Consistent Treatment Benefit With Ramucirumab Across Staging in HCC

Masatoshi Kudo, MD

Better rates of overall survival (OS) were observed in patients with intermediate-stage hepatocellular carcinoma (HCC) who had an elevated baseline alpha fetoprotein (AFP) level when ramucirumab (Cyramza) was used as second-line therapy after sorafenib (Nexavar) compared with second-line placebo. These improvements occurred irrespective of patients' Barcelona Clinic Liver Cancer (BCLC) stage and were based on results of a pooled analysis of the phase III REACH and REACH-2 trials.¹

Among the subset of patients with AFP ≥400 ng/mL who participated in the trials, 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, 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 REACH²and REACH-2,³ramucirumab 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.

In the AFP ≥400 ng/mL subset, the overall response rate (ORR) and disease control rate (DCR) were numerically higher in the ramucirumab arm compared with the placebo arm, irrespective of baseline BCLC stage. In stage B, the ORR was 17% in the ramucirumab arm versus 5% in the placebo arm; in stage C, the ORR rates were 4% and 1%, respectively. DCRs in stage B were 80% with ramucirumab and 59% with placebo, and in stage C, DCRs were 54% and 35%, respectively.

Grade ≥3 treatment-emergent adverse events were consistent with observations from both individual studies; hypertension was the most frequent grade ≥3 adverse event with ramucirumab regardless of disease stage (17%, stage B; 12%, stage C). No difference in liver function measures was observed between arms in either BCLC stage.

References:

1. Kudo M, Finn RS, Morimoto M, et al. Ramucirumab for patients with intermediate-stage hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): Pooled results from two phase III studies (REACH and REACH-2).J Clin Oncol.2020;38(suppl4;abstr 549). meetinglibrary.asco.org/record/182363/abstract.
2. Zhu AX, Park JO, Ryoo BY, et al, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.Lancet Oncol. 2015;16:859—70.
3. Zhu AX, Kang YK, Yen CJ, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib.J Clin Oncol. 2018(suppl):abstract 4003.

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