Ramucirumab, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, was recently approved by the U.S. Food and Drug Administration (FDA) as a single agent for patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with prior progression on or after platinum- or fluoropyrimidine-based chemotherapy.

The FDA approval was based on the results of the REGARD trial, which was previously published in The Lancet. This well-designed trial randomly assigned 355 patients with previously treated advanced or metastatic gastric/GEJ adenocarcinoma in a 2:1 fashion to ramucirumab or placebo.1

The primary endpoint was overall survival, and median survival was modestly improved with ramucirumab compared with placebo (5.2 vs. 3.8 months; hazard ratio [HR] = 0.78; P = 0.047). Six-month and 12-month survival were also improved with ramucirumab (42% and 18% vs. corresponding rates of 32% and 11% in the placebo arm).

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Median progression-free survival was also longer in the ramucirumab arm (2.1 vs. 1.3 months; HR = 0.483, P < 0.0001).Further, stable disease was significantly improved with ramucirumab compared with placebo (~45% vs. ~20%), although objective responses were rare. 

Steven J. Cohen, MD
Steven J. Cohen, MD

Toxicities were manageable and as expected for an antiangiogenic agent. Hypertension, in particular, was increased in the ramucirumab arm (~16% vs. ~8% for placebo), although grade 3 or higher hypertension occurred in 7.6% of patients.  Diarrhea, headache, and hyponatremia were all modestly increased in the ramucirumab arm. 

So, how should ramucirumab be utilized in clinical practice?  Fit patients with advanced or metastatic gastric/GEJ cancers are typically treated initially with chemotherapy combinations including a platinum and a fluoropyrimidine (e.g., FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin], DCF [docetaxel, cisplatin, 5-fluorouracil], ECF [epirubicin, cisplatin, 5-fluorouracil], and variants thereof). For patients with HER2-expressing cancers, trastuzumab is typically added to first-line chemotherapy. However, second-line treatment after progression on first-line therapy has been more challenging.

Randomized studies do support a modest benefit from chemotherapy, with either taxanes or irinotecan. Interestingly, the magnitude of the survival benefit for each of these chemotherapy agents is quite similar to that seen with ramucirumab (~1.5-month improvement in median survival). Thus, for patients with a good performance status, either chemotherapy or ramucirumab are reasonable second-line agents. Patients with contraindications to antiangiogenic therapy (thrombotic or bleeding complications) will probably not be good candidates for ramucirumab and should likely preferentially receive chemotherapy.