Ramucirumab After Sorafenib in Advanced Hepatocellular Carcinoma: An Efficacious Therapy With Applicability Challenges

Get Permission

Thomas A. Abrams, MD

Thomas A. Abrams, MD

In the 2 years since the U.S. Food and Drug Administration’s (FDA) approval of regorafenib in the treatment of patients with sorafenib-refractory advanced hepatocellular carcinoma, we oncologists have witnessed a veritable avalanche of newly approved medicines for the treatment of advanced hepatocellular carcinoma. Lenvatinib was recently approved as an alternative to sorafenib in the first-line treatment of advanced hepatocellular carcinoma, based on the results of the phase III REFLECT study, which met its primary endpoint of overall survival noninferiority to sorafenib.1 Cabozantinib, pembrolizumab, and nivolumab have all been approved for treatment of patients previously treated with sorafenib. Notably, cabozantinib was the only one of these three drugs to gain FDA approval on the strength of a randomized, placebo-controlled phase III study (CELESTIAL).2 With the publication of REACH-2 in The Lancet Oncology earlier this year,3 ramucirumab may well be the next drug to gain FDA approval in the treatment of sorafenib-experienced patients.

Eligibility Criterion: Cornerstone of REACH Trials

As reviewed in this issue of The ASCO Post, REACH-2 was a randomized, double-blind, phase III clinical trial conducted at 92 centers in 20 countries; it compared ramucirumab, a human immunoglobulin G1 monoclonal antibody that inhibits ligand activation of vascular endothelial growth factor (VEGF) 2, with placebo in patients with advanced hepatocellular carcinoma who had previously received sorafenib. Further eligibility criteria included preserved liver function (Child-Pugh A cirrhosis) and performance status (Eastern Cooperative Oncology Group 0 or 1), as well as α-fetoprotein concentrations of at least 400 ng/mL.

The α-fetoprotein eligibility criterion was a cornerstone of the study and was based on observations from the preceding REACH trial, which studied a prespecified subpopulation of 250 patients with advanced, sorafenib-refractory hepatocellular carcinoma and α-fetoprotein titers of 400 ng/mL or higher. Of the patients with high α-fetoprotein titers enrolled in the REACH trial, those randomly assigned to receive ramucirumab had a statistically significant overall survival advantage over those randomly assigned to placebo.4 The fact that the REACH trial failed to meet its overall survival endpoint spurred initiation of REACH-2.

Key Findings From REACH-2

A total of 292 subjects were randomly assigned to REACH-2 in a 2:1 fashion (197 in the ramucirumab arm and 95 in the placebo arm). Approximately half of the patients were treated in the Americas, Europe, Australia, and Israel, whereas the remaining half received treatment in Asia. The study arms were well balanced, although patients randomly assigned to receive ramucirumab had a substantially higher median α-fetoprotein titer compared with those who received placebo (3,920 vs 2,741 ng/mL).

The median overall survival was significantly greater in the ramucirumab arm than in the placebo group (8.5 vs 7.3 months, 95% confidence interval [CI] = 0.531–0.949). The median progression-free survival was also greater in the ramucirumab arm (2.8 vs 1.6 months, 95% CI = 0.339–0.603). A pooled analysis combining REACH-2 subjects with those from the initial REACH trial who had high α-fetoprotein titers confirmed these findings.

Ramucirumab was well tolerated. The most frequently reported treatment-emergent adverse events in the ramucirumab arm were fatigue (27%), peripheral edema (25%), hypertension (25%), and decreased appetite (23%). Hypertension and hyponatremia were the sole grade 3 or higher adverse events to occur in at least 5% of study subjects at significantly greater frequencies in the ramucirumab arm.

‘Unique’ Trial With Tumor-Specific Biomarker Threshold

REACH-2 is unique among the many clinical trials performed in the post-sorafenib advanced hepatocellular carcinoma population. It employed a hepatocellular carcinoma–specific biomarker threshold (α-fetoprotein ≥ 400 ng/mL) to determine eligibility.

