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).
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
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.