Third-Line Therapy in Hepatocellular Carcinoma


Ahmed Kaseb, MD:The next question for our specific case relates to what to do in terms of systemic therapy options. We always rely on 2 major factors, and the overall clinical condition. This patient has remained in good clinical condition with good performance and nutritional status. The next question is in regard to the status of the underlying liver disease and the liver function studies.

As long as the patient is stable from that standpoint as well… By stable, I mean according to their baseline, because this patient remained classified as Child-Pugh B. However, if the bilirubin is also still around 3 mg/dL and the patient is in good condition, should we start third-line therapy? This is also something that we tailor according to every specific case. We look at it from a multidisciplinary approach, whether there are any options in terms of local or systemic therapy for every individual.

For this specific patient, in regard to agents that could be considered in a multidisciplinary manner, one of them could be cabozantinib. This is a tyrosine kinase inhibitor [TKI] recently approved in the second-line setting. The study included patients who underwent 2-plus lines of therapy. Although the number was small, there was proof of concept that you could include patients who progressed on more than 1 line of therapy. So based on that, a lot of practices follow this rationale to start cabozantinib beyond the frontline and second-line setting. However, as mentioned, it has to be done with extreme caution, regarding the liver function status assessment, regarding portal hypertension and esophageal varices assessment, to make sure that we’re not introducing more harm than benefit to our patient.

In this specific case, it has to be tailored to the patient’s clinical condition and status of the underlying liver disease at the time of starting therapy with frequent monitoring. And again, some practices, including mine, will also go with a lower dose up front to make sure the patient is handling it well and to ensure that the liver functions are stable at the lower dose. This is not in the guidelines, but those patients, as I mentioned earlier, get excluded from clinical trials if they have underlying liver disease manifested by Child-Pugh B status.

In general, we tailor our treatment to those patients based on local expertise and a team-based approach that includes an oncologist and hepatologist. This is a very typical scenario to what community physicians have to face. Academic centers usually serve as a tertiary care center. We get most of our referrals from oncologists, so most of them are Child-Pugh A and are fit for therapy and clinical trials. However, a real case scenario is a patient with advanced liver disease that is classified as Child-Pugh B. That’s why it has to be individualized based on the risk-benefit ratio.

Targeted therapy in the second-line space has been expanded recently. We have regorafenib in the second-line setting after progression on sorafenib. We have cabozantinib after progression on sorafenib, including for some patients who have had 2-plus lines of therapy. Then we have ramucirumab, which is approved for patients with an alpha fetoprotein equal to or more than 400 ng/mL.

The options for frontline and second-line therapy in HCC [hepatocellular carcinoma] have been expanded recently. Therefore, it has become a busy field. In my practice, I tailor treatment based on the patient’s general condition. There are some signals in the frontline setting. As we have mentioned, sorafenib versus lenvatinib, depending on the hepatitis status. But again, this is based on meta-analyses and subset analyses, so they are not yet among the guidelines. But this suggests individual preferences that we discuss with our patients. And in the second-line setting, again, we use the same rationale to pick and choose which drug, depending on the tolerance to tyrosine kinase inhibitors, for example, the clinical condition and liver function status.

The third-line setting in HCC has never been addressed in clinical trials in a systematic way. No dedicated studies have reported yet, in a randomized fashion, to look into the third-line setting to see what there will be. Up until this point, if we look at the second-line clinical trials, most of them excluded patients with 2-plus lines, except cabozantinib. A study also included some patients who underwent 2-plus therapies—frontline followed by second-line—and this study was considered a third-line option for them. It was a small number. They didn’t really address the issue of third-line therapy. However, some physicians rely on that to advance their patients after progression on frontline and second-line therapy to cabozantinib. It’s a tyrosine kinase inhibitor. It’s a strong antiangiogenic therapy.

In my practice, if I’m starting cabozantinib for one of my patients, I always use extreme caution in terms of assessing risk of bleeding, for example. We order upper endoscopies for our patients to evaluate their varices. This is not just for cabozantinib. I do this for all strong antiangiogenics, TKIs, and targeted therapies in HCC; and also manage hypertension and assess their cardiac risk. In general, our patients also could be suffering from poor nutrition, low albumin, so we address that as well. Most of the tyrosine kinase inhibitors could affect nutrition. They could affect a patient’s appetite and energy level.

We manage it in a multidisciplinary manner with our dietician, our physical therapist. We involve our supportive care team up front to prepare our patients to start targeted therapies. And also, while on treatment, co-manage those adverse effects and address issues related to malnutrition, for example, with our dietitian, or lack of physical activity with a program that could involve physical therapy. So it’s a team-based approach in this era of HCC, based on the adverse effects of targeted therapies.

Transcript edited for clarity.

Case: A 65-year-old Man With Cirrhosis and HCC

A 65-year-old man with 10-year history of cirrhosis was seen for routine follow-up; referred for further lab and imaging studies based on enlarged lymph nodes and new-onset jaundice.

H & P

  • PE: Yellowing of the skin and sclerae
  • Social History: drinks 20+ alcoholic beverages/ week for the past 15 years
  • ECOG: 0


  • AFP: 550 IU/mL
  • Child-Pugh B
    • Bilirubin: 3 mg/dL
    • Albumin: 3.5 g/dL
    • No hepatic encephalopathy
    • Grade 1 ascites


  • Multiphasic contrast MRI of the abdomen revealed an 8-cm encapsulated mass in the left hepatic lobe showing hypervascularity on arterial phase and washout on venous phase
  • Further imaging of CAP revealed no metastasis
  • Diagnosis: unresectable hepatocellular carcinoma


  • Underwent TACE; follow-up imaging at 1 month showed no response
  • Started on lenvatinib 12 mg once daily; follow-up imaging at 3 months showed no response
  • Received nivolumab 3 mg/kg every 2 weeks


  • 3 months later; patient complained of increasing fatigue
  • AFP; 600 IU/mL
  • MRI showed disease progression in the liver, one new adrenal lesion
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