The authors do not argue that α-fetoprotein provides an unambiguous window into hepatocellular carcinoma disease biology, but they cite well-known data showing that higher α-fetoprotein titers are consistently linked to worse outcomes in advanced hepatocellular carcinoma.5 This finding may be related to the observation that cases of hepatocellular carcinoma associated with higher α-fetoprotein titers are correlated with greater VEGF pathway activity. If so, it provides a possible rationale for why ramucirumab may have specific utility in a population with high α-fetoprotein titers.6

Irrespective of the mechanism, it is an unquestioned boon to our patients to have a well-tolerated drug with proven efficacy in patients with hepatocellular carcinoma who have high α-fetoprotein titers. Provided it is ultimately approved by the FDA, ramucirumab will likely have a clearly defined role in what has now become a crowded second-line space.

Challenges of Treating Real-World Patients

The REACH-2 investigators are to be commended for completing a well-designed trial. However, it suffers from the same applicability challenges that have plagued nearly all clinical trials in advanced hepatocellular carcinoma over the past decade. Due to restrictive eligibility criteria for enrollment, clinical trial subjects are highly selected and representative of just a small fraction of those with advanced hepatocellular carcinoma typically seen in an oncology clinic. The patients with advanced hepatocellular carcinoma we treat in our clinics tend to have poorer liver function and more baseline debility. Many have inadequate social supports. As a result, administering systemic therapies to them is often fraught with amplified toxicities and diminished benefits.

Ramucirumab will likely prove beneficial to many patients who would not have qualified for a clinical trial. That said, we won’t know how ramucirumab actually will perform in an average hepatocellular carcinoma population until we begin to use it in the clinic. For the reasons enumerated here, data from REACH-2 will almost certainly underestimate the inherent difficulties of treating an average population with advanced hepatocellular carcinoma. Well-designed postapproval patient registries can mitigate these issues and provide valuable insights into future clinical trial design. Oncologists have considerable experience incorporating postlabel dose and schedule refinements of cancer medicines into clinical practice. These adjustments minimize the toxicities of these treatments without compromising their efficacy, allowing our patients to enjoy happier, healthier lives despite their incurable, difficult-to-treat malignancies. 

Dr. Abrams is Assistant Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston.

DISCLOSURE: Dr. Abrams has stock and/or ownership interests in Jounce Therapeutics, Guardant Health, and InVitae; is a consultant/advisor with Aduro Biotech, Bristol-Myers Squibb, Kaleido Biosciences, Exelixis/Ipsen, Eisai, Merck, and Bayer; has received research funding from Lilly; and has provided expert testimony for Genentech.


1. Kudo M, Finn RS, Qin S, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 391:1163-1173, 2018.

2. Abou-Alfa GK, Meyer T, Cheng AL, et al: Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379:54-63, 2018.

3. Zhu AX, Kang YK, Yen CJ, 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 20:282-296, 2019.

4. Zhu AX, Park JO, Ryoo BY, 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 16:859-870, 2015.

5. Silva JP, Gorman RA, Berger NG, et al: The prognostic utility of baseline alpha-fetoprotein for hepatocellular carcinoma patients. J Surg Oncol 116:831-840, 2017.

6. Choi SB, Han HJ, Kim WB, et al. VEGF overexpression predicts poor survival in hepatocellular carcinoma. Open Med (Wars) 12:430-439, 2017.

Related Articles

Ramucirumab in Sorafenib-Pretreated Patients With Advanced Hepatocellular Carcinoma

In the phase III REACH-2 trial reported in The Lancet Oncology, Andrew X. Zhu, MD, of Harvard Medical School and Massachusetts General Hospital, and colleagues found that ramucirumab improved overall and progression-free survival vs placebo in patients with advanced hepatocellular carcinoma and...