Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II Trial

Nick Pavlakis, Katrin M. Sjoquist, Andrew J. Martin, Eric Tsobanis, Sonia Yip, Yoon Koo Kang, Yung Jue Bang, Thierry Alcindor, Christopher J. O'Callaghan, Margot J. Burnell, Niall C. Tebbutt, Sun Young Rha, Jeeyun Lee, Jae Yong Cho, Lara R. Lipton, Mark Wong, Andrew Strickland, Jin Won Kim, John R. Zalcberg, John SimesDavid Goldstein

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Abstract

Purpose We evaluated the activity of regorafenib, an oral multikinase inhibitor, in advanced gastric adenocarcinoma. Patients and Methods We conducted an international (Australia and New Zealand, South Korea, and Canada) randomized phase II trial in which patients were randomly assigned at a two-To-one ratio and stratified by lines of prior chemotherapy for advanced disease (one v two) and region. Eligible patients received best supportive care plus regorafenib 160 mg or matching placebo orally on days 1 to 21 of each 28-day cycle until disease progression or prohibitive adverse events occurred. The primary end point was progression-free survival (PFS). Final analysis included data to December 31, 2014. Results A total of 152 patients were randomly assigned from November 7, 2012, to February 25, 2014, yielding 147 evaluable patients (regorafenib, n = 97; placebo, n = 50). Baseline characteristics were balanced. Median PFS significantly differed between groups (regorafenib, 2.6 months; 95% CI, 1.8 to 3.1 and placebo, 0.9 months; 95% CI, 0.9 to 0.9; hazard ratio [HR], 0.40; 95% CI, 0.28 to 0.59; P <.001). The effect was greater in South Korea than in Australia, New Zealand, and Canada combined (HR, 0.12 v 0.61; interaction P < .001) but consistent across age, neutrophil-To-lymphocyte ratio, primary site, lines of chemotherapy, peritoneal metastasis presence, number of metastatic sites, and plasma vascular endothelial growth factor A. A survival trend in favor of regorafenib was seen (median, 5.8 months; 95% CI, 4.4 to 6.8 v 4.5 months; 95% CI, 3.4 to 5.2; HR, 0.74; P = .147). Twenty-nine patients assigned to placebo received open-label regorafenib after disease progression. Regorafenib toxicity was similar to that previously reported. Conclusion In this phase II trial, regorafenib was effective in prolonging PFS in refractory advanced gastric adenocarcinoma. Regional differences were found, but regorafenib was effective in both regional groups. A phase III trial is planned.

Original languageEnglish
Pages (from-to)2728-2735
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number23
DOIs
Publication statusPublished - 10 Aug 2016
Externally publishedYes

Cite this

Pavlakis, N., Sjoquist, K. M., Martin, A. J., Tsobanis, E., Yip, S., Kang, Y. K., Bang, Y. J., Alcindor, T., O'Callaghan, C. J., Burnell, M. J., Tebbutt, N. C., Rha, S. Y., Lee, J., Cho, J. Y., Lipton, L. R., Wong, M., Strickland, A., Kim, J. W., Zalcberg, J. R., ... Goldstein, D. (2016). Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II Trial. Journal of Clinical Oncology, 34(23), 2728-2735. https://doi.org/10.1200/JCO.2015.65.1901