Andrew X. Zhu, MD, PhD
Treatment with second-line ramucirumab (Cyramza) improved median overall survival (OS) by 3.1 months compared with placebo in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels ≥400 ng/ml, according to combined results from the phase III REACH and REACH-2 trials presented at the 2018 World GI Congress.
In the prespecified pooled analysis of the studies (N = 542), the median OS was 8.1 months with ramucirumab compared with 5.0 months for placebo, representing a 30.6% reduction in the risk of death with the VEGFR2 inhibitor (HR, 0.694; 95% CI, 0.571-0.842; P
= .0002). In a random effects model, the treatment benefit with ramucirumab remained consistent, with a 31.1% reduction in the risk of death (HR, 0.689; P
"Ramucirumab's overall survival treatment benefit was consistent and robust across all subgroups and sensitivity analyses, including random effect models, were also consistent," said lead investigator Andrew X. Zhu, MD, PhD, director, Liver Cancer Research, Massachusetts General Hospital. "Ramucirumab represents an important new potential treatment option for patients with HCC and elevated AFP, a population associated with poor prognosis and aggressive disease."
Both phase III trials enrolled patients treated with prior sorafenib with a BCLC stage of B or C and Child-Pugh A HCC. The REACH-2 study only enrolled only those with elevated AFP levels (≥400 ng/ml), based on observed superiority in subgroup analyses of the REACH investigation. The median baseline AFP across all patients in the pooled analysis was 408 ng/ml, and levels were similar between the placebo and ramucirumab arms, Zhu noted.
In both studies, ramucirumab was administered at 8 mg/kg intravenously every 2 weeks. Best supportive care was provided across both cohorts. OS was the primary endpoint, with secondary endpoints focused on objective response rate (ORR) and progression-free survival (PFS).
The median age of patients across studies was 63 years, and the ECOG performance status was primarily 0 (53.7%). Nearly half of patients were from the Americas, Europe, Israel, and Australia (48.3%) compared with other regions. Baseline BCLC stage was C for 86.3% of patients and the majority discontinued prior sorafenib due to progressive disease (87.1%). Baseline etiologies included Hepatitis B (41.7%), Hepatitis C (25.6%), and significant alcohol use (21%). Three-fourths of patients had extrahepatic spread (73.2%) and 35.1% had macrovascular invasion.
In the REACH-2 study, the median OS was 8.5 months with ramucirumab compared with 7.3 months for placebo (HR, 0.710; 95% CI, 0.531-0.949; P
= .0199). In the REACH study, for those with AFP ≥400 ng/ml, the median OS was 7.8 versus 4.2 months (HR, 0.674; 95% CI, 0.508-0.895; P
= .0059). Treatments received following discontinuation of the study had a limited impact on OS, Zhu noted, with a less than 1 month impact in each group.
"The primary endpoint of REACH-2 was met, patients with advanced HCC who received ramucirumab versus placebo demonstrated improved overall survival benefit in patients with baseline high AFP, at greater than 400 ng/ml, confirming the benefit we observed in REACH in the same population," said Zhu.
Across the pooled analysis, the median PFS was 2.8 months with ramucirumab compared with 1.5 months for placebo (HR, 0.572; 95% CI, 0.472-0.694; P
<.0001). The ORR was 5.4% with ramucirumab compared with 0.9% for placebo (P
= .0064). The disease control rate, which combines stable disease with ORR, was 56.3% versus 37.2% for ramucirumab and placebo, respectively (P
OS consistently favored ramucirumab across subgroups, with statistically significant findings. "There was a consistent benefit across prespecified subgroups, with a confidence interval below 1 in most subgroups," said Zhu.
Grade ≥3 adverse events of special interest for the ramucirumab arm versus placebo, respectively, included liver injury/liver failure (19.9% vs 26.5%), hypertension (12.7% vs 3.6%), and bleeding/hemorrhage events (4.7% vs 6.7%). Of the liver-related events, grade ≥3 ascites and hepatic encephalopathy were higher in the ramucirumab group (ascites, 4.7% vs 4.0%; encephalopathy, 2.8% vs 0.4%). For the bleeding events, there were no differences seen between groups for epistaxis and GI hemorrhage.
"As predicted, incidence of low-grade proteinuria (18.7% vs 5.4%) and infusion-related reactions (9.5% vs 3.1%) were also higher in the ramucirumab arm versus placebo," said Zhu. "Other potentially related events were infrequent and comparable between the 2 arms."
Ramucirumab was initially approved in the United States in 2014 and was approved in Europe in 2015. The agent is approved across a variety of settings and indications for patients with advanced gastric or gastro-esophageal junction adenocarcinoma, non–small cell lung cancer, and colorectal cancer. A regulatory submission for ramucirumab as a treatment for HCC is planned in the coming months.
Zhu A, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety across two global randomized Phase 3 studies (REACH-2 and REACH). Ann Oncol. 2018;29 (suppl 5; abstr LBA-001).
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