Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial.

Abstract

BACKGROUND:

VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma.

METHODS:

For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 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 intravenous infusion on days 1-5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117.

FINDINGS:

Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607-0·935, p=0·0106; median progression-free survival 5·7 months [5·5-6·5] vs 5·4 months [4·5-5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768-1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801-1·156, p=0·6757; median overall survival 11·2 months [9·9-11·9] in the ramucirumab group vs 10·7 months [9·5-11·9] in the placebo group). The most common grade 3-4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1).

INTERPRETATION:

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.

FUNDING:

Eli Lilly and Company.

• Authors: Charles S Fuchs, Kohei Shitara, Maria Di Bartolomeo, Sara Lonardi, Salah-Eddin Al-Batran, Eric Van Cutsem, David H Ilson, Maria Alsina, Ian Chau, Jill Lacy, Michel Ducreux, Guillermo Ariel Mendez, Alejandro Molina Alavez, Daisuke Takahari, Wasat Mansoor, Peter C Enzinger, Vera Gorbounova, Zev A Wainberg, Susanna Hegewisch-Becker, David Ferry, Ji Lin, Roberto Carlesi, Mayukh Das, Manish A Shah, RAINFALL Study Group
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 20 Issue 3 Pg. 420-435 (03 2019) ISSN: 1474-5488 [Electronic] England
• PMID: 30718072 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2
• Cisplatin
• Fluorouracil

Topics

• Adenocarcinoma (drug therapy, pathology)
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Cisplatin (administration & dosage)
• Drug-Related Side Effects and Adverse Reactions (classification, pathology)
• Esophageal Neoplasms (drug therapy, pathology)
• Esophagogastric Junction (drug effects, pathology)
• Female
• Fluorouracil (administration & dosage)
• Humans
• Male
• Middle Aged
• Progression-Free Survival
• Stomach Neoplasms (drug therapy, pathology)
• Vascular Endothelial Growth Factor A (genetics)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, genetics)
• Ramucirumab