Ramucirumab (RAM) as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline α-fetoprotein (AFP): An analysis of AFP kinetics in the phase III REACH-2 study.

326 Background: REACH-2 (NCT02435433) demonstrated a significant survival benefit with RAM vs placebo in the second-line treatment of patients with advanced HCC and AFP ≥ 400 ng/mL. This analysis investigated changes in AFP during treatment, as well as potential relationships with survival or progression. Methods: Patients were randomized (2:1) to RAM 8 mg/kg IV or placebo Q2W plus best supportive care until disease progression or unacceptable toxicity. Serum AFP levels were measured at baseline and every 3 cycles. Percent change in AFP from baseline was analyzed at each time point up to Cycle 12 with descriptive statistics and Wilcoxon rank sum test between treatment arms. AFP response was defined as ≥ 20% decrease from baseline. The association between AFP progression and radiographic progression in each time interval was assessed by odds ratio [OR] and Fisher’s exact test. Time to AFP progression and time to radiographic progression (TTP) were evaluated by the Kaplan-Meier method and compared between treatment arms using a stratified log-rank test. AFP progression was defined as ≥ 20% increase from baseline. Hazard ratio (HR) was generated using a stratified Cox regression model. Results: AFP response was significantly higher with RAM compared with placebo (42.1% vs 10.5%, p < 0.0001). Overall survival (OS) was longer in patients with AFP response (13.5 months) than in patients without (6.7 months), irrespective of treatment (HR 0.470, p < 0.0001). The median percent increase in AFP level from baseline was smaller in the patient population treated with RAM (0.4%, 6.1%, 15.4%, 10.8%) than with placebo (45.7%, 98.5%, 122.2%, 91.3%) at Cycles 3, 6, 9 and 12, respectively. Time to AFP progression (HR 0.422, p < 0.0001) and TTP (HR 0.427, p < 0.0001) favored a RAM benefit; subsequent analyses demonstrated a strong association between AFP progression and radiographic progression at 6 weeks (OR 2.44, p < 0.0084) and at 12 weeks (OR 1.89, p = 0.0430). Conclusions: Changes in AFP levels were associated with TTP and OS. RAM prolonged time to AFP progression and radiographic TTP, and slowed the rate of AFP increase during treatment. Clinical trial information: NCT02435433.