First-Line Treatment in Unresectable HCC


An expert in the treatment of HCC comments on first-line therapeutic options for patients with previously untreated, advanced HCC.

Pierre Gholam, MD: What are treatment options for patients who have unresectable HCC [hepatocellular carcinoma] in the first line? We now have 3 well-established therapies, based on large randomized or open-label clinical trials, that we can offer these patients. The first is sorafenib, a therapy that’s been around for over a decade now and has had extensive use in the treatment of these patients. The second is lenvatinib, a treatment that’s been with us now for over 3 years, based on data from a trial called REFLECT that shows noninferiority to sorafenib in the setting of unresectable advanced HCC. The third and most recent addition to our first-line armamentarium is the option of the combination of immunotherapy agent atezolizumab with the vascular pathway-acting antibody bevacizumab to treat patients also with unresectable HCC.

The rationale for using these treatments, either the combination or monotherapy, factors in a number of issues. One has to do with the patient him or herself and what their other comorbidities are, preferences in terms of intravenous versus oral therapy, and other factors. Some have to do with mitigation of the potential adverse events of all these therapies, which for TKIs [tyrosine kinase inhibitors] such as sorafenib and lenvatinib are well-known and characterized, and for agents like atezolizumab and bevacizumab, can also include some potential liabilities, including risk of bleeding, certainly hypertension, epistaxis when it comes to [bevacizumab] and other issues. The treatment of course, has to be tailored to factoring in the efficacy of the drug, but also the individual who is going to receive it. Sorafenib and lenvatinib are both TKIs. They vary in the targets that they address. Sorafenib is best described as a multikinase inhibitor. While it targets RAF, BRAF, and many of the vascular pathways including VEGF, it does a lot of different things at the same time. Lenvatinib is generally thought to be more targeted toward the VEGF and FGFR, and so has a much more singular focus on vascular pathways.

In that sense, if you want to factor in mechanism of action, you will certainly think about these things when deciding on therapy. The reason for using the recently approved a combination of atezolizumab and bevacizumab is what appears to be a fairly significant improvement in overall survival, which we think based on the latest data from the IMbrave150 study, approaches 19.5, 19.6 months, along with an acceptable adverse event profile while factoring in a need for mitigation of serious adverse events. These include GI [gastrointestinal] bleeding, whether variceal or nonvariceal, and accounting for some of the limitations of immunotherapy in the setting of subsets of patients, such as the patient who has autoimmune disease, patients who may have conditions affected adversely by immunotherapy, such as transplants or other issues. When one thinks about what treatment choice to pick in the patient with unresectable HCC in the first line, a variety of factors play into this. This patient has hypertension, which is well controlled.

Certainly, hypertension can occur or be worsened by lenvatinib. But if that is an issue that’s been under initial good control, it may be a very reasonable option in the first line for that patient, as was chosen. I’ll conclude, relevantly to our medical oncology colleagues in the audience, that the NCCN [National Comprehensive Cancer Network] has now established guidelines for selection of appropriate therapy, which include a preferred agent atezolizumab, bevacizumab combination. Two other options that are recommended are sorafenib and lenvatinib, and a variety of other options that they lump under appropriate in certain circumstances. I think those get very little use and probably are not very relevant to our discussion.

Transcript edited for clarity.

A 61-Year-Old Woman with Hepatocellular Carcinoma

Initial Presentation

  • A 61-year-old woman complains of fatigue, RUQ pain and nausea and vomiting
  • PMH: medically controlled hypertension; obesity; diabetes managed with oral medication
  • PE: hepatomegaly with tenderness over the RUQ

Clinical Workup

  • CT scan of chest, abdomen and pelvis, with 4 phase liver evaluation: 4.0-cm hepatic mass in the right hepatic lobe
  • Labs: AFP: 1.5 ng/dL; Alb: 3.9 g/dL; INR: 1.45; Bili: 1.1 mg/dL , HbA1c: 7.0; platelet count 90,000
  • Biopsy of the lung metastasis demonstrated evident hepatocellular carcinoma
  • Child-Pugh A
  • ECOG PS 1


  • Initiated lenvatinib 12 mg QD

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