The results of a global, phase III clinical trial in patients with metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma show that combining paclitaxel with the monoclonal antibody ramucirumab significantly increases overall survival by more than two months after progression on first-line therapy, compared to treatment with paclitaxel alone. Researchers also reported significant improvements in progression-free survival and quality of life for patients who received the combination therapy. This is the largest clinical trial of second-line therapy in this patient population to date.
“A two-month survival gain for patients with gastric cancer receiving second-line therapy is a big improvement,” said lead study author Hansjochen Wilke, MD, Director of the Department of Oncology, Hematology and Center of Palliative Care at Kliniken Essen-Mitte in Essen, Germany. “This study shows that we can achieve more with targeted therapy and chemotherapy together than we can with chemotherapy alone. We’re also encouraged that this regimen not only improves survival but also offers patients a better quality of life.”
Gastric cancer is the second-leading cause of cancer death globally. Patients with advanced gastric cancer who progress after first-line therapy have a poor prognosis, with a median overall survival of approximately 3 to 3.5 months without second-line treatment. Currently, patients whose cancer progresses following first-line therapy receive either second-line chemotherapy with drugs such as docetaxel, paclitaxel, and irinotecan or best supportive care measures. Although 70 to 80 percent of patients receive second-line chemotherapy as part of standard practice in Japan, and live longer as a result, only an estimated 30 percent of patients in Europe and the United States receive an additional line of treatment. According to Dr. Wilke, this geographic difference in treatment may be attributed to the lack of large randomized clinical trials demonstrating clinical benefit of second-line chemotherapy in Western countries.
Ramucirumab is a human IgG1 monoclonal antibody that blocks the vascular endothelial growth factor receptor 2 (VEGFR-2), a common target for inhibiting angiogenesis. Because a tumor needs the nutrients delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapy is to essentially “starve” the tumor.
Six hundred sixty-five patients with metastatic GEJ or gastric adenocarcinoma who exhibited disease progression on or within four months after standard first-line platinum- and fluoropyrimidine-based combination chemotherapy were enrolled in this trial. Patients were randomized to receive either a combination of ramucirumab and paclitaxel or paclitaxel alone. Treatment was continued in four-week cycles until disease progression, unacceptable toxicity, or death.
The addition of ramucirumab to second-line paclitaxel treatment significantly improved response rates, overall survival, and progression-free survival. Overall, 28 percent of patients responded to treatment with ramucirumab and paclitaxel compared to 16 percent of patients treated with paclitaxel alone. The median overall survival was 9.6 months in the ramucirumab + paclitaxel group versus 7.4 months in the paclitaxel group. Median progression-free survival was 4.4 months for the combination therapy compared to 2.9 months for paclitaxel alone. According to Dr. Wilke, patients who received ramucirumab and paclitaxel also reported a reduction in pain and other improvements in their quality of life.
The most common side effects of treatment with ramucirumab and paclitaxel include neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia. Although neutropenia was more frequently reported in the ramucirumab + paclitaxel group, the incidence of febrile neutropenia was comparable to treatment with paclitaxel alone. All of these side effects were manageable, and very few patients discontinued treatment due to toxicities.
The researchers intend to retrospectively analyze tumor samples collected as part of this study in the hope of identifying biomarkers that may help define subgroups of patients more likely to benefit from ramucirumab treatment, as well as to investigate ramucirumab in the first-line setting. The U.S. Food and Drug Administration assigned ramucirumab a priority review designation in October 2013 as a second-line treatment for patients with advanced gastric cancer; a decision is expected in early 2014.
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