Case Stem

A 61-year-old man with metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis presents with worsening fatigue and right upper quadrant abdominal fullness. ECOG performance status is 1. Imaging shows an 8.8 cm infiltrative right lobe mass invading the right portal vein branch (Vp3), and chest CT shows four bilateral subcentimetre pulmonary nodules. He is Child-Pugh A5 (bilirubin 1.0 mg/dL, albumin 3.9 g/dL, INR 1.1), with platelets 68,000/µL, AFP 5,400 ng/mL and creatinine 0.9 mg/dL. Endoscopy shows large oesophageal varices with red wale markings that have not been banded. He has moderate plaque psoriasis controlled with topical betamethasone.

Discussion Questions

1.     Efficacy by disease aetiology (IMbrave150 vs HIMALAYA). How does his MASH-driven liver disease affect your confidence in dual immunotherapy or PD-L1/VEGF blockade compared with tyrosine kinase inhibitors?

2.     Bleeding hazard versus tumour progression. With Vp3 invasion, do you band the varices first before atezolizumab-bevacizumab, or pivot to a non-bevacizumab regimen such as STRIDE to avoid delay?

3.     Autoimmune toxicity. Given his psoriasis, how do you weigh flare risk between STRIDE and single-agent PD-1 blockade based on CheckMate 459?

4.     TKI selection in vascular disease. If bevacizumab and immunotherapy are excluded, would you choose lenvatinib or sorafenib, and what toxicities need monitoring in the first month of lenvatinib?

5.     Second-line strategy. After progression on first-line lenvatinib, what evidence guides second-line therapy?

Answers

Question 1 — Aetiology and choice of therapy

Exploratory subgroup analyses suggest checkpoint inhibitors work less well in non-viral HCC. In IMbrave150, atezolizumab-bevacizumab clearly helped HBV and HCV patients (HR 0.58 and 0.43) but showed no benefit in non-viral disease (HR 1.05). A 2021 Nature meta-analysis supported this and proposed that MASH livers harbour exhausted, tissue-damaging CD8+ T cells, and retrospective data have suggested lenvatinib may do better than atezolizumab-bevacizumab in MASH-related HCC.

However, the evidence is weak and inconsistent. These were small, unplanned subgroups, and HIMALAYA showed the opposite pattern: STRIDE benefited non-viral patients (HR 0.74) but not HCV patients. Guidelines therefore do not use etiology to choose first-line treatment. For this patient, MASH lowers my confidence in atezolizumab-bevacizumab somewhat, tilts me towards STRIDE, and keeps lenvatinib as an equal alternative rather than a fallback. Locally, the much lower cost of generic lenvatinib may decide the matter before aetiology does.

Question 2 — Banding versus avoiding delay

This is a false choice. Large varices with red wale signs need prophylaxis whatever systemic treatment he gets, because portal hypertension will worsen as the tumour thrombus progresses. I would arrange the first band ligation within days (a platelet count of 68,000 is adequate) and start carvedilol at the same time.

The real decision is which regimen can start without waiting for the varices to be fully eradicated. STRIDE can begin within about a week, with banding continuing in parallel, because it has no anti-VEGF component to impair ulcer healing or increase bleeding. HIMALAYA allowed Vp3 disease, and its non-viral data favour STRIDE. Atezolizumab-bevacizumab remains defensible if given after eradication, as the IMbrave150 protocol required, but with thrombocytopenia and red signs it is the weaker choice. A short delay rarely causes liver failure in a Child-Pugh A5 patient on its own; the real danger is variceal bleeding, which is why banding cannot be skipped. Radiotherapy to the portal vein thrombus, supported by the START trial, is an affordable adjunct worth discussing at MDT.

Question 3 — Psoriasis and immunotherapy

About 30–40% of patients with pre-existing autoimmune disease flare on checkpoint inhibitors, and psoriasis is one of the common ones that gives this phenomenon. However most flares are mild and resolve with topical treatment. Psoriasis controlled on topicals alone is not a contraindication.

STRIDE carries more immune toxicity than durvalumab alone: in HIMALAYA, about 20% of STRIDE patients needed high-dose steroids for immune-related events compared with about 10% on durvalumab. The correct single-agent comparison is durvalumab monotherapy, because CheckMate 459 was a negative trial. I would offer STRIDE with dermatology co-management, and step down to durvalumab alone if the flare risk is deemed too high. Flares should be managed with topicals or phototherapy, avoiding methotrexate in cirrhosis; apremilast or IL-17/IL-23 biologics can be used if needed. The bigger risk in this patient is immune hepatitis rather than skin disease, given his ALBI grade 2 liver, so liver function should be checked before every dose.

Question 4 — Lenvatinib or sorafenib

I would choose lenvatinib. In REFLECT it matched sorafenib for survival (13.6 vs 12.3 months, HR 0.92) while doubling progression-free survival (7.4 vs 3.7 months) and giving a much higher response rate (24% vs 9%). With a large tumour, very high AFP and a branch thrombus threatening the main portal vein, a response that shrinks the thrombus can protect liver function. Vp3 disease was allowed in REFLECT, though we must confirm the tumour occupies less than half the liver and has not invaded the bile ducts. Generic lenvatinib is also affordable locally.

In the first month, the main concerns are early hypertension (seen in about 42%), which needs weekly blood pressure checks and treatment to below 140/90, and proteinuria, which needs urine dipstick at each visit. Fatigue, poor appetite, weight loss and diarrhoea are the commonest reasons for dose reduction, so dietetic support should start early. Liver function should be checked every two weeks, with ammonia measured if he becomes confused, because lenvatinib can cause hepatic encephalopathy. Bleeding risk persists, so banding and carvedilol must continue, and full blood count and thyroid function should be monitored.

Question 5 — Second-line therapy after lenvatinib

No randomized trial has tested second-line treatment after lenvatinib; all the evidence comes from patients who had sorafenib first, so any choice is an extrapolation. The relevant trials are RESORCE (regorafenib, OS HR 0.63), CELESTIAL (cabozantinib, HR 0.76), REACH-2 (ramucirumab in patients with AFP ≥400, HR 0.71) and KEYNOTE-394 (pembrolizumab, HR 0.79).

For this patient, ramucirumab is my first choice because his AFP of 5,400 makes him exactly the population REACH-2 selected, and its bleeding risk should be acceptable once the varices are eradicated. Cabozantinib is the next option, as CELESTIAL's broader eligibility comes closest to post-lenvatinib patients. Immunotherapy is reasonable if the psoriasis concern has been resolved. Regorafenib fits less well because its trial required proven sorafenib tolerance, and generic sorafenib, though supported only by retrospective data, may be the only affordable option for a self-funding patient. All these trials required Child-Pugh A at progression, and many patients with his liver reserve and Vp3 disease will have decompensated by then, so best supportive care should be discussed openly.