Background
Phase III, double-blind, placebo-controlled RCT in 355 patients with metastatic or unresectable, locally recurrent gastric or GEJ adenocarcinoma progressing within 4 mo of first-line therapy for metastatic disease (platinum- or fluoropyrimidine-containing regimen) or within 6 mo of adjuvant therapy. Randomized 2:1 to ramucirumab vs placebo. Ramucirumab is a fully human monoclonal antibody targeting VEGFR-2.
Interventions and follow up
Arm A: Best supportive care plus ramucirumab 8 mg/kg IV Q2W (n=238)
Arm B: Best supportive care plus placebo IV Q2W (n=117)
Primary endpoint: Overall survival
Secondary endpoints: PFS, ORR, safety
Median follow up: NR (median treatment duration 8 weeks)
Arm B: Best supportive care plus placebo IV Q2W (n=117)
Primary endpoint: Overall survival
Secondary endpoints: PFS, ORR, safety
Median follow up: NR (median treatment duration 8 weeks)
Results
mOS: 5.2 mo vs 3.8 mo, HR 0.78, 95% CI 0.603-0.998, P=.047 (Arm A vs B)
mPFS: 2.1 mo vs 1.3 mo, HR 0.48, 95% CI 0.38-0.62, P<.001
Disease control rate: 49% vs 23%, P<.001
mPFS: 2.1 mo vs 1.3 mo, HR 0.48, 95% CI 0.38-0.62, P<.001
Disease control rate: 49% vs 23%, P<.001
Adverse events
Overall: Grade ≥3 events 57% vs 58% (Arm A vs B)
Vascular: Hypertension 16% (grade ≥3 8%) vs 8% (grade ≥3 3%); no increase in bleeding or thromboembolic complications
Other: Comparable rates of fatigue and abdominal pain between arms
Vascular: Hypertension 16% (grade ≥3 8%) vs 8% (grade ≥3 3%); no increase in bleeding or thromboembolic complications
Other: Comparable rates of fatigue and abdominal pain between arms
Conclusions
In patients with advanced gastric or GEJ adenocarcinoma progressing after first-line therapy, ramucirumab monotherapy significantly improved overall survival with a manageable safety profile. REGARD was the first trial to show survival benefit of a single biologic agent in this setting.
Key Limitations
Modest absolute OS gain (1.4 mo). Predates routine HER2 and PD-L1 testing. No predictive biomarker for ramucirumab benefit identified. Largely pre-immunotherapy era population.
Clinical Context
FDA approved ramucirumab monotherapy (Apr 2014) for advanced gastric/GEJ adenocarcinoma after prior fluoropyrimidine- or platinum-containing chemotherapy. The subsequent RAINBOW trial established ramucirumab plus paclitaxel as a preferred second-line regimen. ESMO guidelines list ramucirumab-based therapy as a standard second-line option.
References
Fuchs et al., Lancet, 2014, PMID: 24094768
RAINBOW: Wilke H et al, Lancet Oncol, 2014, PMID: 25240821
RAINBOW: Wilke H et al, Lancet Oncol, 2014, PMID: 25240821