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. Issue 3 (March 2019)

• Record Type: Journal Article
• Authors: Luft, Alexander V.; Karaseva, Nina A.; Kowalyszyn, Rubén Dario; Hernandez, Carlos Alberto; Csoszi, Tibor; De Vita, Ferdinando; Pfeiffer, Per; Sugimoto, Naotoshi; Kocsis, Judit; Csilla, Andràs; Bodoky, Gyorgy; Garnica Jaliffe, Georgina; Protsenko, Svetlana; Madi, Ayman; Wojcik, Elzbieta; Brenner, Baruch; Folprecht, Gunnar; Sarosiek, Tomasz; Peltola, Katriina Johanna; Bono, Peter; Ayala, Hubert; Aprile, Giuseppe; Gerardo, Cardellino Giovanni; Huitzil Melendez, Fidel David; Falcone, Alfredo; Di Costanzo, Francesco; Tehfe, Moustapha; Mineur, Laurent; García Alfonso, Pilar; Obermannova, Radka; Senellart, Hélène; Petty, Russell; Samuel, Leslie; Acs, Peter Istvan; Hussein, Maen Abdelkarim; Nechaeva, Marina N.; Erdkamp, F.L.G.; Won, Elizabeth; Bendell, Johanna Chock; Gallego Plazas, Javier; Lorenzen, Sylvie; Melichar, Bohuslav; Escudero, Miguel Angel; Pezet, Denis; Phelip, Jean-Marc; Kaen, Diego Lucas; Reeves, James A. Jr; Longo Muñoz, Federico; Madhusudan, Srinivasan; Barone, Carlo; Fein, Luis Enrique; Gomez Villanueva, Angel; Hebbar, Mohamed; Prausova, Jana; Visa Turmo, Laura; Vidal Barrull, Joana; Yilmaz, Mette Karen Nytoft; Beny, Alex; Van Laarhoven, H.M.W.; DiCarlo, Brian Anthony; Esaki, Taito; Fujitani, Kazumasa; Geboes, Karen; Geva, Ravit; Kadowaki, Shigenori; Leong, Stephen; Machida, Nozomu; Raj, Moses Sundar; Ramirez Godinez, Francisco Javier; Ruzsa, Agnes; Ford, Hugo; Lawler, William E.; Maisey, Nicolas Robert; Petera, Jiri; Shacham-Shmueli, Einat; Sinapi, Isabelle; Yamaguchi, Kensei; Hara, Hiroki; Beck, Joseph Thaddeus; Błasińska-Morawiec, Maria; Villalobos Valencia, Ricardo; Alcindor, Thierry; Bajaj, Madhuri; Berry, Scott; Gomez, Christina Maria; Dammrich, Daniel; Patel, Ravindranath; Taieb, Julien; Ten Tije, A.J.; Burkes, Ronald L.; Cabanillas, Fernando; Firdaus, Irfan; Chua, Cynthia Coo; Hironaka, Shuichi; Hofheinz, Ralf-Dieter; Lim, Howard J.; Nordsmark, Marianne; Piko, Bela; Verma, Udit; Wadsley, Jonathan; Yukisawa, Seigo; Gutiérrez Delgado, Francisco; Denlinger, Crystal S.; Kallio, Raija; Pikiel, Joanna; Wojcik-Tomaszewska, Joanna; Brezden-Masley, Christine; Jang, Raymond Woo-Jun; Pribylova, Jana; Sakai, Daisuke; Bartoli, Maria Alejandra; Cats, A.; Grootscholten, M.I.; Dichmann, Robert Andrew; Hool, Hugo; Shaib, Walid; Tsuji, Akihito; Van den Eynde, Marc; Velez-Cortez, Hector; Asmis, Timothy R.; Fuchs, Charles S; Shitara, Kohei; Di Bartolomeo, Maria; Lonardi, Sara; Al-Batran, Salah-Eddin; Van Cutsem, Eric; Ilson, David H; Alsina, Maria; Chau, Ian; Lacy, Jill; Ducreux, Michel; Mendez, Guillermo Ariel; Alavez, Alejandro Molina; Takahari, Daisuke; Mansoor, Wasat; Enzinger, Peter C; Gorbounova, Vera; Wainberg, Zev A; Hegewisch-Becker, Susanna; Ferry, David; Lin, Ji; Carlesi, Roberto; Das, Mayukh; Shah, Manish A;
• Is Part Of: Lancet oncology. Volume 20:Issue 3(2019)
• Page Start: 420
• Page End: 435
• Publication Date: 2019-03
• Subjects: Oncology -- Periodicals; Neoplasms -- Periodicals; Cancérologie -- Périodiques; Oncologie; Oncology; Periodicals; Electronic journals; 616.994005
• DOI: 10.1016/S1470-2045(18)30791-5
• Languages: English
• ISSNs: 1470-2045

Abstract

Summary: 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.