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 Journal Article


Authors: Fuchs, C. S.; Shitara, K.; Di Bartolomeo, M.; Lonardi, S.; Al-Batran, S. E.; Van Cutsem, E.; Ilson, D. H.; Alsina, M.; Chau, I.; Lacy, J.; Ducreux, M.; Mendez, G. A.; Alavez, A. M.; Takahari, D.; Mansoor, W.; Enzinger, P. C.; Gorbounova, V.; Wainberg, Z. A.; Hegewisch-Becker, S.; Ferry, D.; Lin, J.; Carlesi, R.; Das, M.; Shah, M. A.; RAINFALL Study Group
Contributor: Won, E.
Article Title: 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/m 2 , on the first day) plus capecitabine (1000 mg/m 2 , 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/m 2 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. © 2019 Elsevier Ltd
Keywords: adult; controlled study; treatment response; aged; major clinical study; overall survival; drug tolerability; fatigue; neutropenia; fistula; cisplatin; fluorouracil; placebo; diarrhea; drug efficacy; drug safety; gastrointestinal hemorrhage; hypertension; side effect; capecitabine; progression free survival; quality of life; anemia; bleeding; leukopenia; nausea; randomized controlled trial; thrombocytopenia; vomiting; abdominal pain; febrile neutropenia; lung embolism; acute kidney failure; population research; pneumothorax; sepsis; phase 3 clinical trial; hand foot syndrome; esophageal adenocarcinoma; stomach adenocarcinoma; digestive system perforation; congestive heart failure; proteinuria; heart arrest; cerebrovascular accident; multiple organ failure; venous thromboembolism; lung hemorrhage; decreased appetite; sudden death; small intestine perforation; gastroesophageal junction adenocarcinoma; septic shock; peritonitis; stomach hemorrhage; arterial thromboembolism; ramucirumab; intention to treat analysis; human; male; female; priority journal; article
Journal Title: Lancet Oncology
Volume: 20
Issue: 3
ISSN: 1470-2045
Publisher: Elsevier Science, Inc.  
Date Published: 2019-03-01
Start Page: 420
End Page: 435
Language: English
DOI: 10.1016/s1470-2045(18)30791-5
PUBMED: 30718072
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 April 2019 -- Source: Scopus
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MSK Authors
  1. David H Ilson
    359 Ilson
  2. Elizabeth Siryeon Won
    34 Won