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Phase I/II Trial Opens Door to New Drug Class for Hepatocellular Carcinoma

Carlson, Robert H.

doi: 10.1097/01.COT.0000467333.49491.03


CHICAGO—Overexpression of PD-L1 in hepatocellular carcinoma (HCC) has a poor prognosis, but a Phase I/II study of the anti-PD-1 antibody nivolumab saw a 19 percent response rate among 42 evaluable patients. The data were presented here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA101).

Importantly, the responses have been durable and surpassed 12 months in four patients, and the overall survival rate at 12 months was 62 percent, said the lead author, Anthony B. El-Khoueiry, MD, Assistant Professor of Clinical Medicine and Medical Director of the Clinical Investigations Support Office at the University of Southern California Norris Comprehensive Cancer Center.

“This is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer.”

Nivolumab is a fully human IgG4 monoclonal antibody PD-1 inhibitor. The trial enrolled patients with histologically confirmed advanced hepatocellular carcinoma with Child-Pugh scores of B7 or greater, and progressive disease while taking sorafenib, or intolerant of or refusing to take sorafenib. A total of 75 percent of patients had prior treatment—68 percent with sorafenib.

Sorafenib is the only FDA-approved systemic treatment for HCC. “There is no standard of care after treatment with sorafenib,” El-Khoueiry said

Dose escalation for the 47 patients occurred in parallel cohorts based on etiology: patients with no active hepatitis C or hepatitis B virus infection (24); patients infected with hepatitis C (12); and patients infected with hepatitis B (11). Patients received nivolumab at 0.1 to 10 mg/kg intravenously for up to two years.

The primary endpoint was safety; secondary endpoints included antitumor activity using mRECIST criteria, pharmacokinetics, and immunogenicity.



El-Khoueiry said that 73 percent of patients had extrahepatic metastasis and/or portal vein invasion. Eighteen patients remain on study, and 23 discontinued treatment: 17 due to progressive disease, two due to complete response, two due to drug-related adverse events, and two due to non drug-related adverse events. Drug-related adverse events of any grade occurred in 29 patients (71%).

Grade 3 and 4 adverse events occurred in 19 percent of patients, including AST increase, ALT increase, and lipase increase, but these were not symptomatic, El-Khoueiry said.

The objective response rate was 19 percent (eight patients) defined as tumor shrinkage beyond 30 percent, with complete responses in two patients (both uninfected), and partial responses in patients with hepatitis B or C viral infections as well as in uninfected patients.

El-Khoueiry reported that 62 percent of patients were still surviving with HCC at 12 months.

He concluded his presentation by putting immunotherapy research into a broader perspective: “Obviously not everyone responds to immunotherapy, and even though these therapies have shown durable responses in several tumor types, at some point there is resistance and the therapy does fail. So the future is about finding ways to stimulate the immune system in different ways at the same time.”

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Few Options

The current standard targeted therapy for HCC, the tyrosine kinase inhibitor sorafenib, has a duration of response of approximately two months, and an overall survival rate of less than one year, noted ASCO President Peter Paul Yu, MD, Director of Cancer Research at the Palo Alto Medical Foundation, speaking in an interview before the meeting.

“We didn't have any evidence that immunotherapy is important in treating liver cancer, but we don't have a lot of options,” he said.

Liver cancer is common around the world, Yu said, “and it is a cancer we think will be increasing in the U.S. as a consequence of obesity leading to fatty liver disease leading to increased cirrhosis, and anything that causes cirrhosis takes you to liver cancer.”

He said the objective responses of 19 percent reported in this study were “a big deal”—moreover, two of the 39 patients had a complete response, which is unheard of in this disease. And the duration for these two complete responses was 14 months and 17 months, in a disease for which there is no effective, systemic therapy.”

Yu said these results are a strong signal that immunotherapy can apply to other cancers.

During a news conference at the meeting, the moderator, Lynn Schuchter, MD, said PD-1 immunotherapies continue to break new ground in diseases where nothing else seems to work well: “The fact that this drug might stop advanced liver cancer in its tracks for months, even a year, is great news for patients.”

To understand the full impact of this approach, however, of course, larger trials are needed, she said.

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iPad Extra!



Listen to a podcast interview with Anthony El-Khoueiry, MD, Associate Professor of Clinical Medicine at the University of Southern California Norris Comprehensive Cancer Center, on the iPad edition of this issue, conducted by Peter Goodwin. El Khoueiry assesses the potential role of nivolumab in advanced liver cancer; and Lynn Schuchter MD, Chief of Hematology/Oncology at Abramson Cancer Center of the University of Pennsylvania, provides additional perspective.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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