FDA Approves Second-Line Ramucirumab in AFP-Elevated HCC

The FDA has approved ramucirumab (Cyramza) monotherapy for patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/ML and have been previously treated with sorafenib (Nexavar).¹

The approval was based on findings from the international, double-blind, placebo-controlled, multicenter phase III REACH-2 trial, in which the median overall survival (OS) was 8.5 months with ramucirumab compared with 7.3 months with placebo (HR, 0.71; 95% CI, 0.53-0.95, P = .020) in patients who experienced progression on or intolerance to frontline sorafenib.

Results of REACH-2, which were previously presented at the 2018 ASCO Annual Meeting, also showed that the survival benefit was consistent across all prespecified subgroups.² The 12- and 18-month OS rates both favored ramucirumab at 36.8% versus 30.3% and 24.5% versus 11.3%, respectively. Moreover, 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).

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.^3,4 However, a prespecified subgroup analysis revealed a significant survival benefit in patients with AFP levels ≥400 ng/mL. These data 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. In the study, patients were randomized 2:1 to receive ramucirumab intravenously (IV) at 8 mg/kg plus best supportive care or placebo/best supportive care every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included PFS, time to progression, response rate, time to symptom deterioration, and safety.

The data analysis included 292 patients randomized to ramucirumab (n = 197) or placebo (n = 95). The median age was 64, and men accounted for approximately 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 compared with 6.6 months in the experimental and control arms, respectively. The objective response rate showed a numerical advantage for the ramucirumab arm (4.6% vs 1.1%; nonsignificant at P = .1697 ). However, the disease control rate for ramucirumab was significantly higher than with placebo at 59.9% versus 38.9%, respectively (P = .0006).

Regarding safety, ramucirumab was associated with more treatment-related adverse events (AEs), but it was generally well tolerated. The most commonly reported grade ≥3 AEs in the ramucirumab arm were hypertension (12.2%), ascites (4.1%), and fatigue (3.6%). Moreover, 10.7% of patients in the ramucirumab arm discontinued treatment because of AEs, and 3 fatal treatment-related AEs occurred in the group. One-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%).

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.

References

1. FDA Approves Ramucirumab for Hepatocellular Carcinoma. FDA. Published May 10, 2019. https://bit.ly/2HeWrD7. Accessed May 10, 2019.
2. 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).
3. 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.
4. 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.