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SAN FRANCISCO -- Patients with advanced gastric cancer lived 2 months longer when treated with an investigational angiogenesis inhibitor and chemotherapy, a large randomized trial showed.

Median overall survival increased from 7.36 months with chemotherapy alone to 9.63 months with chemotherapy plus ramucirumab. The combination regimen also led to modest but statistically significant improvement in progression-free survival, as reported at the Gastrointestinal Cancers Symposium (GiCS).

"This is the largest trial of second-line therapy in gastric cancer and clearly demonstrates that second-line therapy improves survival of patients with metastatic or locally advanced unresectable gastric cancer," , of the Center for Internal Oncology/Hematology in Essen, Germany, said during a press briefing.

"This trial and the recently published REGARD trial demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer and gastroesophageal junction cancer."

The trial is the only one reported to date to demonstrate as much as a 2-month survival benefit for any regimen in second-line treatment of gastric cancer, said program moderator , of University Hospitals Case Medical Center in Cleveland. Although gastric cancer is less common in the U.S. than in other parts of the world, the disease remains problematic wherever it occurs.

"It is a poor-prognosis cancer in the U.S. as it is throughout the world," said Krishnamurthi. "We're excited to have what appears to be an active drug in the second-line setting that can be used instead of best supportive care or in addition to second-line chemotherapy for patients who can tolerate chemotherapy. We're anxiously awaiting the word from the FDA about approval of ramucirumab, which is expected later this year."

In general, second-line therapy for metastatic and locally advanced gastric cancer leads to overall survival of 4 to 5 months, underscoring the need for more effective therapies, Wilke said by way of introduction to the trial results. Angiogenic growth factor receptors, such as vascular endothelial growth factor receptor-2 (VEGFR-2) and its ligands, likely contribute to gastric cancer pathogenesis, potentially representing therapeutic targets.

Ramucirumab is a fully human monoclonal antibody that targets VEGFR-2, inhibiting receptor activation required for angiogenesis. Laboratory and preliminary clinical studies suggested the agent might slow tumor progression and improve survival.

A phase III placebo-controlled trial of single-agent ramucirumab (REGARD) demonstrated significant improvement in survival in patients with advanced gastric cancer that had progressed after first-line chemotherapy. The findings provided the impetus for the phase III RAINBOW (Study of Paclitaxel with or without Ramucirumab in Metastatic Gastric Adenocarcinoma).

RAINBOW compared paclitaxel in combination with placebo or ramucirumab in patients with gastric cancer that had progressed after first-line treatment with a platinum/fluoropyrimidine regimen.

Investigators randomized 635 patients to the two regimens and continued treatment until disease progression or development of unacceptable toxicity. The primary endpoint was overall survival.

When the trial ended, the 2-month improvement in survival with ramucirumab translated into a 20% reduction in the hazard ratio versus the control group (HR 0.807, 95% CI 0.678-0.962, P=0.0169). The ramucirumab group had a 6-month survival of 72% and 12-month survival of 40% versus 57% and 30%, respectively, for the placebo group.

The ramucirumab regimen led to a median PFS of 4.40 months versus 2.86 months for the control group, a 36% reduction in the hazard ratio (P<0.0001). The 6-month PFS was 36% with ramucirumab and 17% with placebo, and the 12-month PFS rates were 22% and 16%, respectively.

Ramucirumab was associated with a significantly higher response rate (28% versus 16%, P=0.0001) and disease control rate (80% versus 64%, P<0.0001).

Overall, the combination of paclitaxel and the angiogenesis inhibitor was well tolerated, said Wilke. Grade ≥3 adverse events of interest included hypertension (14.7% versus 2.7% with placebo), bleeding/hemorrhage (4.3% versus 2.4%), gastrointestinal bleeding (3.7% versus 1.5%), proteinuria (1.2% versus 0), and gastrointestinal perforation (1.2% versus 0).

Otherwise, the most most frequent grade ≥3 adverse events were neutropenia (40.7% versus 18.8% in the placebo group), febrile neutropenia (3.1% versus 2.4%), leukopenia (17.4% versus 6.7%), and fatigue (11.9% versus 5.5%).

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