1. Efficacy by Disease Etiology: IMbrave150 vs HIMALAYA
His MASH-related, non-viral HCC makes me somewhat more cautious about relying on immunotherapy. Exploratory analyses from IMbrave150 and HIMALAYA suggest that the benefit of immune-based combinations may be less pronounced in non-viral HCC, particularly MASH-associated disease, than in viral HCC.
Therefore, although atezolizumab/bevacizumab and STRIDE remain evidence-based options, I would consider a TKI such as lenvatinib particularly reasonable if bleeding risk or concerns about immunotherapy efficacy are substantial. i would also choose this because its not as expensive as Atezolizumab/bevacizumab in Nigeria. This should be viewed as an individualized decision rather than evidence that immunotherapy is ineffective in MASH.
2. Managing Bleeding Risk vs Tumour Progression
I would not start bevacizumab before addressing the large high-risk varices, because bevacizumab substantially increases concern about gastrointestinal bleeding.
However, this patient has Vp3 portal-vein invasion and a large tumour, so prolonged delay is undesirable. I would urgently involve the Gastroenterologists/endoscopy teams and perform band ligation as soon as feasible, followed by systemic treatment once the bleeding risk is appropriately controlled.
If the multidisciplinary team believes that waiting several weeks creates an unacceptable risk of tumour progression or hepatic deterioration, STRIDE (tremelimumab + durvalumab) is an attractive alternative because it avoids the anti-VEGF bleeding risk. However the problem is if these drugs are available in Nigeria, NAFDAC approved, and if the patient can afford them.
3. Psoriasis and Checkpoint Blockade
His controlled psoriasis is not an absolute contraindication to immunotherapy, but it increases the possibility of an immune-mediated flare.
I would expect the risk to be greater with CTLA-4 plus PD-L1 blockade (STRIDE) than with single-agent PD-1/PD-L1 inhibition because dual checkpoint blockade produces greater immune activation.
CheckMate 459 showed that nivolumab monotherapy did not significantly improve overall survival compared with sorafenib, although it demonstrated activity and was generally tolerable. Therefore, if psoriasis is a major concern, single-agent checkpoint inhibition may be easier to manage, but its efficacy advantage over standard therapy is less convincing.
4. Choosing a TKI: Lenvatinib vs Sorafenib
If immunotherapy and bevacizumab are unsuitable, I would favour lenvatinib.
REFLECT demonstrated that lenvatinib was non-inferior to sorafenib for overall survival, while producing a substantially higher objective response rate. Importantly, Vp1–Vp3 portal-vein invasion was permitted, although Vp4 disease was excluded.
During the first month I would closely monitor:
- Hypertension
- Proteinuria
- Renal function
- Liver function
- Weight and appetite
- Diarrhoea
- Fatigue
- Hand-foot syndrome
- Thyroid dysfunction
Blood pressure and renal function are particularly important early in treatment because dose interruption or reduction may be required.
5. Second-Line Treatment After Lenvatinib Failure
The key evidence would come from RESORCE, which established regorafenib after progression on sorafenib, but this evidence does not directly establish regorafenib after lenvatinib.
For a patient progressing after first-line lenvatinib, I would therefore consider the available evidence for cabozantinib (CELESTIAL), which demonstrated improved overall survival in previously treated advanced HCC, including patients previously exposed to other systemic therapies.
Another important option is ramucirumab (REACH-2) if AFP remains ≥400 ng/mL, as this patient's baseline AFP is 5,400 ng/mL. REACH-2 specifically demonstrated an OS benefit in patients with AFP ≥400 ng/mL.
Thus, after lenvatinib failure, cabozantinib or AFP-directed ramucirumab would be evidence-supported considerations, with the final choice guided by prior treatment, liver function, toxicity profile, vascular disease and affordability.
References
- Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–1905.
— IMbrave150: establishes atezolizumab + bevacizumab as a first-line systemic option. - Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070.
— HIMALAYA/STRIDE: supports tremelimumab + durvalumab as a first-line option. - Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–1173.
— REFLECT: supports lenvatinib as an alternative to sorafenib, with higher response rates. - Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23:77–90.
— CheckMate 459: important evidence regarding nivolumab monotherapy versus sorafenib. - Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.
— CELESTIAL: provides evidence for cabozantinib after prior systemic therapy. - Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2). Lancet Oncol. 2019;20:282–296.
— REACH-2: particularly relevant because this patient has AFP 5,400 ng/mL, well above the ≥400 ng/mL eligibility threshold.