Ramucirumab Extends Survival in Advanced HCC

Second-line ramucirumab (Cyramza) reduced the risk of death by 29% versus placebo in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein.

Andrew X. Zhu, MD, PhD

Second-line ramucirumab (Cyramza) reduced the risk of death by 29% versus placebo in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP), according to results from the phase III REACH-2 trial presented at the 2018 ASCO Annual Meeting.1

The median overall survival (OS) was 8.5 months with ramucirumab versus 7.3 months with placebo (HR, 0.710; 95% CI, 0.531-0.949, P = .0199) among patients with progression on or intolerance to first-line treatment with sorafenib (Nexavar). Survival in both groups exceeded statistical assumptions of the trial design (4.7 months with placebo, improved to 6.5 months with ramucirumab).

The survival benefit was consistent across all prespecified subgroups. The 12- and 18-month OS rates both favored ramucirumab at 36.8% versus 30.3% and 24.5% versus 11.3%, respectively. The median progression-free survival (PFS) was 2.8 months with ramucirumab compared with 1.6 months with placebo (HR, 0.452; 95% CI, 0.339-0.603; P <.0001). Ramucirumab was associated with more treatment-related adverse events (AEs), but was generally well tolerated.

“The REACH-2 trial is the first positive study in a biomarker-selected patient population, demonstrating a significant and meaningful overall survival benefit and favorable safety profile in hepatocellular carcinoma patients with baseline alpha-fetoprotein greater than or equal to 400 ng/mL, a population associated with poor prognosis,” said Andrew Zhu, MD, PhD, a liver cancer specialist at Massachusetts General Hospital. “Clinically meaningful benefits were demonstrated in secondary endpoints, including progression-free survival and disease control rate.”

In the previously reported REACH trial of patients with advanced HCC, treatment with ramucirumab did not significantly improve OS in the intention-to-treat population (Lancet Oncol 2015;16:859-870).2,3 However, a prespecified subgroup analysis revealed a significant survival benefit in patients with AFP levels ≥400 ng/mL. The observation provided a rationale for a follow-up trial to evaluate ramucirumab in patients with HCC associated with elevated AFP.

Eligibility criteria for the REACH-2 trial included a diagnosis of HCC and Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh score of A, AFP ≥400 ng/mL, disease progression with first-line sorafenib, and disease refractory to or not amenable to local treatment. Patients were randomized 2:1 to ramucirumab or placebo, and the primary endpoint was OS. Secondary endpoints included PFS, time to progression, response rate, time to symptom deterioration, and safety.

Data analysis included 292 randomized patients (197 to ramucirumab, 95 to placebo) enrolled at centers in North and South America, Europe, Israel, Australia, and Asia (excluding Japan). Patients received best supportive care plus either placebo or ramucirumab (8 mg/kg IV) every 2 weeks.

The patients had a median age of 64, and men accounted for about 80% of the study population. A majority of patients had Child-Pugh score A-5, more than 80% had BCLC stage C, and disease etiology was hepatitis B or C in about two-thirds of cases.

The median follow-up time was 7.9 versus 6.6 months in the experimental and control arms, respectively. The objective response rate showed a numerical advantage for the ramucirumab group (4.6% vs 1.1%; nonsignificant at P = .1697 ). Comparison of disease control rates showed a significant advantage for the ramucirumab arm (59.9% vs 38.9%; P = .0006).

The most commonly reported grade ≥3 AEs in the ramucirumab arm were hypertension (12.2%), ascites (4.1%), and fatigue (3.6%). Zhu reported that 10.7% of patients in the ramucirumab arm discontinued treatment because of AEs, and 3 fatal treatment-related AEs occurred in the group. A third of the patients in the ramucirumab group required dose adjustments to manage treatment-related AEs.

Analysis of AEs of special interest also showed low rates of grade ≥3 events in the ramucirumab arm, including liver injury/failure (18.3%, including ascites), hypertension (12.7%), and bleeding/hemorrhage (5.1%).

“REACH-2 confirms the efficacy and safety observed in the prespecified group of patients from REACH with AFP greater than or equal to 400 ng/mL,” said Zhu.

In the previously reported data from the randomized phase III REACH study, the median OS in the full, unselected population was 9.2 months with ramucirumab compared with 7.6 months with placebo (HR, 0.87; 95% CI, 0.72-1.05; P = .14). The numerical difference of 1.6 months between the 2 arms did not cross the barrier for statistical significance.

In the planned analysis of patients with HCC and elevated AFP, the median OS for patients with a baseline AFP ≥400 ng/mL was 7.8 months in the ramucirumab arm compared with 4.2 months with placebo (HR, 0.674; 95% CI, 0.51-0.90; P = .0059). In contrast, for patients with a baseline AFP <400 ng/mL, the median OS was 10.1 months with ramucirumab versus 11.8 months with placebo.

Worldwide, HCC is the second leading cause of cancer mortality, and patients with advanced disease have limited options. Elevated AFP has been associated with aggressive disease and poor prognosis.


  1. Zhu AX, Kang Y-K, Yen C-J, 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;36 (suppl; abstr 4003).
  2. Zhu AX, Ryoo B-Y, Yen C-J, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 232.
  3. Zhu AX, Park JO, Ryoo B-Y, 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(7):859-870. doi: 10.1016/S1470-2045(15)00050-9.
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