Ramucirumab Improves Survival in Advanced Gastric Cancer

Charles S. Fuchs, MD, MPH

Ramucirumab, a monoclonal antibody that targets VEGFR-2, significantly prolonged survival in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following progression on first-line therapy, according to results from the phase III REGARD study published in The Lancet.

The survival advantage experienced by patients in this trial was indicated as the first to be elicited by a single-agent biological treatment in this setting. Based on these data, the FDA has assigned a priority review designation to ramucirumab (previously IMC-1121B) as a second-line treatment for patients with advanced gastric cancer. As part of this program, the agency plans to take action on the drug’s application within 6 months instead of the 10 months it would have anticipated under standard review, placing a decision date in early 2014.

“What we found is that the patients who received the antibody had a significant improvement in their survival as well as reducing the rate of cancer progression,” the lead author of the REGARD trial, Charles Fuchs, MD, MPH, said in a statement. “The results were encouraging and we hope that the drug will ultimately be approved for routine use for patients with stomach cancer.” Fuchs is the director of the Center for Gastrointestinal Cancer at the Dana-Farber Cancer Institute.

In the REGARD study, 355 patients with advanced gastric cancer or GEJ adenocarcinoma were randomized in a 2:1 ratio to receive best supportive care plus either ramucirumab (n=238) or placebo (n=117). In the study, ramucirumab was administered intravenously every 2 weeks at 8 mg/kg for a median duration of 8 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety.

REGARD Trial

Ramucirumab

(n = 238)

Placebo

(n = 117)

HR

P

Median OS (months

5.2

3.8

0.776

.047

Median PFS (months)

2.1

1.3

0.483

<.0001

ORR (%)

3.4

2.6

-

.756

Study involved 355 patients with advanced gastric cancer or GEJ adenocarcinoma. HR indicates hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

The median OS in the ramucirumab arm was 5.2 months compared with 3.8 months for patients in the placebo arm (hazard ratio [HR] = 0.776; 95% CI, 0.603-0.998; P = .047). The median PFS was 2.1 months compared with 1.3 months for ramucirumab and placebo, respectively (HR = 0.483; 95% CI, 0.376-0.620; P <.0001). ORR was 3.4% for ramucirumab and 2.6% for placebo, and disease control rates were 48.7% and 23.1%, respectively.

Approximately 75% of patients in the ramucirumab arm were diagnosed with advanced gastric cancer. Following the discontinuation of treatment, 32% of patients in the ramucirumab arm went on to receive chemotherapy compared with approximately 39% of those on placebo.

Adverse events of any grade were similar between the two groups at 94% compared with 88% for ramucirumab and placebo, respectively. Grade 3 events occurred in 57% of patients in the investigational arm compared with 58% in the placebo arm.

Hypertension was more common in the ramucirumab arm (16% versus 8%); however, grade 3 hypertension occurred in only three patients and no grade 4 hypertension manifested in the trial. In total, five deaths occurred in the investigational arm and two occurred in the placebo group.

“The side effects associated with ramucirumab, except for hypertension, were mostly similar to what patients receiving placebo experienced. The results are very encouraging for patients with stomach cancer,” noted Fuchs in a release. “It’s really impressive that an antibody which had very little side effects could provide a survival benefit.”

In addition to single-agent ramucirumab, a combination strategy with chemotherapy is under investigation in the phase III RAINBOW trial. In this trial, ramucirumab plus paclitaxel is being compared with paclitaxel and placebo for patients with advanced gastric cancer or GEJ adenocarcinoma whose disease progressed on, or did not respond to, initial therapy.

Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastrooesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial [published online ahead of print October 3, 2013]. Lancet. doi:10.1016/S0140-6736(13)61719-5.