Ramucirumab Improves Survival in Poor-Prognosis HCC

Liam Davenport

June 21, 2018

BARCELONA, Spain — Ramucirumab (Cyramza, Lilly), a monoclonal antibody that inhibits vascular endothelial growth factor receptor 2 activation, significantly improves survival in a subset of patients with hepatocellular carcinoma (HCC) who have high levels of the plasma protein α-fetoprotein (AFP), which is associated with a poor prognosis.

The finding comes from a pooled analysis of two clinical trials, in which there were more than 500 patients with raised AFP levels (≥400 ng/mL).

In this subgroup of patients, ramucirumab improved overall survival over placebo in such patients by 31%, extending median survival by 3 months.

It also increased progression-free survival (PFS) and objective response rates (ORRs) and was well tolerated, with few additional adverse effects, reported Andrew X. Zhu, MD, PhD, director of Liver Cancer Research at Massachusetts General Hospital, Boston.

He presented the new data here at the 2018 World Congress on Gastrointestinal Cancer (WCGC).

Highlighting to the audience that the survival benefit was "consistent and robust across all subgroups," Zhu said, "Ramucirumab represents an important new potential treatment option for patients with advanced HCC and elevated AFP, a population associated with aggressive disease."

Approached for comment, Eric van Cutsem, MD, PhD, from University Hospital Gasthuisberg, Leuven, Belgium, and co-chair of the Congress, told Medscape Medical News that the pooled analysis shows that ramucirumab "probably has a role in the poor prognosis group with high AFP."

However, he pointed out that the management of HCC "is rapidly evolving," adding: "We have the checkpoint inhibitors, we have also second-line regorafenib and cabozantinib."

Van Cutsem said that the current study "puts a new drug on the plate, and what we have to figure out in the future is the algorithm and what is its place."

He underlined that there are also early data looking at the combination of checkpoint inhibitors with angiogenesis inhibitors, alongside trials looking at bevacizumab plus atezolizumab, as well ramucirumab with a checkpoint inhibitor.

Nevertheless, van Cutsem said that with these latest data on ramucirumab, "I'm happy to see that it brings a new weapon in the armamentarium."

Details of the Pooled Analysis

Zhu began his presentation by noting that the efficacy of ramucirumab in patients with HCC previously treated with sorafenib had been explored in two phase 3 trials: REACH and REACH-2. The latter met its primary endpoint of improved overall survival with ramucirumab vs placebo in patients with baseline AFP levels of 400 ng/mL or greater.

Because REACH and REACH-2 were both global, randomized, placebo-controlled phase 3 trials with similar protocols and treatment regimens, the researchers undertook a pooled analysis of the two datasets at the individual-patient level to better assess the efficacy and safety of the drug.

The researchers included 250 patients from the REACH study with AFP levels of at least 400 ng/mL at baseline, as well as all 292 participants from REACH-2. All patients had previously been treated with sorafenib, had Barcelona Clinic Liver Cancer stage B/C, and had an Eastern Cooperative Oncology Group performance status of 0 or 1.

The patients  were randomly assigned in a 1:1 (REACH) or 2:1 (REACH-2) fashion to ramucirumab 8 mg/kg or placebo, plus best supportive care, and treated until disease progression or unacceptable toxicity.

In both studies, the primary endpoint was overall survival, with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), and safety.

Most (80.3%) patients were male, and the median age was 63 years. Macrovascular invasion was present in 35.1% of patients, and 73.% had extrahepatic spread of their disease. Sorafenib was discontinued because of disease progression in 87.1% of cases.

Initially looking at the two studies separately, Zhu said that the reduction in mortality risk with ramucirumab was consistent, at a hazard ratio of 0.710 (P = .0199) in REACH-2 and 0.674 (P = .0059) in REACH patients with baseline AFP of 400 ng/mL or greater.

In the pooled analysis, ramucirumab was associated with a significant improvement in median overall survival, at 8.1 months vs 5.0 months, or a gain of 3.1 months, at a hazard ratio of 0.694 (P = .0002).

Zhu noted that no heterogeneity in treatment effect was seen across the studies. Moreover, a random-effect frailty model adjusted for study yielded a result similar to that of the pooled analysis, at a hazard ratio of 0.689 (P = .0002).

He added that preplanned analyses "demonstrated the consistent benefit across different prespecified subgroups, with a confidence interval excluding 1 in most categories".

In some subgroups, the overall survival benefit of ramucirumab was no longer significant, including female patients, patients from Asia (excluding Japan), those in whom the disease cause was hepatitis C, and patients who had undergone prior locoregional therapy.

However, Andreas Sashegyi, PhD, Eli Lilly and Company, Indianapolis, Indiana, who was not directly involved in the study, told Medscape Medical News that the differences are "entirely consistent with the play of chance, including the differential for gender."

Indeed, he said that the study is "almost surprisingly consistent in terms of the results," adding that, with so many subgroups, "it is to be expected" that there would be some differences, which are driven by the small overall sample size.

Sashegyi added that "there is no basis, really, for reading anything into that observed difference."

The results from the pooled analysis also showed that ramucirumab was associated with a significant improvement in PFS vs placebo, at 2.8 months vs 1.5 months or a hazard ratio of 0.572 (P < .0001).

The overall ORR was also significantly improved with ramucirumab, at 5.4% vs 0.9% for placebo (P = .0064), as was the disease control rate, at 56.3% vs 37.2% (P < .0001).

Zhu said that the adverse effect profile seen in the study was "as expected," with relatively similar rates of grade 3 or greater adverse events of special interest across the ramucirumab and placebo groups.

Patients receiving ramucirumab  were, however, more likely than those given placebo to experience grade 3 or greater hypertension, at a rate of 12.7% vs 3.6%, and hepatic encephalopathy, at 2.8% vs 0.4%.

The study was sponsored by Eli Lilly and Company. Andrew Zhou declares research funding from Bayer, Bristol-Meyers Squibb, Eli Lilly, Merck, and Novartis, and consulting for AstraZeneca, Bayer, Bristol-Meyers Squibb, Eisai, Eli Lilly, Exelixis, Merck, Novartis, and Sanofi. Van Cutsem declares grant/research support from Amgen, Boehringer Ingelheim, Celgene, Ibsen, Lilly, Merck, MSD, Novartis, Roche, Servier; consulting for Bristol-Meyers Squibb; and speakers ' bureau for Bayer, Bristol-Meyers Squibb, Celgene, Lilly, Novartis, and Servier.

20th World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-001. Presented June 20, 2018.

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