Regard Phase 3, Randomized Trial of Ramucirumab in Patients with Metastatic Gastric or Gej Adenocarcinoma Following Progression on First-Line Chemotherapy

Abstract

Background: VEGF and VEGF receptor‐2 mediated signaling and angiogenesis contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC‐1121B) is a human IgG1 monoclonal antibody targeting VEGFR‐2. We conducted a placebo‐controlled, double‐blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma following progression on 1st‐line platinum‐ and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) or placebo (PL) every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Pts had disease progression within 4 months (m) after 1st‐line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression‐free survival (PFS), 12‐wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were balanced between arms. RAM significantly reduced all‐cause mortality by 22% when compared to PL (Hazard Ratio [HR] for OS = 0.776; 95% CI, 0.603‐0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The OS and PFS benefit for RAM appeared consistent across subgroups and after adjustment for other prognostic factors (multivariate HR = 0.774; 95% CI, 0.605‐0.991). The HR for PFS was 0.483 (95% CI, 0.376‐0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12‐wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti‐cancer therapy post‐study: 32% RAM; 39% PL. The most frequent grade ≥3 AEs were: hypertension (7.6% RAM; 2.6% PL), fatigue (6.4% RAM; 9.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.9% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), decreased appetite (3.4% RAM; 3.5% PL), bleeding (3.4% RAM; 2.6% PL), and hyponatremia (3.4% RAM; 0.9% PL). Conclusion: Ramucirumab significantly prolonged survival in pts with advanced gastric or GE junction adenocarcinoma following progression on first‐line therapy with an acceptable safety profile. These results confirm VEGFR‐2 as a viable therapeutic target in gastric cancer.