Gholam Contrasts Lenvatinib With Other Options in Child-Pugh B HCC

Pierre Gholam, MD

Associate Professor, Department of Medicine

Case Western Reserve University School of Medicine

Cleveland, OH

CASE SUMMARY

• A 57-year-old woman presented to her primary care physician complaining of abdominal pain and fatigue.
• She had a history of cirrhosis due to heavy alcohol use, Crohn disease controlled with infliximab (Remicade), and a history of variceal bleeding with banding 2 months ago.
• She had been treated with antiviral therapy for a chronic hepatitis B virus infection for the past 10 years.
• Physical exam: mild icterus (jaundice) and hepatomegaly. There were no signs of ascites or hepatic encephalopathy.
• ECOG performance status: 1
• Imaging: CT scan of chest, abdomen, and pelvis, with triphasic liver evaluation: 4.5-cm LI-RADS 5 hepatic mass in the right lobe plus metastatic disease in the lung
• Laboratory results: alanine aminotransferase 68 U/L; aspartate aminotransferase 70 U/L; total bilirubin 2.6 mg/dL; serum albumin 3.9 g/dL; international normalized ratio 2.2; alfa-fetoprotein 480 ng/mL; HBsAg positive; Hepatitis B surface antigen negative; Hepatitis B viral DNA (viral load: 1.5 × 105 IU/mL)
• Clinical diagnosis: Hepatocellular carcinoma (HCC), stage IV, classified as Child-Pugh: B7
• Biopsy was obtained and confirmed the diagnosis of HCC.
• Due to autoimmune disease (Crohn), a nonimmunotherapy was chosen.
• Lenvatinib (Lenvima) 12 mg once daily initiated.

PEERS & PERSPECTIVES IN ONCOLOGY: What data support the use of lenvatinib in a patient like this?

GHOLAM: The evidence that led to the approval of lenvatinib comes from an open-label, phase 3, multicenter, noninferiority trial called REFLECT [NCT01761266], which compared lenvatinib at doses of either 8 or 12 mg, depending on whether your body weight is less than 60 kg or more than 60 kg, vs sorafenib [Nexavar] given in the usual manner at 400 mg twice daily. Patients had unresectable HCC. They had to have 1 lesion you could see. They were stratified by hepatitis B status because the study heavily enrolled in Asia, where hepatitis B is the main driver of disease. The primary end point was [noninferior] overall survival [OS], and there were many secondary end points, but the ones we’ll pay attention to are PFS [progression-free survival] and objective response rate [ORR].

The median OS for lenvatinib was 13.6 months vs 12.3 months, for an HR of 0.92 [95% CI, 0.79-1.06], and this was examined.¹ It met the noninferiority end point, but when they tested for superiority, that did not pan out.

What is clearly superior is the PFS. Lenvatinib had a 7.4-month median PFS vs 3.7 months for sorafenib [HR, 0.66; 95% CI, 0.57-0.77; P < .0001]. The median time to progression was 8.9 months vs 3.7 months, respectively [HR, 0.63; 95% CI, 0.53-0.73; P < .0001], and ORR is almost 3 times greater for lenvatinib at 24% vs 9% for sorafenib.

CASE UPDATE

• The patient experienced modest weight loss and reported loss of appetite leading to a dose reduction to 8 mg once daily, and she was referred for nutritional therapy.
• Imaging at 16 weeks: Partial response
• Eight months after initiation of therapy: Treatment discontinued due to disease progression.

What data are there comparing lenvatinib with atezolizumab (Tecentriq) plus bevacizumab (Avastin)?

This is a real-world study.² I will emphasize this is not a randomized controlled trial. These are data primarily from France and Italy for a group of patients who are taking atezolizumab/bevacizumab vs lenvatinib in the setting of Child-Pugh B disease. This is of interest because all the trials exclude patients who have Child-Pugh B disease. These patients received this treatment until they were no longer deemed candidates for it by their physicians. There were 217 patients; 30% got atezolizumab/bevacizumab and 70% got lenvatinib.

There was a smattering of etiologies with a substantial representation of viral hepatitis and nonviral hepatitis. A good percentage of these patients had surgery. Most of these patients had a good performance status, either 0 or 1. These patients mostly had metastatic disease, primarily extrahepatic disease with some portal vein thrombosis.

