Ramucirumab Moderately Boosts Survival in Advanced Gastric Cancer

Charles S. Fuchs, MD, MPH

Ramucirumab, a fully human monoclonal antibody targeting the vascular endothelial growth factor (VEGF) receptor-2, significantly extended overall survival as a second-line agent in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma that progressed on first-line therapy.

In a phase III clinical trial presented at the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, patients randomized to ramucirumab plus best supportive care had a median overall survival of 5.2 months compared with 3.8 months for patients randomized to placebo plus best supportive care, reported Charles S. Fuchs, MD, MPH, lead author of the study and director of the Gastrointestinal Malignancy Program at Dana-Farber Cancer Institute in Boston, Massachusetts.

The median overall survival obtained with ramucirumab is similar to the 5.3 months achieved with docetaxel or irinotecan as salvage chemotherapy in a similar population of patients (Kang et al. J Clin Oncol 2012), said Fuchs. The advantage with ramucirumab is an adverse event profile that rivaled placebo in the study reported here, with the exception of hypertension, which occurred twice as often in patients randomized to the monoclonal antibody compared with those randomized to placebo.

“The relative benefit of the antibody is very comparable to what has been achieved with chemotherapy,” Fuchs said. “To the extent that it can achieve a similar benefit to second-line chemotherapy and it has an excellent tolerability profile, it makes an exciting option for patients.”

VEGF receptor-2 and its ligands are important mediators of angiogenesis. Ramucirumab binds the extracellular domain of VEGF receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation.

Three-hundred fifty-five patients with gastric or GEJ adenocarcinoma whose disease progressed within 4 months after first-line therapy for metastatic disease or within 6 months after adjuvant therapy were randomized in a 2:1 ratio to infusions of ramicurumab every 2 weeks plus best supportive care or placebo plus best supportive care. First-line therapy consisted of platinum- and/or fluoropyrimidine-containing combination chemotherapy. Patients were treated until disease progression, unacceptable toxicity, or death. The study was conducted in 30 countries and 120 centers. The median duration of therapy was 8.0 months in the ramucirumab arm and 6.0 months in the placebo arm.

The 1.4-month median overall survival advantage with ramucirumab yielded a hazard ratio (HR) of 0.776 (95% confidence interval [CI], 0.603-0.998, P =.0473). The median time to disease progression was 2.1 months for ramucirumab versus 1.3 months for placebo (HR, 0.483, 95% CI, 0.376-0.620; P < .0001). Six-month overall survival was 42% in the ramucirumab arm versus 32% in the placebo arm. At 12 months, overall survival was 18% in the ramucirumab arm versus 11% in the placebo arm.

Tumor assessment showed a two-fold improvement in disease control with ramucirumab. The disease control rate, defined as complete remission, partial remission, or stable disease, was 48.7% in patients randomized to ramucirumab versus 23.1% in the placebo recipients (P <.0001). Nearly half (45.4%) of patients randomly assigned to ramucirumab had stable disease compared with only 20.5% of the placebo group.

The percentage of deaths attributed to adverse events was similar in each arm; 10.6% in the ramucirumab group and 13.0% in the placebo group.

Fatigue was the most commonly report adverse event in each study arm (35.6%, ramucirumab; 40.0%, placebo). Hypertension occurred in 16.1% versus 7.8% of the ramucirumab and placebo arms, respectively. The rates of grade 3 or greater hypertension were 7.6% with ramucirumab and 2.6% with placebo.

“The next logical question is what happens when you add ramucirumab to chemotherapy,” said Fuchs, who noted that another area for investigation might be the use of ramucirumab in the first-line setting.

Fuchs CS, Tomasek J, Cho JY, et al. REGARD: a phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy. J Clin Oncol. 2012;30(suppl 34; abstr LBA5).

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