Final analysis: Randomized, blinded, placebo-controlled phase II trial of sorafenib with and without mapatumumab in patients with advanced hepatocellular carcinoma (HCC).

4029 Background: TRAIL is a member of the tumor necrosis factor ligand super family that induces programmed cell death primarily in tumor cells (including liver tumors) through TRAIL death receptors. Mapatumumab (M) is an agonistic monoclonal antibody that targets one of the TRAIL death receptors, TRAIL-R1, and may promote apoptosis of cancer cells. Methods: Patients (Pts) with chemotherapy-naive advanced HCC were randomized 1:1 to sorafenib 400 mg BID continuously + IV Placebo (SP) or sorafenib 400 mg BID continuously + mapatumumab 30 mg/kg (SM) on day 1 every 21 days. Stratification variables were BCLC C vs B, and ECOG PS 0 vs 1, 2. Eligibility: bilirubin < 3 mg/dL, AST and ALT ≥ 5 x ULN, and INR ≥ 1.5. Radiologic progression was determined by blinded independent central review. The primary endpoint was time to progression (TTP). The sample size of 100 was sufficient to estimate median TTP with a precision of -1.9 to +2.6 months (mo). Results: 101 pts were in the ITT population: 51 SP and 50 SM. Treatment arms were balanced for the stratification variables. Demographics (SP vs SM): mean AFP 3177.7 vs 1534 mg/L, Male 76.5% vs 52%, Age 60.8 vs 60 years. Median (med) duration of M dosing was 3.3 mo and 84% pts received ≥ 90% of planned dose. Med cumulative sorafenib (S) dose (SP vs SM) was 73600 vs 75200 mg; 52.9% (SP) and 54% (SM) received ≥ 90% of the planned S dose. Conclusions: The addition of mapatumumab to sorafenib did not improve TTP (primary endpoint) or other efficacy endpoints. The combination did not substantially change the toxicity profile of sorafenib. Clinical trial information: NCT01258608.Efficacy and safety. Treatment groups SP SM N 51 50 Median TTP (mo)1 5.6 4.1 Median TTP at ECOG 0 (mo) ECOG 1 or 2 (mo) BCLC Stage C(mo) BCLC Stage B (mo) 6.9 5.6 5.4 11.1 4.1 4.2 4.2 4.1 Median OS (mo) 10.1 10.0 Overall Response (pts) 5 7 % % AEs of interest to S and M Diarrhea 37.3 32.0 Blood bilirubin increased 17.6 14.0 Rash 7.8 12.0 Related AEs to S/M Blood bilirubin increased 5.9/3.9 4.0/2.0 Fatal AEs 25.5 24.0 Serious AEs 51.0 40.0 Gastrointestinal disorders 11.8 12.0 1P-value 0.7382, HR (90% CI) 1.192 (0, 1.737). P-value for comparison of treatment groups from stratified log-rank test – stratified by BCLC and ECOG PS.