Abstract 4387: 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

Abstract Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. The safety and therapeutic effects of this immunostimulating agent were explored in 20 patients (pts) (median age 68, 71% males) with chronic HCV infection and advanced HCC (57% BCLC C, 43% Child B, 28% portal vein invasion, 28% AFP > 400 UI/ml). Tremelimumab was administered at a dose of 15 mg/kg IV every 90 days for a median of 2 cycles (range 1-4). Two patients are still under treatment and have received 2 cycles. Tumor response was analyzed in 20 pts that had at least one of the imaging evaluations planned at 3-monthly intervals. Two of these 20 pts had a partial response (12%) and 11 pts had stable disease (65%) as the best tumor response (disease control rate 76.4%). The duration of stable disease was > 12 months in 33% of pts (excluding the 2 pts that are still on treatment). In an intention-to-treat analysis, median overall survival and time to progression were 7.5 months (95%CI 4.6-18.0) and 6.4 months (95%CI 3.9-9.1), respectively. Tremelimumab was globally very well tolerated. 80% of pts had treatment-related adverse events (AE), the most frequent being mild to moderate rash (40%), itching (45%), increased transaminases (30%), fatigue (20%), diarrhea (10%), constipation (10%), and anorexia (10%). Some patients showed a marked, transient increase in transaminases after the first dose that did not result in liver failure. CTCAE v.3.0 grade > 3 treatment-related AE included pruritus (1 case), purpura (1 case) and elevated transaminases (5 cases). No life-threatening AE was observed. A significant and progressive decline in serum HCV viral load was observed (median values: basal 3.78x10e5 copies/ml vs day 120 3.02x10e4 copies/ml, p=0.02; vs day 210 1.69x10e3 copies/ml, p=0.04). This was associated with an increase in anti-HCV immune response in 76% of patients (evaluated by measuring at different time points IFN-g spot forming cells after incubation of PBMC with pools of peptides spanning the whole HCV polyprotein and recombinant core, NS3, NS4 and NS5 proteins). A significant increase in circulating CD4+Foxp3+ cells was also observed at day 30. In conclusion, in this preliminary analysis Tremelimumab has shown a promising antitumor efficacy against HCC and an intense antiviral activity against HCV together with an excellent safety profile even among patients with advanced cirrhosis. Further clinical trials are needed to explore the potential role of Tremelimumab in the treatment of HCV infection and HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4387. doi:1538-7445.AM2012-4387