Novel Antiangiogenic Extends Survival in Advanced Gastric Cancer

Neil Osterweil

January 14, 2014

SAN FRANSICO — Adding an experimental inhibitor of tumor angiogenesis to standard second-line chemotherapy improved overall survival of patients with metastatic gastric cancer by 2 months, an unprecedented gain in this setting.

For patients with metastatic gastric adenocarcinoma or cancer of the gastroesophageal junction, median overall survival was better for those treated with the combination of paclitaxel (Taxol) and ramucirumab than for those treated with paclitaxel monotherapy (9.6 vs 7.4 months).

In the global phase 3 RAINBOW trial, the hazard ratio (HR) for overall survival, the primary end point, was 0.87 (95% confidence interval [CI], 0.678 - 0.962; = .0169).

"This largest gastric cancer second-line trial clearly demonstrates that an effective second-line therapy improves survival of patients with metastatic advanced gastric cancer," said lead author Hansjochen Wilke, MD, from the Kliniken Essen-Mitte in Essen, Germany. He spoke at a teleconference held in advance of the 2014 Gastrointestinal Cancers Symposium.

The results of the RAINBOW trial, combined with findings from the just-published REGARD trial of ramucirumab monotherapy, support the routine use of second-line therapy in patients with advanced gastric cancers who can tolerate the regimens, Dr. Wilke said.

This is the only study to date to demonstrate a 2-month improvement in survival.

"This is the only study to date to demonstrate a 2-month improvement in survival in this setting, and with a relatively high 28% response rate for the combination therapy," said Smitha S. Krishnamurthi, MD, associate professor of medicine at Case Western Reserve University in Cleveland, who moderated the press briefing during which the RAINBOW results were presented.

"We see now in second-line gastric cancer that ramucirumab improves survival, compared with best supportive care alone. We saw that in the REGARD study, and now see that it also adds to the efficacy of chemotherapy," explained Dr. Krishnamurthi, who was not involved in the study.

The symposium is cosponsored by the American Gastroenterological Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

VEGF Shutdown

Vascular endothelial growth-factor receptor (VEGFR)-2 and the VEGF A, C, and D ligands are known mediators of angiogenesis. Ramucirumab is an investigational recombinant human monoclonal antibody that binds the extracellular domain of VEGFR-2 and blocks VEGF ligand binding, shutting down VEGF signaling and inhibiting the growth of new blood vessels that feed the tumor.

The novel antiangiogenic did not, however, improve outcomes in metastatic breast cancer in a trial reported by Medscape Medical News in December 2013.

The story appears to be different in metastatic gastric cancer.

Patients with gastric adenocarcinoma or cancer of the gastroesophageal junction who experienced disease progression during or within 4 months of first-line therapy with a platinum agent and a fluoropyrimidine were randomly assigned to 1 of 2 treatment regimens. All 665 patients received paclitaxel 80 mg/m² on days 1, 8, and 15 of every 4-week cycle until disease progression, unacceptable toxicities, or death. They were also randomly assigned to receive intravenous ramucirumab 8 mg/kg every 2 weeks or placebo.

The ramucirumab and paclitaxel combination was associated with better median progression-free survival than monotherapy (4.4 vs 2.8 months; HR, 0.635; 95% CI, 0.536 - 0.752; < .0001).

Patients treated with the combination also had a significantly better median time to progression (5.5 vs 3.0 months; P < .0001) and a better objective response rate (28% vs 16%; P = .0001).

However, adverse events increased with the combination. Most adverse events of grade 3 or greater occurred at least twice as often with the combination than with paclitaxel alone, including neutropenia (40.7% vs 18.8%), leukopenia (17.4% vs 6.7%), hypertension (14.1% vs 2.4%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported more often with the combination than with monotherapy (3.1% and 2.4%). In contrast, anemia was slightly less common with the combination (9.2% vs 10.3%).

The trial was supported by Eli Lilly. Dr. Wilke and several coauthors report receiving honoraria and/or research funding from the company, and 3 are employees and stockholders in the company. Dr. Krishnamurthi has disclosed no relevant financial relationships.

2014 Gastrointestinal Cancers Symposium (GICS): Abstract LBA7. To be presented January 16, 2014.


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