Immunotherapy and Targeted Therapy for Advanced Liver Cancer (HCC)
For over a decade, sorafenib was the only systemic option for advanced HCC. That changed with the IMbrave150 trial in 2020: atezolizumab plus bevacizumab demonstrated superior overall survival compared to sorafenib and became the new first-line standard. Today, hepatologists managing advanced HCC have multiple effective agents across three or four lines of treatment – and the decisions about which to use, in what sequence, and how to manage their toxicities are as complex as any cancer pharmacotherapy. I am Dr Chetan Kalal, DM Hepatologist at Gleneagles Hospital Mumbai. I prescribe and manage systemic HCC therapy for my patients, coordinating with oncology for complex cases.
Who Needs Systemic Therapy for HCC?
Systemic therapy is indicated for advanced HCC (BCLC stage C) – defined as macrovascular invasion (portal vein thrombosis) or extrahepatic spread (lymph nodes, lung, bone) in a patient with Child-Pugh A liver function and ECOG performance status 0-1. It is also indicated for intermediate HCC (BCLC B) that has progressed despite or is no longer suitable for locoregional therapy (TACE or TARE). In both situations, the liver must be functioning adequately enough to tolerate the treatment – Child-Pugh B7 is the outer limit for most agents.
First-Line Treatment Options
Atezolizumab + Bevacizumab
Standard of care. IMbrave150 RCT (N=501), updated survival analysis: median OS 19.2 vs 13.4 months (HR 0.66) and PFS 6.9 vs 4.3 months versus sorafenib. Critical prerequisite: endoscopy to screen for and treat high-risk varices before starting – bevacizumab carries significant GI bleeding risk if untreated varices are present.
Durvalumab + Tremelimumab
Anti-PD-L1 + anti-CTLA-4 combination (STRIDE regimen). HIMALAYA trial: median OS 16.4 vs 13.8 months (HR 0.78) versus sorafenib, with 36-month OS of 30.7% vs 20.2%. An option when bevacizumab is contraindicated (varices not amenable to treatment, prior bleeding).
Sorafenib
Tyrosine kinase inhibitor (VEGFR, PDGFR, RAF). The original first-line option (SHARP trial), now used when checkpoint inhibitor combinations are contraindicated. Median OS 10.7 vs 7.9 months for placebo (HR 0.69). Side effects: hand-foot skin reaction, diarrhoea, hypertension.
Lenvatinib
Multi-kinase inhibitor non-inferior to sorafenib for OS (REFLECT trial) with higher PFS and objective response rate. An alternative to sorafenib when checkpoint inhibitor combinations are not tolerated.
Second-Line and Beyond
After first-line progression, several agents have shown efficacy in controlled trials:
- Cabozantinib: multi-kinase inhibitor effective in sorafenib-refractory patients (CELESTIAL trial)
- Regorafenib: second-line after sorafenib (RESORCE trial); sequencing after sorafenib, not after lenvatinib or immunotherapy, is important
- Ramucirumab: anti-VEGFR2, effective specifically in patients with AFP ?400 ng/mL (REACH-2 trial)
- Pembrolizumab: anti-PD-1, second-line option in sorafenib-refractory disease
The sequence of agents matters – some second-line agents have only been tested after specific first-line agents. Dr Kalal tailors the sequence to each patient’s prior treatment, liver function trajectory, and adverse event profile.
Managing Immune-Related Adverse Events (irAEs)
Checkpoint inhibitors (atezolizumab, durvalumab, pembrolizumab, tremelimumab) carry a risk of immune-mediated inflammation in any organ. In HCC patients, the most clinically relevant irAEs are immune hepatitis (can mimic progressive HCC – requires biopsy to distinguish), thyroid dysfunction (hypothyroidism in 5-10%), immune pneumonitis, and dermatitis. Dr Kalal monitors liver function, thyroid panel, and clinical symptoms at each visit and manages irAEs using corticosteroids or immunosuppression, with temporary drug holds and re-challenges based on severity grading (CTCAE).
Important before starting atezolizumab-bevacizumab: Bevacizumab significantly increases the risk of variceal haemorrhage in patients with untreated high-risk varices. ESMO and AASLD guidelines require a screening upper GI endoscopy within 6 months before starting, with variceal band ligation if high-risk varices are present. Dr Kalal coordinates this evaluation as part of the pre-treatment workup.
Discuss Advanced HCC Treatment Options
If you have been diagnosed with advanced HCC or have disease that has progressed despite locoregional treatment, Dr Kalal’s team at Gleneagles Hospital Mumbai will review your staging, liver function, and prior treatments to design the optimal systemic therapy plan.