Treatment Approach in Progressive Hepatocellular Carcinoma

Ahmed Kaseb, MD:The patient progressed after 3 months of being on lenvatinib. If we look back at a lenvatinib phase III study, we have to appreciate the fact that patients classified as Child-Pugh B were not included in this study—it was one of the exclusion criteria—so we really don’t have a good idea about response rates and time to progression of patients under the Child-Pugh B category on lenvatinib. However, the patient progressed at 3 months, and that triggered the next question, which is: what to do next. This is a second-line systemic therapy after lenvatinib. If we follow the current guidelines, all of the drugs approved in the second-line setting were done following sorafenib, with the exception of 1 study, a phase III study of cabozantinib, that allowed 2-plus prior systemic therapies.

This patient went through lenvatinib and then his treating physicians decided to embark on immunotherapy with nivolumab. That leads to other questions: Sequencing of therapies, and FDA approval status and insurance approval status, which is very relevant to community physicians given the lack of access to a large number of trials compared to academic centers. Agents in the second-line setting for HCC [hepatocellular carcinoma] were approved after sorafenib failure, so most of the insurance carriers, and the FDA as well, label the indication to specify progression on sorafenib.

Lenvatinib came to the picture after the noninferiority study reached its primary endpoint. Lenvatinib is now undergoing evaluation for this very specific question of sequencing to address this issue. Until then, it may be a challenge, sometimes, for some patients and their treating physicians to get second-line drugs approved after lenvatinib progression. However, most of the time, with the appropriate appeals process, these issues are resolved.

Nivolumab immunotherapy was approved after progression on sorafenib. This study actually included some Child-Pugh B patients, B7 score, and that’s also included in the FDA indication and HCC guidelines.

The patient was treated with nivolumab for about 3 months and then underwent a scan that showed further progression after the patient clinically also experienced increased fatigue. This is what we call clinical and imaging progression. So the question now will be, what is a third-line option for this patient? This is not uncommon nowadays, especially in patients of a good performance status and a stable liver function status. This patient remained classified as Child-Pugh B, however was stable. There was no further deterioration of his liver function status and his ECOG [Eastern Cooperative Oncology Group] performance status remained stable.

It really reflects a real-life scenario of patients managed in community settings by primary oncologists who are seeing a lot of patients with concomitant disease, underlying liver disease in addition to HCC; or those patients who have a good performance status and their bilirubin is also stable over time. This patient was always hovering around 3 [mg/dL]. They continued systemic therapy for this patient. This is not a typical case scenario where you have a Child-Pugh A patient, but is a scenario that community oncologists face all the time and manage through a multidisciplinary approach—especially patients with a good performance status who are classified as Child-Pugh B but stable disease—with frequent monitoring.

In general, we manage this in a multidisciplinary setting. Up front, before embarking on localized therapies, we have to assess risk-benefit ratio. If the patient has a higher risk of liver deterioration and we don’t expect a high chance of response to local therapy, we start with systemic therapy. And then, based on the liver function status, we tailor the dose of therapy. Sometimes we start with a lower dose for a couple of weeks to build up tolerance.

All of these approaches are based on a multidisciplinary approach and the expertise of the treating team. And a lot of times, once you go through a lower dose up front and build up tolerance, if patients tolerate it, it is better than starting with the higher dose. There are some studies and trials looking into that—looking into the lower dose of a TKI [tyrosine kinase inhibitor] and increasing it over time rather than the other way around, which is starting with the higher dose and then lowering it down according to tolerance. These are differences based on specific individual practices and local expertise.

In this era of hepatocellular carcinoma management, there is momentum for immunotherapy. And based on this momentum and signals of activity with single-agent checkpoint inhibitors such as nivolumab and pembrolizumab, they were approved in the last couple of years based on single-arm phase II trials. They were granted conditional approval by the FDA. However, the randomized studies for both agents—pembrolizumab in the second-line against placebo, and nivolumab in the frontline against sorafenib—did not reach their primary endpoints. So this was a setback for single-agent drugs in HCC, when it comes to immunotherapy.

However, both studies, initially the phase II studies and also phase III, are showing some signal of activity in select patients. We don’t yet know what kind of patients are expected preemptively, before starting therapy, to do well with immunotherapy. In general, just like any other systemic therapy, we follow guidelines in terms of starting therapy and following patients clinically. And then, in terms of the frequency of the imaging, some clinical trials put it at 6 weeks, and others put it at 8 weeks or even 12 weeks.

In routine practice, we go by clinical condition as well as imaging to assess response to therapy. In patients who are clinically deteriorating, we tend to get the scans earlier than scheduled. What we average is around 8 weeks to 12 weeks, depending on the specific practice. If a patient is clinically stable, we image around this range—8 to 12 weeks—which is generally acceptable. But if there is clinical deterioration, we get it sooner.

This patient has advanced Child-Pugh B disease, so that could have been one of the contributing factors to the lack of response to local therapy and lines of systemic therapy.

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

Labs

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

Imaging

• 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

Treatment

• 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

Follow-up

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