REACH-2 Indicates Ramucirumab Efficacy For HCC Patients With High α-Fetoprotein

Hepatocellular carcinoma patients with an α-fetoprotein concentration of at least 400 ng/mL have better overall survival with second-line ramucirumab than placebo

medwireNews: The REACH-2 study has achieved its primary endpoint of improved overall survival (OS) with second-line ramucirumab therapy compared with placebo for patients with hepatocellular carcinoma (HCC) and elevated serum α-fetoprotein. 

After a median follow-up of 7.6 months, median OS was 8.5 months for the 197 patients who were randomly assigned to receive the VEGFR2 inhibitor ramucirumab at a dose of 8 mg/kg every 2 weeks versus 7.3 months for the 95 patients who were given placebo, giving a significant hazard ratio (HR) for death of 0.710.  

Progression-free survival was also significantly better with ramucirumab than placebo, at a median of 2.8 versus 1.6 months and a HR of 0.452, although the objective response rate did not significantly differ between the groups, at 5% vs 1%. 

The most common grade 3 and more severe treatment-emergent adverse events reported in the ramucirumab and control arms were hypertension (13 vs 5%), hyponatraemia (6 vs 0%) and elevated aspartate aminotransferase (3 vs 5%). Serious adverse events at any grade occurred in a corresponding 35% and 29% of participants; three patients in the ramucirumab arm died from treatment-related causes, namely acute kidney injury, hepatorenal syndrome and renal failure. 

Noting that “roughly half” of patients who have stopped sorafenib treatment have α-fetoprotein concentrations of 400 ng/mL or higher, the researchers suggest that “[t]he efficacy and safety results of the pivotal REACH-2 study show that ramucirumab could be a well-tolerated second-line treatment” in this population.

And they add: “The safety profile also makes ramucirumab a good potential candidate for assessment in combination with other agents, including immune checkpoint inhibitors, and in previous lines of therapy.”

The investigators explain in The Lancet Oncology that the patients had all previously received first-line sorafenib for HCC alone or with cirrhosis. The patients had Barcelona Clinic Liver cancer stage B or C disease, Child-Pugh class A liver Disease, and an ECOG performance status of 0 or 1.  

In addition, the patients had an α-fetoprotein serum concentration of at least 400 ng/mL, which has previously been associated with a poor prognosis and elevated VEGFR expression. 

“To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma”, say Andrew Zhu, from Harvard Medical School in Boston, Massachusetts, USA, and co-investigators.  

However, the author of a linked comment writes that there is not a validated cutoff for elevated α-fetoprotein concentration and suggests that higher concentrations are “probably coincidental and happen to manifest in patients with advanced disease” so that its “effect on prognosis seems dependent on when it is measured.” 

Ghassan Abou-Alfa, from Memorial Sloan Kettering Cancer Center in New York, USA, therefore concludes: “The findings of REACH-2 are positive, but they are not, as Zhu and colleagues claim, the first positive findings from a phase 3 study done in a biomarker-selected patient population with hepatocellular carcinoma.”



Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised , double-blind, placebo-controlled, phase 3 trial . Lancet Oncol; Advance online publication 18 January 2019. S1470-2045(18)30937-9

Abou-Alfa GK. Ramucirumab and the controversial role of α -fetoprotein in hepatocellular carcinoma . Lancet Oncol; Advance online publication 18 January 2019. S1470-2045(19)30009-9

medwireNews ( ) is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group