Etiology of HCC Plays a Critical Role in Treatment Choice as Landscape Grows, Says Mody


Kabir Mody, MD, discusses the evolution of the hepatocellular carcinoma treatment landscape over the past year during a presentation at the 2018 International Society of Gastrointestinal Oncology.

Kabir Mody, MD

The treatment landscape for unresectable hepatocellular carcinoma (HCC) has achieved significant growth over the past year with the addition of several new agents, including the FDA-approved multikinase inhibitor lenvatinib (Lenvima) as a new frontline treatment option after a nearly 10-year drought.

“We [have evolved] certainly in the last couple of years with HCC, and I think that there is a lot more progress to come. The evolution will get faster and faster as the years go [on],” said Kabir Mody, MD, during a presentation at the 2018 International Society of Gastrointestinal Oncology.

Decisions for first-line treatments for patients with HCC between lenvatinib or other upcoming treatments and the established standard of care for frontline therapy may depend, in part, on the etiology of the disease, suggested Mody, an assistant professor of medicine at Mayo Clinic in Jacksonville, Florida.

Hepatitis C is the most common [underlying etiology] for HCC in the United States, according to Mody. Others include hepatitis B, alcoholic liver disease, fatty liver disease, aflatoxin, and additional causes of cirrhosis.

“Given the clinical and preclinical data that we have, we may want to think about, from a sequencing standpoint, the etiology of the patient’s underlying liver disease as a way to separate out who we put on sorafenib [Nexavar] versus who we put on other drugs,” he said.

Sorafenib was previously the only available targeted therapy in HCC since its FDA approval in 2007. However, in August 2018, the FDA approved lenvatinib as a frontline treatment option for patients with unresectable disease, based on the phase III REFLECT trial.1

In the international, randomized, noninferiority trial, patients (n = 954) with unresectable HCC received frontline treatment with lenvatinib at either 8 mg or 12 mg once per day based on body weight (n = 478) or sorafenib at 400 mg twice daily (n = 476). Nearly a fifth of patients had more than 3 sites of disease involvement, and half of patients had underlying hepatitis B infection.

Lenvatinib demonstrated an improvement in progression-free survival (PFS) by 3.7 months and was shown to be noninferior for overall survival (OS) compared with sorafenib. The median OS for lenvatinib was 13.6 months (95% CI, 12.1-14.9) compared with 12.3 months (95% CI, 10.4-13.9) with sorafenib (HR, 0.92; 95% CI, 0.79-1.06), meeting the criteria for non-inferiority.

“Overall, the OS with lenvatinib was deemed noninferior to sorafenib; however, the PFS [showed a] statistically significant improvement with lenvatinib,” Mody said.

During his presentation, Mody also noted slightly different toxicity profiles between the 2 multikinase inhibitors.

Grade 3/4 adverse events (AEs) were more common with lenvatinib versus sorafenib (52% vs 49%, respectively). The most common any-grade AEs for lenvatinib were hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31%). Palmar-plantar erythrodysesthesia (52%), diarrhea (46%), hypertension (30%), and decreased appetite (27%) were the most common any-grade AEs in the sorafenib arm.

The decision between lenvatinib and sorafenib should largely be based on the patient’s etiology of underlying liver disease, according to Mody. “The etiology does play a critical role in HCC and we prefer to look at [this factor] as a stratification in clinical studies. For example, sorafenib has a multitude of mechanisms and we know from preclinical data that the hepatitis C core protein has activating activities upon Raf, ERK, and MEK.”

In a phase II study of sorafenib, phosphorylated extraceullular signaling-regulated kinase (pERK) levels correlated with investigator-assessed median time to progression (TTP) in patients (n = 137) with unresectable HCC who received no prior systemic therapy.2

Thirty-three patients had tissue available for tumor-cell pERK staining and comparative analysis. Of these patients, there was a significantly significant difference in TTP between patients with higher tumor-cell pERK staining intensity (2 to 4+, n = 18) versus those with lower intensity (0 to 1+, n = 15;P= .00034). Patients with tumors expressing higher pERK levels had a longer TTP.

Among all patients, the median TTP was 4.2 months and the median OS was 9.2 months.

“These data suggest that tumors containing higher levels of pERK are more sensitive, or respond, to sorafenib,” the authors of the study concluded.


  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. 2016;391(10126): 1163-1173. doi: 10.1016/S0140-6736(18)30207-
  2. Abou-Abou GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2006;24(26):4293-4300. doi: 10.1200/JCO.2005.01.3441.
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