Addition of First-Line Ramucirumab to Cisplatin and Fluoropyrimidine in Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
In the phase III RAINFALL trial reported in The Lancet Oncology, Fuchs et al found no apparent benefit of the addition of the VEGFR-2 inhibitor ramucirumab to first-line cisplatin and fluoropyrimidine treatment in metastatic gastric or gastroesophageal junction adenocarcinoma.
Study Details
The double-blind trial was comprised of 645 patients with HER2-negative disease from 126 sites in 20 countries. They were randomly assigned between January 2015 and September 2016 to receive ramucirumab plus fluoropyrimidine and cisplatin (n = 326) or placebo plus fluoropyrimidine and cisplatin (n = 319). Treatment consisted of cisplatin 80 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice daily for 14 days every 21 days and either ramucirumab 8 mg/kg or placebo on days 1 and 8 every 21 days. 5-Fluorouracil 800 mg/m2 via intravenous infusion on days 1 to 5 was permitted for patients unable to take capecitabine.
The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population among the first 508 patients. A sensitivity analysis of progression-free survival was performed using central review of computed tomography scans.
Progression-Free Survival
Median progression-free survival on investigator assessment was 5.7 months in the ramucirumab group vs 5.4 months in the placebo group (hazard ratio [HR] = 0.753, P = .0106). However, sensitivity analysis based on independent central review yielded median progression-free survival of 5.5 vs 5.4 months (HR = 0.961, P = .74). Median overall survival was 11.2 months vs 10.7 months (HR = 0.962, P = .68.)
Adverse Events
The most common grade 3 or 4 adverse events were neutropenia (26% of ramucirumab group vs 27% of placebo group), anemia (12% vs 14%), and hypertension (10% vs 2%). Serious adverse events occurred in 50% of the ramucirumab group and 47% of the placebo group, with the most common being vomiting (4% vs 7%) and diarrhea (3% vs 6%). Seven treatment-related deaths occurred in each group, due to acute kidney injury, cardiac arrest, gastric hemorrhage, peritonitis, pneumothorax, septic shock, and sudden death in the ramucirumab group, and cerebrovascular accident, multiple organ dysfunction syndrome (n = 2), pulmonary embolism (n = 2), sepsis, and small intestine perforation in the placebo group.
The investigators concluded, “Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population.”
Charles S. Fuchs, MD, of Yale Cancer Center, Smilow Cancer Hospital, Yale School of Medicine, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Eli Lilly and Company. The study authors' full disclosures can be found at thelancet.com.
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