Masatoshi Kudo, MD, PhD
Ramucirumab (Cyramza) as second-line therapy after sorafenib (Nexavar) induces improved overall survival (OS) compared with placebo, irrespective of BCLC (Barcelona Clinic Liver Cancer) stage, in patients with intermediate-stage hepatocellular carcinoma (HCC) and an elevated baseline level of alpha fetoprotein (AFP), according to an exploratory analysis of pooled results from 2 phase III studies.
Among the subset of patients with AFP ≥400 ng/mL who participated in REACH2
the median OS in patients randomized to ramucirumab was 8.1 months compared with 5.0 months in placebo recipients (HR, 0.69; 95% CI, 0.57-0.84). That advantage was maintained in patients with BCLC stage B HCC, in whom median OS was 13.7 versus 8.2 months in the ramucirumab and placebo arms, respectively (HR, 0.43; 95% CI, 0.23-0.83), as well as in patients with BCLC stage C disease, in whom median OS was 7.7 months in the ramucirumab arm versus 4.8 months in the placebo arm (HR, 0.72; 95% CI, 0.59-0.89).1
The median progression-free survival (PFS) was also superior in the patients with AFP ≥400 ng/mL randomized to ramucirumab, regardless of BCLC stage. In BCLC stage B, the median PFS was 4.2 months versus 2.8 months in the ramucirumab and placebo arms (HR, 0.33; 95% CI, 0.17-0.64), respectively; and in BCLC stage C, median PFS was 2.8 and 1.5 months (HR, 0.60; 95% CI, 0.49-0.74), respectively. In the overall pooled population of patients with AFP ≥400 ng/mL from the 2 trials, median PFS was 2.8 months in the ramucirumab group and 1.5 month in the placebo group (HR, 0.57; 95% CI, 0.47-0.69).1
These data were reported at the 2020 GI Cancers Symposium by Masatoshi Kudo, MD, PhD, professor and chairman, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
“Currently transarterial chemoembolization [TACE] is guideline-recommended standard of care for intermediate-stage HCC in many countries,” he said. “Early introduction of systemic therapy such as targeted agents or immunotherapy may become standard of care for patients with intermediate-stage HCC with high tumor burden so we looked at only intermediate-stage patients with high tumor burden. In this substudy, OS and PFS were better with treatment in the intermediate-stage patients compared with advanced stage.” Many patients in this analysis received prior TACE, he noted.
In both REACH and REACH-2, ramucirumab was investigated in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline AFP ≥ 400 ng/mL.
REACH is a multinational randomized phase III trial investigating ramucirumab as second-line treatment following first-line therapy with sorafenib in patients with advanced HCC. Inclusion criteria included BCLC stage B/C, Child-Pugh class A, and ECOG performance status of 0 or 1. Patients were randomly allocated to ramucirumab (n = 283), 8 mg/kg intravenously on day 1 of a 14-day cycle, or placebo (n = 282). The primary endpoint, OS, in the ramucirumab group was 9.2 months (95% CI, 8.0-10.6) versus 7.6 months in the placebo group, a difference that was not significant (HR, 0.87; 95% CI, 0.72-1.05). On subgroup analysis, it was discovered that in patients with a baseline AFP level ≥400 ng/mL (n = 250), OS in the ramucirumab group was 7.8 months versus 4.2 months in the placebo group (HR, 0.67; 95% CI, 0.51-0.90, P = .006).
REACH-2 (N = 292) expanded on this subgroup finding by enrolling only patients with a baseline AFP ≥400 ng/mL, randomizing them in a 2:1 ratio to ramucirumab (n = 197) or placebo (n = 95).
The median OS was 8.5 months in the ramucirumab arm versus 7.3 months in the placebo arm, and the difference was significant (HR, 0.710; 95% CI, 0.531-0.949; P = .0199). This advantage to ramucirumab occurred despite baseline imbalances in favor of the placebo group: the median baseline AFP level was 3920 ng/mL in the ramucirumab group and 2741 ng/mL in the placebo group.
No patients with BCLC stage B disease had macrovascular invasion or extrahepatic spread. I stage C, about 40% had macrovascular invasion and 79% (ramucirumab arm) and 84% (placebo arm) had extrahepatic spread. Fifty percent (placebo arm) and 73% (ramucirumab arm) of patients with BCLC stage B HCC had prior TACE compared with 55% overall in patients with stage C HCC.
Median baseline AFP level in stage B patients was 1817 ng/mL in the ramucirumab arm and 2958 ng/mL in the placebo arm. In stage C patients, median baseline AFP levels were 4472 and 4375 ng/mL in the 2 arms, respectively.
On multivariate analysis, along with baseline AFP, baseline BCLC staging emerged as an independent prognostic factor for the OS difference between ramucirumab and placebo.