Nick Mulcahy

April 09, 2013

Washington, DC — Promising results from a phase 3 trial of the investigational agent ramucirumab (Lilly) suggest that there will eventually be a new standard of care in advanced gastric cancer.

Principal investigator Charles Fuchs, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, presented the findings here at the American Association for Cancer Research 104th Annual Meeting

He and his colleagues compared second-line ramucirumab with placebo in patients with gastric or gastroesophageal junction metastatic cancer.

Median overall survival was better in the 238 patients who received ramucirumab than in the 117 patients who received placebo (5.2 vs 3.8 months), Dr. Fuchs reported.

This difference means that ramucirumab significantly reduced all-cause mortality by 22%, compared with placebo (hazard ratio [HR] for overall survival, 0.78; P = .0473).

"This represents the first single-agent biologic therapy that has improved survival in gastric cancer and gastroesophageal junction cancer," Dr. Fuchs told Medscape Medical News in an interview.

There was a 52% reduction in disease progression with ramucirumab (HR, 0.48; P <.0001). Median progression-free survival was 2.1 months with ramucirumab and 1.3 months with placebo.

These improvements seem modest, Dr. Fuchs acknowledged. However, the benefits seen in the second line with ramucirumab are equal to the duration of benefit seen in the first line with platinum- and/or fluoropyrimidine-containing combination chemotherapy, he noted.

"This could really change second-line therapy," said Dr. Fuchs.

I'm thrilled that we were able to move the needle a little bit

The prognosis of these patients is not good, he noted. Patients who are newly diagnosed with gastric or gastroesophageal junction metastatic cancer have a median survival of only 8 to 10 months. "I'm thrilled that we were able to move the needle a little bit" with ramucirumab, Dr. Fuchs said.

Another clinician stopped short of saying that the experimental agent is a potential new standard of care in the second line.

Instead, Luis Diaz, MD, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, said that ramucirumab will be a "new agent in the physician's toolbox for the treatment of gastric cancer."

Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody that targets VEGFR-2. These study results validate VEGFR-2 signaling as a therapeutic target in gastric cancer, the authors write in the study abstract. They and other researchers have hypothesized that VEGF- and VEGFR-2-mediated signaling and angiogenesis contribute to gastric cancer pathogenesis.

Dr. Diaz agrees with the authors, saying that the study reinforces the role of anti-VEGF therapy in solid tumors.

Ramucirumab, which is not yet approved for use in any tumor, is being tested in a number of other cancers, said Dr. Fuchs. A phase 3 trial known as RAINBOW is currently underway, and is investigating ramucirumab with and without paclitaxel in the second-line treatment of metastatic gastric and gastroesophageal junction cancers.

Dr. Fuchs explained that his great hope for the trial is that its success spurs more research in the treatment of these cancers. "Hopefully, we will have more new agents," he said.

"Trivial" Toxicity

Patients were randomized in a 2:1 manner to receive intravenous ramucirumab 8 mg/kg or placebo every 2 weeks until disease progression, unacceptable toxicity, or death.

The disease control rate was better with ramucirumab than with placebo (49% vs 23%; P < .0001). The poststudy use of anticancer therapy was comparable in the 2 groups (32% vs 39%).

The overall survival benefit for ramucirumab was consistent across subgroups and after adjustment for other prognostic factors (multivariate HR, 0.774; 95% confidence interval [CI], 0.605 - 0.991).

As Dr. Fuchs noted, the benefits of second-line ramucirumab are comparable to those seen with first-line chemotherapy. However, there is still a big difference between the 2 approaches: "Same survival but far less toxicity," he summarized.

In this trial, ramucirumab's toxicity was "really trivial and essentially the same as placebo," said Dr. Fuchs.

The most frequent adverse events of grade 3 of higher for ramucirumab and placebo were hypertension (7.6% vs 2.6%), fatigue (6.4% vs 9.6%), anemia (6.4% vs 7.8%), abdominal pain (5.9% vs 2.6%), ascites (4.2% vs 4.3%), decreased appetite (3.4% vs 3.5%), bleeding (3.4% vs 2.6%), and hyponatremia (3.4% vs 0.9%).

The study was funded by Eli Lilly. Some of the study authors are employees of Eli Lilly and some have financial ties to the company.

American Association for Cancer Research (AACR) 104th Annual Meeting: Abstract LB 67 Presented April 7, 2013.


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