Balancing Efficacy With Toxicity Among the Agents for HCC

Catherine Frenette, MD:The 2 groups of lenvatinib [Lenvima] versus sorafenib [Nexavar] in the REFLECT trial were not stratified by AFP [alpha-fetoprotein] level. They were also not stratified by their underlying cause of liver disease. The patients in the lenvatinib group did have a slightly higher AFP than the patients in the sorafenib group. This may actually have resulted in a favorable imbalance in the positive for sorafenib. Additionally, hepatitis C patients were more frequent in the sorafenib group as compared with the lenvatinib group. This may have given a benefit to sorafenib. The reason for this discussion is that we recall, in the SHARP trial, when they broke out a subgroup of patients who were treated with sorafenib and had hepatitis C, had quite a longer median survival. In the SHARP trial, the overall survival [OS] in the subgroup was 10.7 months. In the hepatitis C—treated population with sorafenib, there may have been a longer OS than would have been seen in patients who were stratified for that risk factor.

We have to remember toxicity profiles with these medications. We know that tyrosine kinase inhibitors have toxicities; that’s what we have to deal with regarding our patients. In the REFLECT trial, we saw more hypertension in the lenvatinib group of 42% compared with 30% in the sorafenib group; however, lenvatinib also had less hand-foot-skin reaction as compared with sorafenib. The lenvatinib group had 27% hand-foot-skin reaction compared with 52% in the sorafenib group. This was notable when we think about the grade 3 and 4 hand-foot-skin reaction, which is so particularly painful for our patients. In the lenvatinib group, only 3% of them had grade 3 to 4 hand-foot-skin reaction, compared with 11% of the sorafenib group. We also have to remember that lenvatinib has a higher rate of proteinuria. 25% of the patients on lenvatinib had some element of proteinuria, compare with 11% of the sorafenib patients. For our patients who are being treated with lenvatinib, we need to monitor their urine proteins and address that if it becomes an issue. The lenvatinib-treated group did have a higher rate of treatment-related, treatment-emergent adverse events—57% versus 49% for sorafenib.

Serious adverse effects [SAE] were also higher in lenvatinib—43% versus 30% with sorafenib. However, part of these higher rates of adverse events may have been accounted for because the lenvatinib-treated arm had a longer treatment of duration. The treatment of duration for lenvatinib was 5.7 months and in sorafenib was 3.7 months. So as the patients are treated longer, we expect to see more serious adverse events.

There’s not a lot of data for lenvatinib in patients with decompensated liver function as of yet. The REFLECT trial included predominantly Child-Pugh A patients. There were a few patients with Child-Pugh B who got into the trial, but again, it was really geared toward the Child-Pugh A patient. We now have 10 years of experience with sorafenib in conjunction with decompensated liver function. We know those patients need a dose reduction in many cases. They may not tolerate it at all and consequently have adverse side effects. We need to gain more experience with lenvatinib treating our decompensated patients. At this point, I would be cautious using lenvatinib for our decompensated patients until we get more data and experience.

Transcript edited for clarity.

A 77-Year-Old Male With Unresectable HCC and Extrahepatic Involvement

• History and physical exam
  • An otherwise healthy, 77-year-old Caucasian male with a history of alcohol use
  • Presented to his PCP complaining of abdominal pain, fatigue and an unexplained 10-lb weight loss
  • Currently consumes 3-4 alcoholic drinks per day
  • ECOG PS 0
• Imaging
  • CT scan: 4.5-cm hepatic lesion with arterial hypervascularity, portal venous washout, and a pseudocapsule indicative of hepatocellular carcinoma; no evidence of vascular invasion
  • Bone scan: left-sided iliac mass (3.1 cm)
  • Chest CT: clear
• Diagnosis: unresectable HCC with extrahepatic involvement
  • BCLC stage C
  • Child-Pugh A
  • AFP Level: 3548.4 ng/mL
  • Weight: 72 kg
• Lenvatinib 12 mg QD was initiated.
  • He experienced modest weight loss and reported loss of appetite for which he was referred for nutritional therapy
  • Imaging at 16 weeks: partial response (0.5 cm)
  • 8 months after initiation of therapy: treatment discontinued due to disease progression