Combinations May Be the Future in Advanced HCC

Michael A. Morse, MD, FACP:We now have a lot more optimism for treating hepatocellular carcinoma. Where there were no drugs when I started my career, now we’ve got 2 frontline therapies, and we’ve got 5 second-line therapies. But clearly, most individuals eventually progress, and the disease is eventually lethal. A critical area of unmet need is what to do for that patient who’s progressed through multiple lines of therapy. Even more important is what to do with the first line. Can we do better than the response rates and the progression-free survival that we have right now?

A very exciting area of research in hepatocellular carcinoma is combining the therapies we have. We know that immunotherapy has a benefit in the second-line setting. We know that TKIs [tyrosine kinase inhibitors] have benefit in first line and second line and indeed in patients who are even third line. When we combine these, we’re starting to see, in preliminary trials, higher response rates and longer progression-free survivals than we saw with single agents.

Some interesting trials going on in the first line are combining pembrolizumab with lenvatinib, or cabozantinib with atezolizumab, or even 2 immune therapies. For example, there’s a frontline trial of durvalumab, which is an anti—PD-1 [programmed cell death protein 1] therapy. This is not yet approved for hepatocellular carcinoma. There is also an anti–CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] therapy, tremelimumab, which is also not yet FDA approved, but they’re being combined. I think we have a lot of optimism that we might start seeing combinations give better response rates, better progression-free survival, and better overall survival. The most important thing is that patients who are appropriate for clinical trials should be offered the possibility of enrolling, so we can complete these trials and see if they are truly an advance.

In this particular case, this individual had surgery. When they relapsed, they had advanced disease and went on to systemic therapy. But many individuals we see have localized disease where they aren’t surgical candidates but would be a candidate to have either an ablation, or chemoembolization, bland embolization, or a Y-90 [yttrium-90] radioembolization. There are some other technologies that are in development for treating localized disease. When those individuals are treated, often you will see regression of disease or long-term control. But unfortunately, in the vast majority, there will eventually be progression of disease.

An important question in research of hepatocellular carcinoma is, can we give adjuvant therapy to slow that recurrence time or reduce the risk of recurrence? Unfortunately, sorafenib has been looked at in this setting and has not shown an improvement in progression-free or overall survival. We don’t actually know with lenvatinib, but the area that’s very exciting is trying to use immune therapies as a mechanism for reducing the risk of recurrence or slowing the time to recurrence. This is not standard yet, but there are some key trials that are just starting to combine the therapies we have for more advanced disease with locoregional therapy.

Transcript edited for clarity.

Case: 63-Year-Old Male with R/R mHCC

February 2018: Initial presentation

• A 63-year-old man with chronic HBV infection referred for further imaging studies based on suspicious findings during routine ultrasound for HCC

Initial Clinical Workup

• AFP: 300 IU/mL
• Child-Pugh A
  • Platelets: 210,000 cells/mcL
  • Bilirubin: 1.2 mg/dL
  • Albumin: 3.6 g/dL
  • INR: 1.1
  • No hepatic encephalopathy
  • Ascites not present
• Imaging: CT revealed 2 lesions in right hepatic lobe (2cm, 5cm); no extrahepatic disease; no cirrhosis; no portal hypertension
• BCLC: B
• PS: 0

Treatment

• Patient underwent right hepatectomy; negative margins; no vascular invasion
• AFP: WNL

December 2018

• On routine follow-up, imaging showed new lesion in left hepatic lobe (~2.3cm)
• Chest CT showed 3 small lesions (<1cm) in upper left lobe of lung
• Patient started on lenvatinib 12 mg QD; experienced moderate diarrhea and fatigue
• Imaging at 3 and 6 months showed partial response
• AFP: 100 IU/mL
• BCLC: C
• PS: 0

August 2019

• Routine follow-up blood sample reveals AFP 450 IU/mL
• CT scan showed progression in the lung and 2 new liver lesions; remains Child-Pugh A
• Patient started on cabozantinib 60 mg QD
• Patient developed grade 2 diarrhea; dose-reduction to 40 mg QD
• Imaging at 3 months showed stable disease
• Imaging at 6 months showed partial response