Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial

Abstract

Background The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) C 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. Methods Patients with advanced HCC and AFP C 400 ng/ mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP C 400 ng/mL. Results In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in Electronic supplementary material The online version of this article (

Better Efficacy of Ramucirumab in Japanese Patients than in the Global Population with Unresectable Hepatocellular Carcinoma

“…In the Japanese cohort, the objective response rate determined by RECIST 1.1 was 9.8% in the ramucirumab arm (95% CI, 2.4–17.3) compared with 2.5% in the placebo arm (95% CI, 0–7.3), with a disease control rate of 67.2% in the ramucirumab arm (55.4–79.0) and 35.0% (20.2–49.8) in the placebo arm. These results were more favorable than the corresponding results in the overall global population despite a higher baseline AFP level in the Japanese cohort (7,373 ng/mL) than in the global cohort (4,105 ng/mL) (Table 6) [3, 14].…”

“…The results of pooled analysis in REACH (AFP ≥400 ng/mL) and REACH-2 were reported for both the Japanese and global cohorts (Table 6) [3, 14]. The OS of the placebo arm was shorter in REACH (AFP ≥400 ng/mL) (4.2 months) than in REACH-2 (7.3 months), which may be attributed to the considerably higher AFP value (7,022 ng/mL) in REACH (AFP ≥400 ng/mL) as compared with that (2,741 ng/mL) in REACH-2 (Table 6).…”

“…In the subgroup analysis, the Japanese population of REACH-2 showed a median OS of 10.2 months in the ramucirumab group compared with 5.4 months in the placebo group (HR: 0.599; 95% CI, 0.303–1.187, p = 0.1377). OS and HR were more favorable in the Japanese population than in the overall global population (OS: 10.2 vs. 8.5 months, respectively, and HR: 0.599 vs. 0.710, respectively) [14] (Table 5) despite a higher baseline AFP in the Japanese cohort (7,942 ng/mL) than in the global cohort (3,920 ng/mL) (Table 5). Similarly, PFS in the Japanese cohort was 4.1 months in the ramucirumab arm and 1.7 months in the placebo group (HR: 0.282; 95% CI, 0.144–0.553; p < 0.0001; Table 5) [14].…”

“…OS and HR were more favorable in the Japanese population than in the overall global population (OS: 10.2 vs. 8.5 months, respectively, and HR: 0.599 vs. 0.710, respectively) [14] (Table 5) despite a higher baseline AFP in the Japanese cohort (7,942 ng/mL) than in the global cohort (3,920 ng/mL) (Table 5). Similarly, PFS in the Japanese cohort was 4.1 months in the ramucirumab arm and 1.7 months in the placebo group (HR: 0.282; 95% CI, 0.144–0.553; p < 0.0001; Table 5) [14]. These results were more favorable than those obtained in the global cohort (PFS = 2.8 months; HR = 0.452).…”

“…The safety profile in Japanese population was extremely favorable too: the only adverse events with a grade ≥3 were hypertension in 6 patients (14.6%) and loss of appetite in 2 patients (4.9%). Liver function impairment was observed in 11 patients (26.8%), of which 3 (7.3%) presented with ≥ grade 3 liver dysfunction [14].…”