Antibody Gets High Marks in Small Hepatocellular Carcinoma Trial

Photo by ©AACR/Phil McCarten 2012

Ignacio Melero, MD, PhD

Three-fourths of patients with advanced hepatocellular carcinoma (HCC) associated with hepatitis C (HCV) infection achieved disease control with antibody therapy directed at a T-cell antigen, according to data from a preliminary clinical study presented at the 2012 AACR Annual Meeting.

Two of 17 evaluable patients had partial responses and 11 others had stable disease during treatment with tremelimumab, a CTLA-4 receptor antagonist. The entire cohort had a median progression-free survival of 6.4 months and a median overall survival of 7.5 months.

Patients also had substantial declines in viral load, suggesting a possible role for the antibody in treating HCV.

“A disease control rate in excess of 75% and a time to progression longer than 4 months suggest that tremelimumab could be active against hepatocellular carcinoma,” said Ignacio Melero, MD, PhD, a consultant oncologist at the Universidad de Navarra in Pamplona, Spain. “These results show that further clinical development of this agent is warranted in both hepatocellular carcinoma and HCV infection.”

Worldwide, HCC is the second-leading cause of cancer death, and HCV infection is the principal causative factor for HCC in most Western populations, said Melero. Sorafenib (Nexavar) is the only systemic therapy shown to extend survival in patients with advanced HCC.

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A disease control rate in excess of 75% and a time to progression longer than 4 months suggest that tremelimumab could be active against hepatocellular carcinoma.”

—Ignacio Melero, MD, PhD

Tremelimumab has demonstrated activity in several preclinical cancer models and has produced evidence of efficacy in melanoma. The agent had not been tested in HCC, nor had its antiviral activity been evaluated. However, Melero and colleagues had evidence of lymphocyte invasion in HCC and CTLA-4 expression in HCV, providing a rationale for clinical investigation of tremelimumab in HCV-associated HCC.

Investigators enrolled 21 patients with HCC and HCV infection and treated 20 with the antibody. The median number of treatment courses was two, and some patients received as many as four courses.

Analysis of target lesion response showed that four patients had progressive disease during treatment. The remaining 13 derived clinical benefit in the form of stable disease or partial response.

Investigators found that viral load also decreased in response to tremelimumab. The patients had a baseline mean of 3.78 x 105 copies, which had declined significantly at day 120 to 3.02 x 104 copies (P = .02), and then to 1.69 x 103 copies on day 210 (P = .04). The difference from baseline was no longer significant by day 300 but remained lower compared with baseline out to 360 days.

Some patients had particularly dramatic declines in viral load, transiently achieving undetectable levels in some cases, Melero reported.

In general, tremelimumab was well tolerated. Although most patients had treatment-related adverse events, the most common were mild or moderate rash, itching, liver-enzyme elevation, fatigue, diarrhea, constipation, and anorexia. Some patients had marked but transient increases in liver enzymes after the initial dose of therapy, but none demonstrated evidence of liver failure.

Melero I, Sangro B, Riezu-Boj JI, et al. Antiviral and antitumoral effects of the anti-CTLA4 agent tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection: Results from a phase II clinical trial. Presented at the American Association for Cancer Research; March 31-April 4, 2012; Chicago, IL. Abstract 4387.