regorafenib and cabozantinib are also used after first-line treatment. Indirect comparisons suggest regorafenib may have a slight survival advantage over cabozantinib (roughly three additional months), though this difference wasn’t statistically significant. Regorafenib does appear to cause fewer dose reductions and lower rates of severe diarrhea and fatigue.
For a specific subset of patients whose blood levels of alpha-fetoprotein (a protein produced by some liver tumors) are 400 ng/mL or higher, ramucirumab is an option. This drug blocks a growth signal used by blood vessels feeding the tumor. In this high-AFP group, median overall survival was 8.1 months. It’s the only liver cancer drug approved based on a biomarker rather than just prior treatment history.
Locoregional Treatments for Intermediate-Stage Disease
Patients with multifocal tumors that are still confined to the liver and haven’t invaded blood vessels are typically treated with therapies delivered directly to the tumor through the hepatic artery. The two main approaches are chemoembolization (TACE), which delivers chemotherapy beads that also block blood flow, and radioembolization (Y90), which delivers tiny radioactive microspheres.
TACE remains the recommended first-line locoregional treatment. However, Y90 radioembolization shows advantages over time. While one-year survival is essentially identical between the two approaches, Y90 pulls ahead at two years (43% higher odds of survival) and three years (48% higher odds). Y90 also delivers better tumor control, with significantly higher one-year progression-free survival. Stereotactic body radiation therapy (SBRT), which uses precisely focused external radiation beams, is another option in this space.
Treatment With Impaired Liver Function
Most major clinical trials enrolled only patients with well-preserved liver function (classified as Child-Pugh A). This left a gap for the many patients whose liver function is moderately impaired (Child-Pugh B), often from the underlying cirrhosis that caused their cancer in the first place.
A meta-analysis of 22 studies covering nearly 700 Child-Pugh B patients found that immunotherapy appears safe in this group, with side effect rates no higher than those seen in patients with better liver function. About 14% of Child-Pugh B patients had a measurable tumor response to treatment. Survival outcomes were worse than in Child-Pugh A patients, but this likely reflects the poorer baseline health rather than a lack of drug activity. Nivolumab specifically has shown improved survival and better tolerability compared to sorafenib in this population.
Experimental Approaches in Clinical Trials
CAR-T cell therapy, which involves engineering a patient’s own immune cells to recognize and attack cancer, is being tested in liver cancer. These treatments target a protein called GPC3 that sits on the surface of many liver cancer cells. The National Cancer Institute lists active trials using GPC3-targeted CAR-T cells for advanced hepatocellular carcinoma, though this approach remains investigational and is not yet available outside of clinical trials.