TY - JOUR
T1 - Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL)
T2 - a double-blind, randomised, placebo-controlled, phase 3 trial
AU - RAINFALL Study Group
AU - Fuchs, Charles S.
AU - Shitara, Kohei
AU - Di Bartolomeo, Maria
AU - Lonardi, Sara
AU - Al-Batran, Salah Eddin
AU - Van Cutsem, Eric
AU - Ilson, David H.
AU - Alsina, Maria
AU - Chau, Ian
AU - Lacy, Jill
AU - Ducreux, Michel
AU - Mendez, Guillermo Ariel
AU - Alavez, Alejandro Molina
AU - Takahari, Daisuke
AU - Mansoor, Wasat
AU - Enzinger, Peter C.
AU - Gorbounova, Vera
AU - Wainberg, Zev A.
AU - Hegewisch-Becker, Susanna
AU - Ferry, David
AU - Lin, Ji
AU - Carlesi, Roberto
AU - Das, Mayukh
AU - Shah, Manish A.
AU - Luft, Alexander V.
AU - Karaseva, Nina A.
AU - Kowalyszyn, Rubén Dario
AU - Hernandez, Carlos Alberto
AU - Csoszi, Tibor
AU - De Vita, Ferdinando
AU - Pfeiffer, Per
AU - Sugimoto, Naotoshi
AU - Kocsis, Judit
AU - Csilla, Andràs
AU - Bodoky, Gyorgy
AU - Garnica Jaliffe, Georgina
AU - Protsenko, Svetlana
AU - Madi, Ayman
AU - Wojcik, Elzbieta
AU - Brenner, Baruch
AU - Folprecht, Gunnar
AU - Sarosiek, Tomasz
AU - Peltola, Katriina Johanna
AU - Bono, Peter
AU - Ayala, Hubert
AU - Aprile, Giuseppe
AU - Gerardo, Cardellino Giovanni
AU - Huitzil Melendez, Fidel David
AU - Falcone, Alfredo
AU - Verma, Udit
N1 - Funding Information:
CSF reports a consulting role for Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, Unum Therapeutics; reports serving on the Board of Directors for CytomX Therapeutics; and reports receiving unexercised stock options in CytomX Therapeutics. KS reports consulting or advisory role fees or honoraria from Astellas Pharma, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Abbvie, and Yakult; grants and personal fees from Eli Lilly and Ono Pharmaceutical; and grants from Dainippon Sumitomo Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, and Merck Sharpe and Dohme (MSD), all outside the submitted work. SL reports advisory role or speakers bureau fees from Amgen, Bayer, BMS, Eli Lilly, Merck, and Roche, all outside the submitted work. S-EA-B has an advisory role with Roche, Celgene, Eli Lilly, Nordic Pharma, Bristol-Myers Squibb and Merck Sharp & Dohme; is a speaker for Roche, Celgene, Eli Lilly, Nordic Pharma, AIO gGmbH, MCI, promedicis, and Forum für Medizinische Fortbildung; is CEO/Founder of IKF Klinische Krebsforschung GmbH; and has received research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Eli Lilly, German Cancer Aid (Krebshilfe), German Research Foundation and the Federal Ministry of Education of Research. EVC reports grants from Amgen, Bayer, BMS, Boehringer, Celgene, Ipsen, Eli Lilly, Merck, Merck KgA, Novartis, Roche, Servier, outside the submitted work. DHI reports research trial support and advisory board fees from Eli Lilly during the conduct of the study. IC reports grants to his institution from Eli Lilly, Janssen-Cilag, Merck Serono, and Sanofi Oncology; and advisory board fees from Eli Lilly, Bristol-Myers Squibb, MSD, Roche, Five Prime Therapeutics, Astra-Zeneca, Bayer, Merck Serono, outside the submitted work; and a research grant from Eli Lilly during the conduct of the study. MDu reports advisory board or speaker fees from Merck Serono, Ipsen, Bayer, and Amgen; grants and advisory board fees from Roche, outside the submitted work; advisory board and speaker fees from Eli Lilly during the conduct of the study; and a family member who works for Sandoz. DT reports lecture fees from Eli Lilly, Taiho Pharmaceutical, Yakult, Chugai Pharmaceutical, Ono Pharmaceutical, and MSD; and grants from Taiho Pharmaceutical, all outside the submitted work. PCE reports speaker board fees from Eli Lilly, Five Prime, Merck, Astellas, Loxo, Taiho, and Celgene, all outside the submitted work. ZAW reports serving as a consultant and receiving grants from Eli Lilly, Merck, and BMS, all outside the submitted work. DF, JL, RC, and MDa are employees of Eli Lilly. MDB, MA, JL, GAM, AMA, WM, VG, SH-B, and MAS have no potential conflicts of interest to report.
Funding Information:
We thank the patients, investigators, and institutions involved in this study. We also thank Rebecca Hozak and Sameera Wijayawardana for biomarker analysis, Ran Wei for statistical analyses, Ling Gao for pharmacokinetic work, Astra Liepa for quality-of-life analyses, Matt DiStasi for figure assistance, and Mary Dugan Wood for writing assistance. All named people were Eli Lilly employees or collaborators at the time of their involvement with the study and were compensated as such. This work was supported by Eli Lilly and Company.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
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U2 - 10.1016/S1470-2045(18)30791-5
DO - 10.1016/S1470-2045(18)30791-5
M3 - Article
C2 - 30718072
AN - SCOPUS:85062194050
SN - 1470-2045
VL - 20
SP - 420
EP - 435
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 3
ER -