Adding VEGFR2 Inhibitor Ramucirumab to Paclitaxel Increases Overall Survival as Second-Line Treatment for Advanced Gastric Cancer


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Hansjochen Wilke, MD

The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.

—Hansjochen Wilke, MD

In the phase III RAINBOW trial reported in The Lancet Oncology, Hansjochen Wilke, MD, Director of Medical Oncology/Hematology at Kliniken Essen-Mitte, Essen, Germany, and colleagues found that adding the vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor ramucirumab (Cyramza) to paclitaxel improved overall survival in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma.

Study Details

In this double-blind trial, conducted in 170 centers in 27 countries in North and South America, Europe, Asia, and Australia, 665 patients with advanced gastric or gastroesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned between December 2010 and September 2012 to receive ramucirumab plus paclitaxel (n = 330) or placebo plus paclitaxel (n = 335) until disease progression, unacceptable toxicity, or withdrawal of consent.

Ramucirumab was given intravenously at 8 mg/kg on days 1 and 15 and paclitaxel was given at 80 mg/m2 on days 1, 8, and 15 every 28 days. Randomization was stratified by geographic region, time to progression on first-line therapy, and disease measurability. The primary endpoint was overall survival in the intention-to-treat population.

The ramucirumab and placebo groups were generally balanced for age, sex, ethnicity, and Eastern Cooperative Oncology Group (ECOG) performance status. The site of the primary tumor was gastric in 80% and 79% of the ramucirumab and placebo groups, and gastroesophageal junction in 20% and 21%. In both groups, measurable disease was found in 81% of patients.

The time to progression on first-line therapy was < 6 months in 76% in both groups, disease progression occurred during first-line therapy in 69% and 65%, and tumor grade was well-differentiated in 8% and 7%, moderately differentiated in 29% and 32%, and poorly differentiated in 56% in both. Histologic subtype was intestinal in 44% and 40%, and diffuse in 35% and 40%.

Primary tumor was present in 63% and 62%, number of metastatic sites was at least three in 37% and 31%, and patients had peritoneal metastases in 49% and 45%, ascites in 39% and 32%. Prior treatment included a platinum/fluoropyrimidine/anthracycline triplet in 23% and 26%, a platinum/fluoropyrimidine doublet in 77% and 73%, a HER2 or EGFR inhibitor or other in 9% and 8%, prior surgery in 40% and 38%, total gastrectomy in 16% and 19%, and partial gastrectomy in 24% and 18%.

The two groups were also balanced with respect to geographic regions consisting of Europe, Israel, Australia, and United States (region 1; 60% in both); Argentina, Brazil, Chile, and Mexico (region 2; 7% and 6%); and Japan, South Korea, Hong Kong, Singapore, and Taiwan (region 3; 33% and 34%).

Overall Survival Outcomes

As of the data cutoff (July 2013), median follow-up for overall survival was 7.9 months. Median overall survival was 9.6 months in the ramucirumab group vs 7.4 months in the placebo group (stratified hazard ratio [HR] = 0.807, P = .017). Six-month overall survival was 72% vs 57%, and 12-month overall survival was 40% vs 30%.

In multivariate analysis, factors independently associated with longer overall survival consisted of region 3, ECOG performance status 0, weight loss < 10%, no more than two metastatic sites, absence of ascites, well or moderately differentiated tumor, and previous gastrectomy. After adjustment for these factors, the hazard ratio for overall survival was 0.745 (P = .0010).

Differences by Region

Median overall survival was shorter in the non-Asian geographic regions (1 and 2); ramucirumab treatment was associated with significantly better overall survival in these regions (median, 8.5 vs 5.9 months, HR = 0.73, 95% confidence interval [CI] = 0.59–0.91), but not in the Asian region (region 3; median, 12.1 vs 10.5 months, HR = 0.97, 95% CI = 0.73–1.34).

After discontinuation, 48% of the ramucirumab group and 46% of the placebo group received antineoplastic therapy, including chemotherapy in 48% and 45%. Greater proportions of patients in region 3 (69% and 66%) received subsequent treatment compared with those in region 1 (38% and 36%) and region 2 (30% and 33%).

Univariate subgroup analyses showed that stratified hazard ratios for overall survival favored ramucirumab treatment (except in measurable disease) and were significant for a variety of subgroups including measurable disease, geographic region 1, female sex, and age < 65 years.

Progression-Free Survival and Response Rates

Median progression-free survival was 4.4 months vs 2.9 months (HR = 0.635, P < .0001). Six-month progression-free survival was 36% vs 17%, and 9-month progression-free survival was 22% vs 10%. Subgroup analysis showed significant hazard ratios favoring ramucirumab for most subgroups. Median progression-free survival was 4.2 vs 2.9 months (HR = 0.64, 95% CI = 0.52–0.79) in regions 1 and 2 and 5.5 vs 2.8 months (HR = 0.63, 95% CI = 0.47–0.83) in region 3.

Objective response was observed in 28% vs 16% of patients (P = .0001), and disease control rates were 80% vs 64% (P < .0001). Median duration of response was 4.4 vs 2.8 months. Objective response rates were 25% vs 14% (odds ratio [OR] = 2.09, 95% CI = 1.28–3.41) in regions 1 and 2 and 34% vs 20% (OR = 2.24, 95% CI = 1.18–4.24) in region 3.

Adverse Events

Grade 3, 4, and 5 adverse events occurred in 47%, 22%, and 12% of the ramucirumab group and in 39%, 8%, and 16% of the placebo group, with grade 5 events consisting mostly of disease progression. Grade ≥ 3 adverse events that occurred in > 5% of the ramucirumab group consisted of neutropenia (41% vs 19%), leukopenia (17% vs 7%), hypertension (14% vs 2%), fatigue (12% vs 5%), anemia (9% vs 10%), and abdominal pain (6% vs 3%); febrile neutropenia occurred in 3% vs 2%.

Serious adverse events occurred in 47% vs 42% of patients. Adverse events led to dose reductions of ramucirumab in 5% and paclitaxel in 24% of the ramucirumab group and dose reductions of placebo in < 1% and paclitaxel in 7% of the placebo group, with treatment discontinuation being required in 12% and 11%.

Adverse events leading to death that were considered related to study drug treatment occurred in six patients (2%) in the ramucirumab group and in five patients (2%) in the placebo group.

The investigators concluded: “The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.” ■

Disclosure: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit www.thelancet.com/oncology. Dr. Wilke is the corresponding author for the Lancet Oncology article.

Reference

1. Wilke H, Muro K, Van Cutsem E, et al:  Lancet Oncol 15:1224-1235, 2014.


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Adding VEGFR2 Inhibitor Ramucirumab to Paclitaxel Increases Overall Survival as Second-Line Treatment for Advanced Gastric Cancer

In the phase III RAINBOW trial reported in The Lancet Oncology, Hansjochen Wilke, MD, Director of Medical Oncology/Hematology at Kliniken Essen-Mitte, Essen, Germany, and colleagues found that adding the vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor ramucirumab (Cyramza) to...


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