Aiwu Ruth He, MD, PhD

Decisions in the Clinic: Treating Patients With Hepatocellular Carcinoma

Question

After a patient is diagnosed with hepatocellular carcinoma (HCC), what are the first treatment options you consider? What are the key patient factors that influence your decision making?

Answer

The stage of the hepatocellular carcinoma is the key patient factor that influences my decision making. The patient needs to be evaluated by the multidisciplinary team to determine if the patient is a candidate for curative treatment options [such as] curative resection or liver transplantation. Patients without curative treatment options will be evaluated for palliative local-regional therapy and systemic therapy.

Question

What is the role of molecular profiling in HCC management? In what ways can it be useful to have a tissue diagnosis for patients?

Answer

HCC can be diagnosed by the American Association for the Study of Liver Diseases (AASLD) image criteria if the lesions in the cirrhotic liver meet the hallmark imaging characteristics during the multiphasic flow of contrast, including arterial phase hyperenhancement, subsequent washout appearance, and capsule appearance. If the liver lesions do not meet the image criteria of HCC, biopsy is needed to make the diagnosis.

Currently, molecular profiling of HCC is not a standard of care procedure used to determine the treatment plan for HCC. However, there are emerging, promising clinical trials that select HCC patients based on specific gene mutation or gene expression for treatment, such as the Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma (ClinicalTrials.gov Identifier: NCT02834780). In this study, the patient is enrolled in only if his or her HCC overexpresses the FGF19 gene.

Question

What research from the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting did you find to be most relevant to treating patients with hepatocellular carcinoma?

Answer

The outcome data from CELESIAL trial and REACH-2 studies added two additional treatment options in the treatment of advanced-stage HCC [cabozantinib and ramucirumab], pending US Food and Drug Administration (FDA) approval.^1,2

The early promising data on the combination immune therapy as presented in two posters at ASCO 2018 were also interesting.

First, the “Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC)” (ClinicalTrials.gov Identifier: NCT02715531) poster showed that among 21 efficacy-evaluable patients with a minimum follow-up of 16 weeks and a median survival follow-up of 8.3 months, partial responses occurred in 13 patients (62%) regardless of HCC etiology, region (Asia or US), baseline a-fetoprotein levels (greater than or equal to 400 ng/mL or less than 400 ng/mL), or extrahepatic spread of tumor.³ The median estimates for progression-free survival, duration of response, time to progression and overall survival have not yet been reached.

Second, a phase 1b trial of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma (uHCC) (ClinicalTrials.gov Identifier: NCT03006926).⁴ Among 26 efficacy-evaluable patients, the overall response rate was 42%, with 1 patient in CR and 10 patients in PR. No unexpected safety signals were observed. The data suggest that combining this anti-VEGF and immune checkpoint inhibitor may induce a synergistic response in HCC treatment.

The combinations of atezolizumab plus bevacizumab and lenvatinib plus pembrolizumab are being evaluated in randomized phase 3 studies.

In addition, early clinical data from a phase 1/2 trial combining the anti-PD-L1 and CTLA-4 immunotherapy agents durvalumab and tremelimumab (ClinicalTrials.gov Identifier: NCT02519348) demonstrated safety and a durable ORR of 18%.⁵

The combination of anti-PD-L1 and CTLA-4 immunotherapy is being compared with sorafenib in a randomized, multicenter phase 3 study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study (ClinicalTrials.gov Identifier: NCT03298451).

Question

How might the data on agents like cabozantinib (e.g., from the CELESTIAL trial), lenvatinib (REFLECT trial), and ramucirumab (REACH-2) change your decision making for patients?

Answer

The treatment landscape for advanced stage HCC is evolving, with the recent FDA approval of regorafenib (based on findings in the RESORCE trial⁶) and nivolumab (Checkmate-040 trial7) treatment in 2017, and lenvatinib (REFLECT trial⁸) in August of 2018, following the approval of the first systemic therapy sorafenib in 2007.

In the CELESTIAL trial, cabozantinib was shown to prolong the overall survival compared to placebo in patients with unresectable HCC and who had one or two lines of systemic therapy.¹ Cabozantinib treatment is currently under review by FDA for approval.

In the REACH-2 trial, ramucirumab has shown a significant survival benefit that reduced the risk of death (29%) compared to the placebo in patients with HCC and AFP greater than or equal to 400 ng/mL that progressed on or were intolerant to sorafenib.²

Both cabozantinib and ramucirumab are currently under review by FDA for approval.

We now have 2 approved first-line therapies: sorafenib and lenvatinib, and 2 approved second-line therapies: regorafenib and nivolumab.

Two additional second-line or beyond therapies are under FDA review for approval: cabozantinib and ramucirumab. There are no data to support using 1 treatment over the other, or how the treatment should be sequenced.

It is good news that patients with advanced HCC have many systemic treatment options, and management of the side effects of each treatment carefully is the key to improve patient’s outcome.

Question

Are there any ongoing clinical trials you would recommend for patients with advanced, unresectable HCC?

Answer

Yes, several including IMbrave150: A randomized phase 3 study of 1L atezolizumab plus bevacizumab vs sorafenib in locally advanced or metastatic hepatocellular carcinoma (ClinicalTrials.gov Identifier: NCT03434379); Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase 1b study in hepatocellular carcinoma (HCC) (ClinicalTrials.gov Identifier: NCT02715531); A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study (ClinicalTrials.gov Identifier: NCT03298451); a phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC) (ClinicalTrials.gov Identifier: NCT03006926); and a Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma (ClinicalTrials.gov Identifier: NCT02834780).