If you look at complete response rates, they were 4% and 3% in the lenvatinib and atezolizumab/bevacizumab arms, respectively, and a partial response rate of 31% and 15% in the lenvatinib and atezolizumab/bevacizumab arms, respectively. ORR was doubled for lenvatinib vs sorafenib in this group [35% vs 18%], and disease control rate was just about the same [65% vs 55%, respectively].

There appears to be a more favorable OS in the lenvatinib Kaplan-Meier survival curves compared with the atezolizumab/bevacizumab curves. If you look at PFS, the 2 Kaplan-Meier curves are almost completely superimposed.

Looking at OS for BCLC [Barcelona Clinic Liver Cancer] B—that’s intermediate-stage disease, not metastatic disease—vs BCLC C, which is metastatic disease, in the intermediate-stage disease, although the curves eventually meet up at about 20 months, there may be an early, more favorable response with lenvatinib. In the setting of metastatic disease, this is not so much the case, perhaps making the case that for the patient who has more progressive liver disease who does not have metastatic disease, it may not be a bad idea to give them lenvatinib.

There are some adverse events [AEs] you never see with TKIs, like immune-mediated AEs, and some you never see with immune checkpoint inhibitors, like hand-foot-skin reaction. There was more diarrhea in the lenvatinib arm [and] hypertension in both because bevacizumab gives you hypertension.

What other observational data on treatment for Child-Pugh B disease are available?

Almost 12 years ago, we started the GIDEON registry. This is an observational registry of patients who, at the time, were taking sorafenib. There was no other treatment than sorafenib. This registry has over 5000 patients, but they reported data on 3371 patients.³ This had the unique capability of taking patients with all stages. Back then we would give sorafenib even to someone with Child-Pugh B cirrhosis which is very advanced disease, although that was a much smaller proportion of patients.

If you look at the OS and PFS, not shockingly at all, for patients who had very advanced liver disease, that drove primarily their mortality in Child-Pugh C patients. They had a much steeper mortality than patients who had Child-Pugh B than patients who have Child-Pugh A. Within Child-Pugh B, there were some interesting notable differences. Child-Pugh B is a continuum. It’s not a monolith, and patients who had [B9], tended to do poorer than patients who had B7 [Table³]. B7 is typically someone who has excellent preserved liver function but maybe only a trace amount of ascites.

Did REFLECT yield data on treating patients with Child-Pugh B status?

There was a post hoc analysis from REFLECT.⁴ There is a subset of patients who started with Child-Pugh A status and then became Child-Pugh B at 8 weeks post randomization. They took those patients and they analyzed them, and they did landmark analysis at week 8.

If you look at those patients, the complete response rate for Child-Pugh A was about 2%, and 0% for the Child-Pugh B group [with lenvatinib]. Partial response rate was 40% [for Child-Pugh A] and 28% for the Child-Pugh B group. Stable disease was not very different. Progressive disease rates were 16% and [20%], respectively. ORR was about 42% for Child-Pugh A vs [28.8% for Child-Pugh B], respectively. So, clearly, the patient who progressed over time potentially had worse outcomes from a variety of standpoints.

Looking at PFS, clearly patients who have Child-Pugh A did best, then patients who have Child-Pugh B were next after that. But both of these were better than the sorafenib Child-Pugh A and Child-Pugh B arms. That is even more true in the OS curves, where Child-Pugh A lenvatinib vs sorafenib were very similar, but Child-Pugh B with lenvatinib had a considerably better Kaplan-Meier OS curve than Child-Pugh B with sorafenib.

_REFERENCES

_{1. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1}

_{2. Rimini M, Persano M, Tada T, et al. Survival outcomes from atezolizumab plus bevacizumab versus lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients. J Cancer Res Clin Oncol. 2023;149(10):7565-7577. doi:10.1007/s00432-023-04678-2}

_{3. Marrero JA, Kudo M, Venook AP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65(6):1140-1147. doi:10.1016/j.jhep.2016.07.020}

_{4. Huynh J, Cho MT, Kim EJH, Ren M, Ramji Z, Vogel A. Lenvatinib in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function. Ther Adv Med Oncol. 2022;14:17588359221116608. doi:10.1177/17588359221116608}