Background
Phase III randomized, double-blind, placebo-controlled trial in 665 patients with metastatic or unresectable locally advanced gastric/gastro-oesophageal junction (GEJ) adenocarcinoma progressing on first-line platinum and fluoropyrimidine (with or without anthracycline). Tested whether adding the VEGFR-2 antibody ramucirumab to paclitaxel improves outcomes in the second-line setting.
Interventions and follow up
Arm A: Ramucirumab 8 mg/kg IV D1, D15 plus paclitaxel 80 mg/m2 IV D1, D8, D15 every 28 days
Arm B: Placebo plus paclitaxel 80 mg/m2 IV D1, D8, D15 every 28 days
Primary endpoint: Overall survival
Median follow-up: 7.9 mo
Arm B: Placebo plus paclitaxel 80 mg/m2 IV D1, D8, D15 every 28 days
Primary endpoint: Overall survival
Median follow-up: 7.9 mo
Results
Median OS: 9.6 mo vs 7.4 mo, ramucirumab+paclitaxel vs placebo+paclitaxel (HR 0.807, 95% CI 0.678-0.962, P=.017)
Median PFS: 4.4 mo vs 2.9 mo (HR 0.635, 95% CI 0.536-0.752, P<.001)
Objective response rate: 28% vs 16% (P=.0001)
Median PFS: 4.4 mo vs 2.9 mo (HR 0.635, 95% CI 0.536-0.752, P<.001)
Objective response rate: 28% vs 16% (P=.0001)
Adverse events
Hematologic (grade ≥3): Neutropenia 41% vs 19%, leucopenia 17% vs 7%; febrile neutropenia similar (3% vs 2%)
Vascular/VEGF-related (grade ≥3): Hypertension 14%, bleeding/hemorrhage 4%, proteinuria 1%, GI perforation ~1%
Neurologic: Any-grade neuropathy 46% vs 37%
Deaths: AE-related death 12% vs 16%; drug-attributable fatal AE 2% in both arms
Vascular/VEGF-related (grade ≥3): Hypertension 14%, bleeding/hemorrhage 4%, proteinuria 1%, GI perforation ~1%
Neurologic: Any-grade neuropathy 46% vs 37%
Deaths: AE-related death 12% vs 16%; drug-attributable fatal AE 2% in both arms
Conclusions
Ramucirumab plus paclitaxel significantly prolonged overall and progression-free survival versus paclitaxel alone in previously treated advanced gastric/GEJ adenocarcinoma, establishing it as a standard second-line regimen.
Key Limitations
Predominantly Western/Asian populations may limit generalizability across all regions; biomarker-unselected, with no validated predictive marker for ramucirumab benefit. The absolute OS gain (~2.2 mo) is modest, and added toxicity/cost considerations apply.
Clinical Context
FDA approved ramucirumab with paclitaxel for advanced gastric/GEJ adenocarcinoma after prior fluoropyrimidine/platinum chemotherapy (2014); EMA approval same year. ESMO guidelines endorse ramucirumab+paclitaxel as a preferred second-line option, sequencing after first-line platinum/fluoropyrimidine.