1. Efficacy by Disease Etiology (IMbrave150 vs HIMALAYA)
Subgroup analyses from trials such as IMbrave150 (atezolizumab plus bevacizumab) and HIMALAYA (STRIDE: tremelimumab plus durvalumab) suggest that immune checkpoint inhibitor (ICI) regimens elicit a more robust response in viral hepatocellular carcinoma (HCC) than in non-viral HCC, such as metabolic dysfunction-associated steatohepatitis (MASH). Exploratory preclinical and clinical data indicate that MASH-driven liver disease creates a pro-inflammatory, NASH-induced CD8+ T-cell tissue microenvironment that may lead to functional immune exhaustion rather than effective anti-tumor surveillance. Although post-hoc meta-analyses continue to show survival benefits for immune checkpoint blockade over tyrosine kinase inhibitors (TKIs) across all subgroups, the relative overall survival benefit from dual immunotherapy or PD-L1/VEGF blockade is reduced in non-viral etiologies compared to viral hepatitis. As a result, in a MASH-driven setting, the decision to choose atezolizumab/bevacizumab or STRIDE over a TKI like lenvatinib depends less on etiology alone and more on overall clinical risk factors, including portal vein invasion, bleeding parameters, and liver reserve.
2. Managing Bleeding Hazard Against Tumor Progression
For this patient, Vp3 portal vein invasion carries a high risk of rapid disease progression and liver decompensation if systemic treatment is delayed. Because eradication of high-risk, large esophageal varices with endoscopic band ligation (EBL) usually requires sequential sessions spaced two to four weeks apart, waiting this long to start systemic therapy would create an unacceptable risk of tumor thrombus expansion, total portal vein occlusion, and liver failure. Thus, it is preferable to move away from a bevacizumab-containing regimen and use a non-VEGF-inhibiting regimen such as STRIDE (or a TKI), rather than delay treatment for band ligation. The STRIDE regimen does not involve anti-VEGF-mediated endothelial disruption and avoids the increased gastrointestinal bleeding risk associated with bevacizumab. This allows prompt initiation of systemic therapy after starting primary or secondary prophylaxis with non-selective beta-blockers (such as carvedilol), without postponing life-preserving cancer treatment.
3. Autoimmune Toxicity Risks with Checkpoint Blockade
A history of moderate plaque psoriasis managed with topical corticosteroids increases the risk of treatment-induced cutaneous or systemic autoimmune flares with immune checkpoint inhibition. CTLA-4 inhibition acts during initial T-cell priming in lymphoid tissue and leads to broad, non-specific proliferation of self-reactive T-cells, while PD-1/PD-L1 axis inhibition acts later in peripheral tissues. Safety data from trials, supported by broader ICI experience including the CheckMate 459 study, show that dual CTLA-4 and PD-L1 blockade (such as the high single-dose tremelimumab in STRIDE) is associated with a significantly higher rate of Grade 3/4 immune-related adverse events and autoimmune disease flares compared to single-agent PD-1 blockade. If immunotherapy is still considered, single-agent anti-PD-1 blockade or PD-L1 monotherapy has a substantially lower risk of triggering severe psoriasis exacerbations than a dual CTLA-4-containing regimen.
4. Selecting Tyrosine Kinase Inhibitors in Extensive Vascular Disease
If bleeding hazards rule out bevacizumab and active psoriasis rules out immunotherapy, lenvatinib is preferred over sorafenib as the TKI. The phase III REFLECT trial showed that lenvatinib was non-inferior to sorafenib for overall survival, with significantly better objective response rates (ORR) and progression-free survival (PFS). Although REFLECT excluded patients with main trunk portal vein invasion (Vp4), it did include those with branch invasion (Vp1–Vp3), making lenvatinib appropriate for this patient’s Vp3 thrombosis. During the first month of lenvatinib (dosed at 8 mg daily based on body weight and platelet status), key toxicities to monitor closely include hypertension, proteinuria, fatigue, decreased appetite/weight loss, palmar-plantar erythrodysesthesia (hand-foot skin reaction), and early liver function deterioration.
5. Second-Line Strategy Following First-Line TKI Failure
After disease progression or intolerance to first-line lenvatinib, second-line systemic therapy is guided mainly by extrapolations from clinical trials, since phase III second-line trials (RESORCE for regorafenib, CELESTIAL for cabozantinib, and KEYNOTE-394 for pembrolizumab) enrolled patients after sorafenib failure. Cabozantinib is supported by CELESTIAL trial evidence, which demonstrated a survival benefit in advanced HCC after prior TKI exposure, making it an established multi-kinase inhibitor option post-lenvatinib. Regorafenib is supported by the RESORCE trial, provided the patient initially tolerated a TKI. Furthermore, if psoriasis remains quiescent and immunotherapy becomes an option at progression, alternatives include anti-PD-1 monotherapy (such as pembrolizumab based on KEYNOTE-394) or anti-CTLA-4/PD-1 combinations (ipilimumab plus nivolumab based on CheckMate 040).
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