Vascular endothelial growth factor (VEGF)– and VEGF receptor-2 (VEGFR-2)–mediated signaling and angiogenesis seem to have an important role in the pathogenesis of gastric cancer. In the phase III REGARD trial reported in Lancet, Charles S. Fuchs, MD, MPH, of Dana-Farber Cancer Institute, Boston, and colleagues investigated whether the monoclonal antibody VEGFR-2 antagonist ramucirumab could prolong survival in patients with previously treated advanced gastric cancer.¹ Ramucirumab treatment was associated with significantly prolonged overall survival and progression-free survival, validating VEGFR-2 signaling as an important target in this setting.

Study Details

This international double-blind trial enrolled 355 patients aged 24 to 87 years with advanced gastric or gastroesophageal junction adenocarcinoma that had progressed after first-line platinum-containing or fluoropyrimidine-containing chemotherapy. Patients were randomly assigned 2:1 to receive best supportive care plus either ramucirumab at 8 mg/kg intravenously (n = 238) or placebo (n = 117) once every 2 weeks.

Patients were enrolled at 119 centers in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Randomization was stratified by weight loss (≥ 10% vs < 10% in the previous 3 months), geographic region (North America, Europe, Australia, and New Zealand vs South and Central America, India, South Africa, and Middle East vs Asia), and location of the primary tumor (gastric vs gastroesophageal junction). The primary endpoint was overall survival.

The ramucirumab and placebo groups were generally well matched for age (median, 60 years in both), sex (71% and 68% male), race (76% and 78% white, 16% and 15% Asian), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 28% and 26%, 1 in 72% and 73%), weight loss in previous 3 months (< 10% in 83% in both), and geographic region (North America, Europe, Australia, New Zealand for 69% and 68%; Asia for 8% and 7%; South and Central America, India, South Africa, and Middle East for 25% and 26%).

The two arms were also similar in terms of primary tumor location (gastric in 75% and 74%), histologic subtype (intestinal in 22% and 30%, diffuse in 40% and 38%, unknown in 38% and 32%), presence of primary tumor (73% and 74%), number of metastatic sites (0–2 in 68% and 61%), measurable disease (92% and 91%), progression-free interval after previous treatment (< 6 months in 65% and 71%), and previous treatment (fluoropyrimidine/platinum in 84% and 75%, fluoropyrimidine/other systemic agent in 5% and 15%, fluoropyrimidine alone in 7% and 6%, platinum/other systemic agent in 4% in both). More placebo patients had peritoneal metastasis (38% vs 27%).

Overall Survival Outcomes

Median overall survival was 5.2 months (interquartile range, 2.3–9.9 months) in the ramucirumab group and 3.8 months (interquartile range, 1.7–7.1 months) in the placebo group (hazard ratio [HR] = 0.776, P = .047). Estimated overall survival was 41.8% vs 31.6% at 6 months and 17.6% vs 11.8% at 12 months. ECOG performance status (≥ 1 vs 0), location of the primary tumor (gastroesophageal junction vs gastric), and presence of peritoneal metastases were identified as significant independent predictors of overall survival on a stepwise Cox proportional hazards model; after adjustment for these factors, ramucirumab was still associated with a significant improvement in overall survival (HR = 0.774, P = .042).

After addition of the predefined stratification factors to the multivariable analysis, the effect of ramucirumab remained significant (HR = 0.767, P = .037). The effect of ramucirumab was consistent across almost all subgroups, including the prespecified stratification factors. Hazard ratios were 0.823 (95% confidence interval [CI] = 0.608–1.114) among patients with gastric cancer and 0.756 (95% CI = 0.472–1.211) among those with gastroesophageal junction cancer.

Outcome did not differ significantly between men and women (P = .063). After discontinuation of study drug, more placebo patients received systemic antineoplastic treatment.

Progression-Free Survival and Response Rates

Median progression-free survival was 2.1 months in the ramucirumab group vs 1.3 months in the placebo group (HR = 0.483, P < .0001). Progression-free survival rates were 40.1% and 15.8% at 12 weeks. The effect of ramucirumab on progression-free survival was maintained after adjustment for other significant baseline prognostic factors and was consistent across almost all subgroups.

Objective response was observed in 3% of patients in the ramucirumab group (1 complete response) and 3% of patients in the placebo group, and stable disease was observed in 45% vs 21%, yielding disease control rates of 49% vs 23% (P < .0001). Duration of disease control was significantly longer in the ramucirumab group (median, 4.2 vs 2.9 months, P = .036).

Toxicities

Adverse events of any grade occurred in 94% of patients in the ramucirumab group and 88% of patients in the placebo group, with hypertension being more common in the ramucirumab group (16% vs 8%). Ramucirumab was not associated with increased rates of fatigue, decreased appetite, vomiting, anemia, increased bleeding, venous thrombosis, proteinuria, gastrointestinal perforation, fistula formation, or infusion-related reactions.

Grade 3 or higher adverse events occurred in 57% vs 58% of patients, with grade 3 hypertension being more common in the ramucirumab group (8% vs 3%). After hypertension, the most common adverse events of grade 3 or higher in the ramucirumab group were fatigue (6% vs 10%), abdominal pain (6% vs 3%), and anemia (6% vs 8%). Grade 3 or higher arterial thromboembolic events were more common in the ramucirumab group (1% vs 0%, P = .55). Death in five ramucirumab patients (2%; due to intestinal perforation in two patients, myocardial infarction, gastric hemorrhage, and pneumonia) and in two placebo patients (2%; due to intestinal perforation and pulmonary embolism) were considered related to study drug.

Anti-ramucirumab antibodies were detected in 3% of ramucirumab patients and < 1% of placebo patients. None of these patients had an infusion-related reaction, and no patients developed neutralizing antibodies to ramucirumab.

Conclusion

The investigators concluded:

Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy…. In view of our findings, ramucirumab could be an important treatment option in [these] patients…. Additionally, this novel drug has a mechanism of action and toxic-effect profile that is distinctly different and non-overlapping with standard chemotherapy for oesophagogastric adenocarcinoma…. Our results validate the role of VEGFR-2 signalling as an important therapeutic target in advanced gastric and gastro-oesophageal junction adenocarcinoma. Future analyses are needed to identify potential predictive biomarkers for ramucirumab. A recently completed randomised clinical trial (ClinicalTrials. gov, number NCT01170663) has reported a survival benefit when ramucirumab is added to second-line paclitaxel in patients with advanced oesophagogastric adenocarcinoma, while an ongoing randomised clinical trial (NCT01170663) is assessing a combination of ramucirumab with first-line chemotherapy in this patient population. ■

Disclosure: The study was funded by ImClone Systems. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. October 3, 2013 (early release online).