Frontline Treatment in HCC: Systemic vs Locoregional Therapy

Pierre Gholam, MD: In most settings of care, for patients who have what we call BCLC [Barcelona Clinic Liver Cancer] stage B, they have a significant burden of disease, multilobar disease, but with no evidence of extravascular, extrahepatic spread or macrovascular invasion. In other words, this is a tumor that has not invaded—outside the liver it has not gone into the portal vein, a hepatic vein, or the hepatic artery. Most people would refer these patients to a competent interventional radiologist to ensure that the patient is able to benefit from treatments in that setting.

In patients who have fairly limited disease burden, the disease burden lists intervention, which could be ablative therapy—or more commonly these days is in the form of transarterial chemoembolization, or transarterial radioembolization—actually offers patients a significant benefit in terms of improvement in survival.

In patients who have macrovascular invasion, or extrahepatic spread, or in many patients in whom the burden of disease is so extensive throughout the liver—one would not realistically conceive that the patient would survive locoregional therapy that affects most of their liver, because their liver functions would decline very significantly—reasonable minds would agree that systemic therapy is the way to go from the start in those patients. For BCLC stage C patients, and a subset of BCLC stage B patients—sometimes we like to refer to those patients as the “bad Bs,” which have extended throughout the liver and do not allow a radiologist to safely administer therapy—systemic therapy is the way to go.

When systemic therapy is contemplated, our current algorithm calls for 2 tyrosine kinase inhibitors that are currently FDA approved in the first line for the treatment of HCC [hepatocellular carcinoma]. These include sorafenib, the first FDA-approved drug for that purpose 11 or 12 years ago, and lenvatinib, a drug that was approved in the past 2 years as a first-line treatment for patients with HCC.

Both these drugs are tyrosine kinase inhibitors, and they have somewhat different targets. Although a key target for both, to varying extent, are vascular pathways—specifically VEGF, a targeted pathway; in the case of lenvatinib, PDGF; RET; and KIT. All these are pathways that have been very significantly involved in the pathogenesis of HCC.

The evidence that supports the use of lenvatinib in the treatment of HCC comes from the REFLECT trial. REFLECT, as I will remind this audience, is an international open-label randomized phase 3 noninferiority trial, the results of which were published in The Lancet with Masatoshi Kudo as the first author, almost 2 years ago. The study basically looked at sorafenib as a comparator arm versus lenvatinib in the first-line treatment of HCC. The findings, which are well known to this audience, include a median survival time for lenvatinib of 13.6 months versus 12.3 months. This met the noninferiority criteria.

Additionally for lenvatinib, a few interesting other highlights of the study included a progression-free survival, which in the case of lenvatinib was 7.4 months versus 3.7 months with sorafenib for a hazard ratio of about 0.66. These findings led to the FDA approving lenvatinib as a first-line agent in addition to sorafenib.

Transcript edited for clarity.

Case: A 61-Year-Old Man with Stage 4 Hepatocellular Carcinoma

Initial presentation

• A 61-year-old man presented with nausea, vomiting, decreased appetite and occasional generalized itching
• PMH: diabetes, medially controlled; hepatitis C and B coinfection diagnosed and treated 6 years ago; diagnosed with HCC December 2018
• PE: scleral icterus; jaundice; spleen palpable 4-cm below the costal margin
  
  

Clinical workup

• Labs: AFP 436 ng/mL, bilirubin 1.6 mg/dL, AST 105 U/L, ALT 110 U/L, ALP 390 U/L, INR 1.9, albumin 3.8 g/dL, BUN 13 mg/dL, creatinine 1 mg/dL, plt 95,000
• HBV+, HCV+
• Abdominal ultrasound revealed 3 small hepatic lesions
• Chest/abdominal/pelvic CT scan confirmed 2 focal nodules in the right and 1 in the left hepatic lobe measuring 3.6 cm, 4.9 cm and 5.2 cm, a suspicious lesion in the right lower lung lobe; wide-spread lymphadenopathy was noted
• Biopsy findings showed grade 3 hepatocellular carcinoma with marked fibrosis
• Surgical consult: unresectable due to tumor size and location
• Child-Pugh A; BCLC stage C
• ECOG 1
  
  

Treatment and Follow-Up

• 2018: treated with lenvatinib 400 mg PO q12hr; he experienced diarrhea for 2 weeks which resolved; achieved PR
• 2020: Imaging showed a new lung lesion
  • Treatment was with cabozantinib 60 mg PO qDay was initiated