Ramucirumab for Patients with Intermediate-Stage Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Results from Two Phase 3 Studies (REACH and REACH-2)

Abstract

<b><i>Background:</i></b> Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. <b><i>Methods:</i></b> A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0–1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. <b><i>Results:</i></b> Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546–1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23–0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59–0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. <b><i>Conclusions:</i></b> Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.

Clinical Evaluation of Ramucirumab for the Treatment of Hepatocellular Carcinoma (HCC): Place in Therapy

“… 37 Benefits of ramucirumab were consistent with those of the overall population regardless of the race. Furthermore, ramucirumab treatment benefits were observed regardless of patient age, 38 , 39 liver disease stage, 40 prior transarterial chemoembolization (TACE), 41 and reason for sorafenib discontinuation. 42 These are summarized in Table 3 .…”

Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma

“… 1 , 115 Retrospective studies suggested that systemic therapy may achieve better ORR and PFS compared with TACE in intermediate-stage HCC patients with high tumor burden. 116 , 117 Currently clinical practice guidelines suggest upfront systemic therapy for intermediate-stage HCC with huge bilobar tumors or infiltrative tumors. 11 , 13 , 14 , 31 Clinical trials of upfront systemic therapy, on the other hand, generally enrolled patients whose tumors exceeded the Milan criteria or the up-to-seven criteria ( Table 5 ).…”

Withdrawn

“…Data were extracted from REFLECT [16], RESORCE [5], and CELESTIAL [6] trials for LENVA, Regorafenib (REGO), and Cabozantinib (CABO), respectively. For Ramucirumab (RAMU), data were extracted from a pooled meta-analysis of independent patient data [17] from REACH [18] and REACH-2 [7] trials. Characteristics of the included RCTs are showed in online supplementary Tables 1 and 2 (for all online suppl.…”

“…OS curves of patients treated with second-line therapies were extracted from all 8 phase III RCTs [3,4,[11][12][13][14][15][16] for SORA and from REFLECT [16], RESORCE [5], and CELESTIAL [6], for LENVA, REGO, and CABO, respectively. For RAMU, data were extracted from a pooled meta-analysis of independent patient data [17] including patients with AFP higher than 400 ng/mL from REACH and REACH-2 trials [7,18].…”