Experts Anticipate a Growing Menu of Frontline Options in Liver Cancer

Christin Melton, ELS
Published: Wednesday, Jul 04, 2018
Aiwu Ruth He, MD, PhD

Aiwu Ruth He, MD, PhD

The recent introduction of novel therapies for patients with hepatocellular carcinoma (HCC) ended a 10-year drought in new drugs for the tumor type and may represent the leading edge of a wave of change in how the malignancy is managed, according to experts who participated in an OncLive Peer Exchange® program.

In 2017, the FDA approved regorafenib (Stivarga) and nivolumab (Opdivo) for patients with HCC previously treated with sorafenib (Nexavar). Sorafenib, a multikinase inhibitor, was approved for unresectable HCC in 2007, making it the first systemic therapy for advanced liver cancer. For a decade, it was the only available targeted therapy for HCC, and patients whose disease stopped responding to the drug had few options other than enrolling on a clinical trial.

Now, researchers say several promising new agents are poised to join the growing armamentarium. “The landscape for hepatocellular carcinoma is shifting. I suspect we will have more frontline therapy options to choose from,” A. Ruth He, MD, PhD, said during the Peer Exchange panel discussion.

The panelists reviewed data for lenvatinib (Lenvima), which is under priority review by the FDA as a firstline treatment for HCC, and for novel drugs under investigation in the second line, such as cabozantinib (Cabometyx/Cometriq) and pembrolizumab (Keytruda). The panelists agreed that although novel treatments offer benefits, they introduce new challenges for clinicians, including sequencing and management of adverse events (AEs), especially for patients with comorbid liver diseases.

Emerging First-Line Approaches

Lenvatinib

Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor and fibroblast growth factor (FGF) receptors, platelet-derived growth factor receptor α, and the RET and KIT oncogenes.1 Lenvatinib was compared with sorafenib in the randomized multicenter phase III REFLECT trial that enrolled patients with untreated, unresectable HCC (N = 954).1 “There was a fair response rate with lenvatinib; over 20% of patients—1 in 4 patients—had a partial response [PR],” Catherine Frenette, MD, said. In comparison, sorafenib was associated with a 9% PR rate.1 Compared with the sorafenib arm, the lenvatinib arm demonstrated significantly longer time to progression (9 vs 4 mo; P <.0001) and longer progression-free survival (PFS; 7 vs 4 mo; P <.0001).1 Frenette said it was interesting that these superior outcomes in the lenvatinib arm “didn’t translate to a statistically significant prolonged overall survival [OS] with lenvatinib compared with sorafenib.” The study found lenvatinib noninferior to sorafenib.1 A new drug application for lenvatinib based on the REFLECT findings is pending, with the FDA scheduled to make a decision by August 24, 2018.

Dr He said that, absent an evidence-based strategy for choosing between sorafenib and lenvatinib in the first line, clinicians will have to consider each agent’s toxicity profile. Ghassan K. Abou- Alfa, MD, who moderated the program, said that although he agreed that AEs would be a factor in treatment selection, “There are other things that can play a role as well.” He pointed to the 2 drugs’ different molecular targets and the significant improvements in OS and PFS with lenvatinib in the subgroup of patients with an α-fetoprotein (AFP) level ≥200 ng/mL (HR, 0.78 and 0.59, respectively).1

Riccardo Lencioni, MD, said a patient’s hepatitis status might be another consideration. “There are data that suggest that patients with hepatitis B–related cirrhosis and HCC will have less benefit from sorafenib than patients with hepatitis C–related cirrhosis and HCC,” he said. A 2017 meta-analysis of 3 trials involving 1643 patients found that sorafenib improved OS in patients negative for hepatitis B virus (HBV) and positive for hepatitis C virus (HCV) but not for patients positive for HBV.2 Lencioni said the data suggest “one could prioritize sorafenib for HCV HCC patients and lenvatinib for HBV HCC patients.”

Checkpoint Immunotherapy

The checkpoint inhibitor nivolumab is also being compared with sorafenib as frontline therapy in the randomized phase III CheckMate-459 trial, which has a primary endpoint of OS. “These are previously untreated patients with advanced HCC, Child-Pugh A, who will be randomized to nivolumab versus the current standard of care, sorafenib,” said Anthony B. El-Khoueiry, MD. He said he believed the trial has completed accrual and results are pending.


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