Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial

Harry H Yoon, J. C. Bendell, F. S. Braiteh, I. Firdaus, P. A. Philip, A. L. Cohn, N. Lewis, D. M. Anderson, E. Arrowsmith, J. D. Schwartz, L. Gao, Y. Hsu, Y. Xu, D. Ferry, Steven Robert Alberts, Z. A. Wainberg

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).

PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken.

RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS.

CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.

CLINICALTRIALSGOV IDENTIFIER: NCT01246960.

Original languageEnglish (US)
Pages (from-to)2196-2203
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2016

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Esophagogastric Junction
Stomach
Adenocarcinoma
Disease-Free Survival
Therapeutics
Survival
Placebos
Vascular Endothelial Growth Factor Receptor-2
ramucirumab
Population
Esophagus
Neoplasms
Monoclonal Antibodies
Confidence Intervals

Keywords

  • esophageal cancer
  • gastric cancer
  • gastroesophageal junction
  • ramucirumab
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma : a randomized, double-blind, multicenter Phase II trial. / Yoon, Harry H; Bendell, J. C.; Braiteh, F. S.; Firdaus, I.; Philip, P. A.; Cohn, A. L.; Lewis, N.; Anderson, D. M.; Arrowsmith, E.; Schwartz, J. D.; Gao, L.; Hsu, Y.; Xu, Y.; Ferry, D.; Alberts, Steven Robert; Wainberg, Z. A.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 27, No. 12, 01.12.2016, p. 2196-2203.

Research output: Contribution to journalArticle

Yoon, Harry H ; Bendell, J. C. ; Braiteh, F. S. ; Firdaus, I. ; Philip, P. A. ; Cohn, A. L. ; Lewis, N. ; Anderson, D. M. ; Arrowsmith, E. ; Schwartz, J. D. ; Gao, L. ; Hsu, Y. ; Xu, Y. ; Ferry, D. ; Alberts, Steven Robert ; Wainberg, Z. A. / Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma : a randomized, double-blind, multicenter Phase II trial. In: Annals of oncology : official journal of the European Society for Medical Oncology. 2016 ; Vol. 27, No. 12. pp. 2196-2203.
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abstract = "BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80{\%} power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken.RESULTS: Of 168 randomized patients, 52{\%} of tumors were located in the stomach/GEJ and 48{\%} in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95{\%} confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2{\%} versus 46.4{\%}) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS.CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.CLINICALTRIALSGOV IDENTIFIER: NCT01246960.",
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TY - JOUR

T1 - Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma

T2 - a randomized, double-blind, multicenter Phase II trial

AU - Yoon, Harry H

AU - Bendell, J. C.

AU - Braiteh, F. S.

AU - Firdaus, I.

AU - Philip, P. A.

AU - Cohn, A. L.

AU - Lewis, N.

AU - Anderson, D. M.

AU - Arrowsmith, E.

AU - Schwartz, J. D.

AU - Gao, L.

AU - Hsu, Y.

AU - Xu, Y.

AU - Ferry, D.

AU - Alberts, Steven Robert

AU - Wainberg, Z. A.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken.RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS.CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.CLINICALTRIALSGOV IDENTIFIER: NCT01246960.

AB - BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken.RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS.CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.CLINICALTRIALSGOV IDENTIFIER: NCT01246960.

KW - esophageal cancer

KW - gastric cancer

KW - gastroesophageal junction

KW - ramucirumab

KW - vascular endothelial growth factor

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DO - 10.1093/annonc/mdw423

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